Publications by authors named "Yutao Liu"

226 Publications

Systemic Inflammation Index Values Are Associated With Worsened Disease Severity and Poor Response to Autoimmune Encephalitis Treatment.

Front Neurol 2021 5;12:709553. Epub 2021 Oct 5.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Both specific and innate immune responses play important roles in autoimmune encephalitis (AE). We aimed to explore the predictive value of the systemic inflammation index (SII) at admission as a peripheral biomarker of treatment response of AE. A total of 146 patients diagnosed with AE in the First Affiliated Hospital of Zhengzhou University from January 1, 2018 to September 22, 2020 were retrospectively and consecutively analyzed as per the inclusion criteria and divided into two groups according to their response to immunotherapy after 30 days. The predictive value of the SII as a peripheral biomarker for AE treatment response was calculated using the receiver operating characteristic curve analysis, which showed that the best SII cut-off value for predicting poor response to AE treatment was 863.3; the area under the curve was 0.75, with 83.0% sensitivity and 72.0% specificity. The risk factors for poor response to AE treatment were analyzed; univariable analysis showed that the rate of decreased level of consciousness, rate of cognitive or mental behavior abnormality, cerebrospinal fluid pressure, blood neutrophils, platelets, time until treatment initiation, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and SII were significantly higher in patients with poor response to AE immunotherapy after 30 days than in patients with good response. Meanwhile, the blood lymphocyte counts and Glasgow Coma Scale (GCS) scores in patients with poor response were significantly lower than those in patients with good response (all < 0.05), and multivariable binary logistic regression with backward stepwise method showed that decreased levels of consciousness, time until treatment initiation and SII were associated with poor response to immunotherapy. Moreover, the SII ≤ 863.3 group had lower rates of decreased consciousness levels, admission to the intensive care unit, and mechanical ventilation; lower cerebrospinal fluid pressure, blood neutrophil count, and platelet count; and higher blood lymphocyte count and GCS scores. The SII was associated with worsened disease severity and poor response to treatment after 30 days of the initially diagnosed AE, and patients with an SII > 863.3 were more likely to have poor response to immunotherapy.
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http://dx.doi.org/10.3389/fneur.2021.709553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523674PMC
October 2021

The Feasibility of Using Biomarkers Derived from Circulating Tumor DNA Sequencing as Predictive Classifiers in Patients with Small-Cell Lung Cancer.

Cancer Res Treat 2021 Oct 5. Epub 2021 Oct 5.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Purpose: To investigate the feasibility of biomarkers based on dynamic circulating tumor DNA (ctDNA) to classify small cell lung cancer (SCLC) into different subtypes.

Materials And Methods: Tumor and longitudinal plasma ctDNA samples were analyzed by next-generation sequencing of 1,021 genes. PyClone was used to infer the molecular tumor burden index (mTBI). Pre-treatment tumor tissues [T1] and serial plasma samples were collected (pre-treatment [B1], after two [B2], six [B3] cycles of chemotherapy and at progression [B4]).

Results: Overall concordance between T1 and B1 sequencing (n=30) was 66.5%, and 89.5% in the gene of RB1. A classification method was designed according to the changes of RB1 mutation, named as subtype Ⅰ (both positive at B1 and B2), subtype Ⅱ (positive at B1 but negative at B2), and subtype Ⅲ (both negative at B1 and B2). The median progressive-free survival for subtype Ⅰ patients (4.5 months [95%CI: 2.6-5.8]) was inferior to subtype Ⅱ (not reached, p<0.0001) and subtype Ⅲ (10.8 months [95%CI: 6.0-14.4], p=0.002). The median overall survival for subtype Ⅰ patients (16.3 months [95%CI: 5.3-22.9]) was inferior to subtype Ⅱ (not reached, p=0.01) and subtype Ⅲ (not reached, p=0.02). Patients with a mTBI dropped to zero at B2 had longer median overall survival (not reached vs. 19.5 months, p=0.01). The changes of mTBI from B4 to B1 were sensitive to predict new metastases, with a sensitivity of 100% and a specificity of 85.7%.

Conclusion: Monitoring ctDNA based RB1 mutation and mTBI provided a feasible tool to predict the prognosis of SCLC.
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http://dx.doi.org/10.4143/crt.2021.905DOI Listing
October 2021

Identification of Estrogen Signaling in a Prioritization Study of Intraocular Pressure-Associated Genes.

Int J Mol Sci 2021 Sep 24;22(19). Epub 2021 Sep 24.

Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA.

Elevated intraocular pressure (IOP) is the only modifiable risk factor for primary open-angle glaucoma (POAG). Herein we sought to prioritize a set of previously identified IOP-associated genes using novel and previously published datasets. We identified several genes for future study, including several involved in cytoskeletal/extracellular matrix reorganization, cell adhesion, angiogenesis, and TGF-β signaling. Our differential correlation analysis of IOP-associated genes identified 295 pairs of 201 genes with differential correlation. Pathway analysis identified β-estradiol as the top upstream regulator of these genes with mediating 25 interactions. Several genes (i.e., , , and ) regulated by β-estradiol/ were highly expressed in non-glaucomatous human trabecular meshwork (TM) or Schlemm's canal (SC) cells and specifically expressed in TM/SC cell clusters defined by single-cell RNA-sequencing. We confirmed gene and protein expression in human TM cells and TM/SC tissue with quantitative real-time PCR and immunofluorescence, respectively. 17β-estradiol was identified in bovine, porcine, and human aqueous humor (AH) using ELISA. In conclusion, we have identified estrogen receptor signaling as a key modulator of several IOP-associated genes. The expression of ESR1 and these IOP-associated genes in TM/SC tissue and the presence of 17β-estradiol in AH supports a role for estrogen signaling in IOP regulation.
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http://dx.doi.org/10.3390/ijms221910288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508848PMC
September 2021

Metastatic NSCLCs With Limited Tissues: How to Effectively Identify Driver Alterations to Guide Targeted Therapy in Chinese Patients.

JTO Clin Res Rep 2021 May 24;2(5):100167. Epub 2021 Mar 24.

Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.

Introduction: Molecular diagnostics of newly diagnosed patients with metastatic NSCLC (mNSCLC) with limited tissue samples often face several obstacles in routine practice using next-generation sequencing (NGS), mainly owing to insufficient tissue or DNA; thus, how to effectively identify the molecular profiling of these cases to accurately guide targeted therapy remains elusive. We evaluated whether an optimized workflow with the combined use of multiple technologies could be helpful.

Methods: Tissue NGS was used as the frontline method. Amplification refractory mutation system polymerase chain reaction, immunohistochemistry, fluorescence in situ hybridization, and plasma NGS were used as supplements.

Results: Among 208 mNSCLC cases with limited tissue (cohort 1), molecular genotyping using single-tissue NGS failed in 42 (20.2%) and actionable alterations were identified in only 112 of 208 cases (53.8%). In comparison, the optimized workflow in 1184 additional mNSCLC cases with limited tissue (cohort 2) increased the discovery rate of actionable alterations from 59.7% detected by tissue NGS to 70.4%. It was because that driver alterations were identified using amplification refractory mutation system polymerase chain reaction plus immunohistochemistry or fluorescence in situ hybridization in 53 of 78 (67.9%) tissue NGS-failed cases, and using plasma NGS in 73 of 143 (51.0%) tissue NGS-failed cases, which led to matched targeted therapies in 57 cases with clinical response. Moreover, the median turnaround time of the optimized workflow was significantly shorter than that of repeated biopsy for tissue NGS ( < 0.001).

Conclusions: The optimized workflow can improve mutation detection and may avoid repeated biopsy, thus allowing the timely initiation of targeted therapies for patients with newly diagnosed mNSCLC.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474491PMC
May 2021

Tocochromanols and Chlorophylls Accumulation in Young Pomelo () during Early Fruit Development.

Foods 2021 Aug 28;10(9). Epub 2021 Aug 28.

Key Laboratory of South China Modern Biological Seed Industry, Ministry of Agriculture and Rural Areas, National S&T Innovation Center for Modern Agricultural Industry, Guangzhou 510520, China.

Pomelo is an important cultivar of the genus Citrus that contains a variety of beneficial nutrients, and its young fruit is an agricultural by-product that is currently not fully utilized because it is often thrown away during cultivation and management. In this study, the dynamics of tocochromanol during young pomelo development were investigated by measuring chlorophyll content, tocochromanol accumulation, and expression levels of related genes during early fruit development. The results showed that chlorophyll content decreased overall during these four developmental stages and had some synergism with tocochromanol. Four tocochromanol components were detected in pomelo of both genotypes, and α-tocopherol was the main component. The tocochromanol content of honey pomelo was highest in the first period, reaching 70 ± 5 μg/g in dry weight (DW), and golden pomelo peaked in the second period at 86.10 ± 0.18 μg/g DW, with an overall decreasing trend in both genotypes. The different gene expression patterns of the tocochromanol biosynthesis pathway could partially explain the changes in these components and further elucidate the regulatory mechanisms of tocochromanol accumulation during early fruit development. As a natural product, young pomelo fruit is an attractive source of tocochromanol and has potential application in industrial production. The results of this study may provide directions for the high additional value utilization of young pomelo fruit.
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http://dx.doi.org/10.3390/foods10092022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465361PMC
August 2021

Image Features of Magnetic Resonance Imaging under the Deep Learning Algorithm in the Diagnosis and Nursing of Malignant Tumors.

Contrast Media Mol Imaging 2021 30;2021:1104611. Epub 2021 Aug 30.

Department of Hematology-Oncology, The Third Hospital of Jilin University, Changchun 130033, Jilin, China.

In order to explore the effect of convolutional neural network (CNN) algorithm based on deep learning on magnetic resonance imaging (MRI) images of brain tumor patients and evaluate the practical value of MRI image features based on deep learning algorithm in the clinical diagnosis and nursing of malignant tumors, in this study, a brain tumor MRI image model based on the CNN algorithm was constructed, and 80 patients with brain tumors were selected as the research objects. They were divided into an experimental group (CNN algorithm) and a control group (traditional algorithm). The patients were nursed in the whole process. The macroscopic characteristics and imaging index of the MRI image and anxiety of patients in two groups were compared and analyzed. In addition, the image quality after nursing was checked. The results of the study revealed that the MRI characteristics of brain tumors based on CNN algorithm were clearer and more accurate in the fluid-attenuated inversion recovery (FLAIR), MRI T1, T1c, and T2; in terms of accuracy, sensitivity, and specificity, the mean value was 0.83, 0.84, and 0.83, which had obvious advantages compared with the traditional algorithm ( < 0.05). The patients in the nursing group showed lower depression scores and better MRI images in contrast to the control group ( < 0.05). Therefore, the deep learning algorithm can further accurately analyze the MRI image characteristics of brain tumor patients on the basis of conventional algorithms, showing high sensitivity and specificity, which improved the application value of MRI image characteristics in the diagnosis of malignant tumors. In addition, effective nursing for patients undergoing analysis and diagnosis on brain tumor MRI image characteristics can alleviate the patient's anxiety and ensure that high-quality MRI images were obtained after the examination.
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http://dx.doi.org/10.1155/2021/1104611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423572PMC
August 2021

Evaluation of Carotenoids Accumulation and Biosynthesis in Two Genotypes of Pomelo () during Early Fruit Development.

Molecules 2021 Aug 20;26(16). Epub 2021 Aug 20.

Key Laboratory of South China Modern Biological Seed Industry, Ministry of Agriculture and Rural Areas, National S&T Innovation Center for Modern Agricultural Industry, Guangzhou 510520, China.

Pomelo is rich in bioactive compounds (carotenoids, phenolics and essential oil) in the early stage of fruit development, but it is often wasted in the cultivation and management process. To gain an insight into the carotenoid metabolism pathway in pomelo, the carotenoid profiles and the expression patterns of carotenogenic genes were investigated in two genotypes of pomelo during early fruit development. The results showed that a higher carotenoid content was observed in honey pomelo as compared with golden pomelo, which may be related to different gene regulation mechanisms. Lutein, α-carotene, and β-carotene were the main carotenoids in pomelo young fruit, and lutein was the highest one. The accumulation of carotenoids during fruit early development in honey pomelo is related to the transcriptional regulation of and . In golden pomelo, the rate-limiting gene for carotenoids is and . In addition, the expression of seven genes except in honey pomelo was higher than that in golden pomelo. The results are helpful to further clarify the regulatory mechanism of carotenoid accumulation during early fruit development and provide a direction for the high-value utilization of young fruits in pomelo.
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http://dx.doi.org/10.3390/molecules26165054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400066PMC
August 2021

Resolution-Enhancing Structure for the Electric Field Microsensor Chip.

Micromachines (Basel) 2021 Aug 7;12(8). Epub 2021 Aug 7.

State Key Laboratory of Transducer Technology, Aerospace Information Research Institute, Chinese Academy of Sciences, Beijing 100190, China.

Electrostatic voltage is a vital parameter in industrial production lines, for reducing electrostatic discharge harms and improving yields. Due to such drawbacks as package shielding and low resolution, previously reported electric field microsensors are still not applicable for industrial static monitoring uses. In this paper, we introduce a newly designed microsensor package structure, which enhances the field strength inside the package cavity remarkably. This magnification effect was studied and optimized by both theoretical calculation and ANSYS simulation. By means of the digital synthesizer and digital coherent demodulation method, the compact signal processing circuit for the packaged microsensor was also developed. The meter prototype was calibrated above a charged metal plate, and the electric field resolution was 5 V/m, while the measuring error was less than 3 V, from -1 kV to 1 kV in a 2 cm distance. The meter was also installed into a production line and showed good consistency with, and better resolution than, a traditional vibratory capacitance sensor.
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http://dx.doi.org/10.3390/mi12080936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400472PMC
August 2021

TGFBR2 mutation predicts resistance to immune checkpoint inhibitors in patients with non-small cell lung cancer.

Ther Adv Med Oncol 2021 14;13:17588359211038477. Epub 2021 Aug 14.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Pan-jia-yuan South Lane, Chaoyang District, Beijing, 100021, China.

Background: Resistance or even hyper-progression to immune checkpoint inhibitors (ICIs) manifesting as accelerated disease progression or death has impeded the clinical use of ICIs. The transforming growth factor beta (TGFβ) receptor pathway has been identified in contributing to immune dysfunction, which might be associated with resistance to ICIs. We aimed to explore the role of TGFβ in the resistance to ICIs in non-small cell lung cancer (NSCLC) in this study.

Methods: Public cohorts with patients treated with ICIs or chemotherapy including POPLAR/OAK ( = 853), MSKCC ( = 1662) and Van Allen ( = 57) and TCGA ( = 3210) cohorts were obtained and analyzed.

Results: The expression of immune-checkpoint related genes, including (), (), (TIGIT), (), (), and () were significantly upregulated in transforming growth factor beta TGFβ receptor 2 (TGFβR2)-mutated patients than those with wild-type TGFBR2 ( < 0.05). In the POPLAR/OAK cohort, TGFBR2-mutated patients showed shorter progression-free survival (PFS) [  = 0.004; hazard ratio (HR), 2.83; 95% confidence interval (CI), 1.34-6.00] and overall survival (OS) (  = 0.0006; HR, 3.46; 95% CI, 1.63-7.35) than those with wild-type TGFBR2 when treated with ICIs but not chemotherapy. In the merged MSKCC and Van Allen cohorts, a similar result was observed that the OS was inferior in patients with mutated TGFBR2 compared with those with wild-type TGFBR2 ( = 0.007; HR, 2.53; 95% CI, 1.25-5.12). The association between TGBFR2 mutation and survival remained significant in multivariable cox regression in both POPLAR/OAK cohort ( = 0.02; HR, 2.53; 95% CI, 1.17-5.45) and merged cohort ( = 0.008; HR, 2.63; 95% CI, 1.29-5.35). We further evaluated the association between TGFBR2 mutations and OS in multiple types of tumors. The association between TGFBR2 mutations and OS remained significant in NSCLC ( = 0.02; HR, 2.47; 95% CI, 1.16-5.26), but not in other type of tumors.

Conclusions: We identified that TGFBR2 mutation predicted the resistance to ICIs in NSCLCs. The clinical delivery of ICIs should be cautious in those patients.
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http://dx.doi.org/10.1177/17588359211038477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366138PMC
August 2021

A fructose/H symporter controlled by a LacI-type regulator promotes survival of pandemic Vibrio cholerae in seawater.

Nat Commun 2021 07 30;12(1):4649. Epub 2021 Jul 30.

The Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Tianjin, P. R. China.

The bacterium Vibrio cholerae can colonize the human intestine and cause cholera, but spends much of its life cycle in seawater. The pathogen must adapt to substantial environmental changes when moving between seawater and the human intestine, including different availability of carbon sources such as fructose. Here, we use in vitro experiments as well as mouse intestinal colonization assays to study the mechanisms used by pandemic V. cholerae to adapt to these environmental changes. We show that a LacI-type regulator (FruI) and a fructose/H symporter (FruT) are important for fructose uptake at low fructose concentrations, as those found in seawater. FruT is downregulated by FruI, which is upregulated when O concentrations are low (as in the intestine) by ArcAB, a two-component system known to respond to changes in oxygen levels. As a result, the bacteria predominantly use FruT for fructose uptake under seawater conditions (low fructose, high O), and use a known fructose phosphotransferase system (PTS, Fpr) for fructose uptake under conditions found in the intestine. PTS activity leads to reduced levels of intracellular cAMP, which in turn upregulate virulence genes. Our results indicate that the FruT/FruI system may be important for survival of pandemic V. cholerae in seawater.
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http://dx.doi.org/10.1038/s41467-021-24971-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324912PMC
July 2021

Reduction of pitch error of the micro-prism array in brightness enhancement film by compensating z-axis positioning accuracy.

Appl Opt 2021 Jun;60(18):5278-5284

Brightness enhancement film (BEF), as a polyethylene terephthalate (PET) film with the micro-prism array on the surface, is an indispensable core optical component for a back light unit (BLU) in liquid crystal display. Roll-to-roll (RTR) imprinting approach is the most mature and reliable technology to produce the BEF in the industry. Of course, the machining accuracy of the micro-prism array on the roller mold will directly determine the optical performance of BEF manufactured by RTR. The objective of this paper is to reduce pitch error of the machined micro-prism array on the roller mold based on geometric error viewpoint. First, geometric error of the ultra-precision horizontal drum roll lathe that has the main influence on the pitch accuracy of the machined micro-prism array is identified through volumetric error model and sensitivity analysis. Then, the compensation operation is performed for the dominant geometric error component according to the theoretical analysis results. Finally, a verification experiment after compensation is conducted to fabricate the micro-prism array on the roller mold using plunge cutting method. The measurement result shows the micro-prism array with a less than 25 nm pitch error, while a 6.018 nm area roughness is obtained, which validates the effectiveness of the geometric error analysis and compensation to reduce the pitch error of the machined micro-prism array on the roller mold.
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http://dx.doi.org/10.1364/AO.424665DOI Listing
June 2021

Generation of induced pluripotent stem cell line (ZZUi027-A) derived from skin fibroblasts from a Parkinson's disease patient with RAB39B gene mutation.

Stem Cell Res 2021 08 4;55:102454. Epub 2021 Jul 4.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address:

Parkinson's disease is a common neurogenetic degenerative disease that can be caused by a variety of genetic mutations. RAB39B gene mutations have recently been identified as a cause of Parkinson's disease. We collected skin tissue samples from a family with mutations in RAB39B for our clinical study. Additionally, we constructed patient-derived induced pluripotent stem cells (iPSCs) from the patient's uncle using an unintegrated reprogramming plasmid transfection method to create a reliable cell model for the subsequent study of Parkinson's disease.
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http://dx.doi.org/10.1016/j.scr.2021.102454DOI Listing
August 2021

Provokes Exosome Secretion and Paracrine Immune Senescence in Bystander Dendritic Cells.

Front Cell Infect Microbiol 2021 1;11:669989. Epub 2021 Jun 1.

Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA, United States.

Periodontitis is a disease of ageing or inflammaging, and is comorbid with other more severe age-related chronic diseases. With advanced age comes an increase in accumulation of senescent cells that release soluble and insoluble pro-inflammatory factors collectively termed the senescence associated secretory phenotype (SASP). In the present report, we examined whether immune cells typical of those at the oral mucosa-microbe interface, are vulnerable to cellular senescence (CS) and the role of dysbiotic oral pathogen . Bone marrow-derived dendritic cells (DCs) from young (yDCs) and old (oDCs) mice were co-cultured with CS inducer doxorubicin or , plus or minus senolytic agent rapamycin. CS profiling revealed elevated CS mediators SA-β-Gal, p16 , p53, and p21 in oDCs, or yDCs in response to doxorubicin or , reversible with rapamycin. Functional studies indicate impaired maturation function of oDCs, and yDC exposed to ; moreover, OVA-driven proliferation of CD4+ T cells from young OTII transgenic mice was impaired by oDCs or yDCs+Pg. The SASP of DCs, consisting of secreted exosomes and inflammasome-related cytokines was further analyzed. Exosomes of DCs cocultured with (PgDCexo) were purified, quantitated and characterized. Though typical in terms of size, shape and phenotype, PgDCexo were 2-fold greater in number than control DCs, with several important distinctions. Namely, PgDCexo were enriched in age-related miRNAs, and miRNAs reported to disrupt immune homeostasis through negative regulation of apoptosis and autophagy functions. We further show that PgDCexo were enriched in fimbrial adhesin protein mfa1 and in inflammasome related cytokines IL-1β, TNFα and IL-6. Functionally PgDCexo were readily endocytosed by recipient yDCs, amplifying functional impairment in maturation and ability to promote Ova-driven proliferation of OTII CD4+ T cells from young mice. In conclusion induces premature (autocrine) senescence in DCs by direct cellular invasion and greatly amplifies senescence, in paracrine, of bystander DCs by secretion of inflammatory exosomes. The implications of this pathological pathway for periodontal disease is under investigation in mouse models.
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http://dx.doi.org/10.3389/fcimb.2021.669989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204290PMC
July 2021

Generation of induced pluripotent stem cell line (ZZUi028-A) from a 52-year-old Chinese Han healthy female individual.

Stem Cell Res 2021 05 5;53:102381. Epub 2021 May 5.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address:

Skin fibroblasts were donated by a healthy 52-year-old Han Chinese woman. The induced pluripotent stem cell (iPSC) line was constructed using an episomal reprogramming method that made the generated iPSCs integration-free. This iPSC line expressed the common pluripotency markers, could be differentiated into three germ layers, and showed normal karyotype in vivo. The iPSC line can be used to generate different cell types, which could be used as a control in drug development and studies on pathological mechanisms.
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http://dx.doi.org/10.1016/j.scr.2021.102381DOI Listing
May 2021

Generation of induced pluripotent stem cell line (ZZUi0026-A) from a patient with spinocerebellar ataxia type 3.

Stem Cell Res 2021 05 29;53:102205. Epub 2021 Jan 29.

The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address:

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disease caused by CAG repeat expansion of the ATXN3 gene encoding ataxin-3 protein and is mainly manifested by motor symptoms such as ataxia and non-motor symptoms such as cognitive dysfunction. In this study, we obtained skin fibroblasts from a SCA3 patient and successfully constructed induced pluripotent stem cells (iPSCs) using the reprogramming plasmids expressing OCT3/4, SOX2, KLF4, LIN28, and L-MYC. The generated iPSC line had a stable karyotype, expressed pluripotency markers, and could differentiate into all three germ layers in vitro. In addition, the iPSC line may be a useful model for identifying SCA3-related pathological mechanisms.
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http://dx.doi.org/10.1016/j.scr.2021.102205DOI Listing
May 2021

A novel 3D culture model of fungal keratitis to explore host-pathogen interactions within the stromal environment.

Exp Eye Res 2021 06 15;207:108581. Epub 2021 Apr 15.

Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address:

Fungal keratitis (FK) pathology is driven by both fungal growth and inflammation within the corneal stroma. Standard in vitro infection models ̶ involving co-culture of the pathogen and the corneal cells in tissue culture medium ̶ are sufficient to probe host responses to the fungus; however, they lack the physiological structure and nutrient composition of the stroma to accurately study fungal invasiveness and metabolic processes. We therefore sought to develop a culture model of FK that would allow for both host and fungal cell biology to be evaluated in parallel. Towards this end, we employed a previously described system in which primary human cornea fibroblasts (HCFs) are cultured on transwell membranes, whereupon they secrete a three-dimensional (3D) collagen matrix that resembles the human stroma. We demonstrated that two common mold agents of FK, Fusarium petroliphilum and Aspergillus fumigatus, penetrated into these constructs and caused a disruption of the collagen matrix that is characteristic of infection. HCF morphology appeared altered in the presence of fungus and electron microscopy revealed a clear internalization of fungal spores into these cells. Consistent with this apparent phagocyte-like activity of the HCFs, mRNA and protein levels for several pro-inflammatory cytokines/chemokines (including TNFα, IL-1β, IL-6, and IL-8) were significantly upregulated compared to uninfected samples. We similarly found an upregulation of several HCF metalloproteases (MMPs), which are enzymes that breakdown collagen during wound healing and may further activate pro-inflammatory signaling molecules. Finally, several fungal collagenase genes were upregulated during growth in the constructs relative to growth in tissue culture media alone, suggesting a fungal metabolic shift towards protein catabolism. Taken together, our results indicate that this 3D-stromal model provides a physiologically relevant system to study host and fungal cell pathobiology during FK.
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http://dx.doi.org/10.1016/j.exer.2021.108581DOI Listing
June 2021

Proteomic Characterization, Biodistribution, and Functional Studies of Immune-Therapeutic Exosomes: Implications for Inflammatory Lung Diseases.

Front Immunol 2021 25;12:636222. Epub 2021 Mar 25.

Department of Periodontics, Dental College of Georgia at Augusta University, Augusta, GA, United States.

Dendritic cell (DC)-derived exosomes (DC EXO), natural nanoparticles of endosomal origin, are under intense scrutiny in clinical trials for various inflammatory diseases. DC EXO are eobiotic, meaning they are well-tolerated by the host; moreover, they can be custom-tailored for immune-regulatory or -stimulatory functions, thus presenting attractive opportunities for immune therapy. Previously we documented the efficacy of immunoregulatory DCs EXO (regDCs EXO) as immunotherapy for inflammatory bone disease, in an model. We showed a key role for encapsulated TGFβ1 in promoting a bone sparing immune response. However, the on- and off-target effects of these therapeutic regDC EXO and how target signaling in acceptor cells is activated is unclear. In the present report, therapeutic regDC EXO were analyzed by high throughput proteomics, with non-therapeutic EXO from immature DCs and mature DCs as controls, to identify shared and distinct proteins and potential off-target proteins, as corroborated by immunoblot. The predominant expression in regDC EXO of immunoregulatory proteins as well as proteins involved in trafficking from the circulation to peripheral tissues, cell surface binding, and transmigration, prompted us to investigate how these DC EXO are biodistributed to major organs after intravenous injection. Live animal imaging showed preferential accumulation of regDCs EXO in the lungs, followed by spleen and liver tissue. In addition, TGFβ1 in regDCs EXO sustained downstream signaling in acceptor DCs. Blocking experiments suggested that sustaining TGFβ1 signaling require initial interaction of regDCs EXO with TGFβ1R followed by internalization of regDCs EXO with TGFβ1-TGFβ1R complex. Finally, these regDCs EXO that contain immunoregulatory cargo and showed biodistribution to lungs could downregulate the main severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target receptor, ACE2 on recipient lung parenchymal cells TGFβ1 In conclusion, these results in mice may have important immunotherapeutic implications for lung inflammatory disorders.
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http://dx.doi.org/10.3389/fimmu.2021.636222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027247PMC
April 2021

Omics analyses in keratoconus: from transcriptomics to proteomics.

Curr Ophthalmol Rep 2020 Dec 2;8(4):216-225. Epub 2020 Sep 2.

Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912.

Purpose Of Review: To summarize the recent advances in transcriptomics and proteomics studies of keratoconus using advanced genome-wide gene and protein expression profiling techniques.

Recent Findings: Second-generation sequencing including RNA sequencing has been widely used to characterize the genome-wide gene expression in corneal tissues or cells affected by keratoconus. Due to different sample types, sequencing platforms, and analysis pipeline, different lists of genes have been identified to be differentially expressed in KC-affected samples. Gene ontology and pathway/network analyses have indicated the involvement of genes related with extracellular matrix, WNT-signaling, TGFβ pathway, and NRF2-regulated network. High throughput proteomics studies using mass spectrometry have uncovered many KC-related protein molecules in pathways related with cytoskeleton, cell matrix, TGFβ signaling, and extracellular matrix remodeling, consistent with gene expression profiling.

Summary: Both transcriptomics and proteomics studies using genome-wide gene/protein expression profiling techniques have identified significant genes/proteins that may contribute to the pathogenesis of keratoconus. These molecules may be involved in functional categories related with extracellular matrix and TGFβ signaling. It is necessary to perform comprehensive gene/protein expression studies using larger sample size, same type of samples, up-to-date platform and bioinformatics tools.
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http://dx.doi.org/10.1007/s40135-020-00253-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987107PMC
December 2020

Electrochemically Regulated Li Deposition by Crown Ether.

ACS Appl Mater Interfaces 2021 Apr 24;13(13):15872-15880. Epub 2021 Mar 24.

Hubei Key Lab of Electrochemical Power Sources, College of Chemistry and Molecular Science, Wuhan University, Wuhan 430072, China.

The lithium-secondary battery is considered to be the most prospective electrochemical energy storage in the upcoming decades. However, its real application still much depends on the effective strategy toward Li dendrite growth. After years of effort, many successful works have been reported on improving the solid-electrolyte interphase (SEI), either via electrolyte optimization or building artificial SEI while intrinsically adjusting the electrochemical reduction of Li has been rarely mentioned. Inspired by the successful works in the electroplating industry, in this paper, a Li-chelating agent, benzo-15-crown-5 (B15C5) was used to regulate Li-reduction kinetics from an electrochemical view. Owing to the coordination with Li, Li + complex + e → Li[complex] is generated and proved by a decreased value. B15C5 confined within the PVC matrix has been coated on a Li anode. With thus-obtained B15C5-PVC-Li, dendrite growth has been significantly reduced and prolonged cycling has been observed in Li|Li symmetric cells. Electrochemically modulated Li deposition has been further accessed by the full cell of LiFePO|Li, and 163 mA h/g capacity is stably released after 400 cycles at 1.0 mA/cm. This study provides an alternate approach to address the dendrite growth issue and sheds more light on the Li-deposition kinetics.
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http://dx.doi.org/10.1021/acsami.1c01476DOI Listing
April 2021

Generation of induced pluripotent stem cell line (ZZUi019-A) derived from skin fibroblasts from a healthy volunteer.

Stem Cell Res 2021 05 12;53:102285. Epub 2021 Mar 12.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address:

The research on nervous system diseases is limited by the difficulty in obtaining nerve cells from humans. The development of induced pluripotent stem cells (iPSCs) technology and the experimental system provide a feasible method for directional induced differentiation of nerve cells in vitro. In this project, we recruited a 50-year-old Han Chinese man as a healthy volunteer, and successfully constructed his skin fibroblast-derived iPSCs using the non-integrated reprogramming method. At the same time, the related pluripotency identification experiments were completed. This cell line will be included in the normal control group in follow-up experiments, providing an important reference for the study of neurological diseases.
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http://dx.doi.org/10.1016/j.scr.2021.102285DOI Listing
May 2021

Anlotinib combined with durvalumab in a patient with recurrent multifocal brain metastases of small cell lung cancer after definitive concurrent chemoradiotherapy and palliative radiotherapy of the lung and brain: a case report.

Ann Palliat Med 2021 Feb;10(2):2379-2386

Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

The brain is a common metastatic site of small cell lung cancer (SCLC), but systematic treatment options are limited by the blood-brain barrier. Currently, the optimal treatment regimen remains controversial, especially for patients already treated by brain radiotherapy. Anlotinib is a novel oral multitarget tyrosine kinase inhibitor which has shown significant improvement in progression-free survival and overall survival in third-line or beyond therapy of advanced SCLC in a randomized, double-blind phase II study (ALTER1202 trial) based on a Chinese population sample. Emerging data has also suggested that immunotherapy, such as the programmed death ligand 1 (PD-L1) inhibitor, has a relatively high response rate in brain metastatic SCLC, although there is a lack of large sample-size studies. Integrating anlotinib and immunotherapy for recurrent or relapsing brain metastases (BMs) of SCLC has not been previously reported, but it is possible that these two treatments may have synergistic effects and provide even better outcomes. Here, we present a case of stage III SCLC who developed lung and BMs after concurrent chemoradiotherapy (cCRT) and achieved radiographic locally complete regression following whole brain irradiation (WBI) with a simultaneous integrated boost (SIB) technique. Durvalumab was delivered as maintenance therapy. Asymptomatic multifocal recurrence of BMs occurred after the administration of the second dose of durvalumab. After administration of combined durvalumab and anlotinib, the BMs achieved near-complete regression and no severe toxicity was reported. This suggests a potential synergistic effect of combined durvalumab and anlotinib in previously treated BMs in a patient with SCLC and may provide a direction for future clinical decisions.
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http://dx.doi.org/10.21037/apm-20-2390DOI Listing
February 2021

Generation of induced pluripotent stem cell line (ZZUi0024-A) from a 51-year-old patient with APP gene mutation in Alzheimer' s disease.

Stem Cell Res 2021 05 24;53:102267. Epub 2021 Feb 24.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, China. Electronic address:

Alzheimer's disease (AD) is a neurodegenerative disease that manifests mainly as cognitive, behavioral, and neuropsychiatric changes and impairs social functions and activities of daily living. The β-amyloid precursor protein (APP) gene is one of the most common pathogenic genes associated with AD. We isolated dermal fibroblasts from a 51-year-old woman with an APP gene mutation (c.1756G > A). The induced pluripotent stem cells (iPSCs) were successfully constructed by transferring the reprogramming plasmids expressing OCT3/4, SOX2, KLF4, LIN28, and L-MYC. The generated iPSC line was pluripotent, as verified by immunofluorescence, flow cytometry, and teratoma formation test. The iPSC line will have broad prospects in drug screening, cell transplantation, and gene therapy.
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http://dx.doi.org/10.1016/j.scr.2021.102267DOI Listing
May 2021

Functional analysis of a chaetoglobosin A biosynthetic regulator in Chaetomium globosum.

Fungal Biol 2021 03 27;125(3):201-210. Epub 2020 Nov 27.

School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, 150000, China. Electronic address:

Cytochalasins are a group of fungal secondary metabolites with diverse structures and bioactivities, including chaetoglobosin A production. Chaetoglobosin A is produced by Chaetomium globosum and has potential antifungal activity. Bioinformatics analysis of the chaetoglobosin A gene cluster (che) showed it that consists of nine open reading frames, including those encoding polyketide synthases (PKSs), PKS extender units, post-PKS modifications, and proposed regulators. Here, the role of the CgcheR regulator was investigated using gene disruption experiments. The CgcheR disruptant (ΔCgcheR) completely abolished the production of chaetoglobosin A, which was restored by the introduction of a copy of the wild-type CgcheR gene, suggesting that CgcheR is involved in chaetoglobosin A biosynthesis. A transcriptional analysis of the CgcheR disruptant indicated that CgCheR activates the transcription of chaetoglobosin biosynthetic genes in a pathway-specific manner. Furthermore, constitutive overexpression of CgcheR significantly improved the production of chaetoglobosin A from 52 to 260 mg/L. Surprisingly, CgcheR also played a critical role in sporulation; the CgcheR disruptant lost the ability to produce spores, suggesting that the regulator modulates cellular development. Our results not only shed light on the regulation of chaetoglobosin A biosynthesis, but also indicate a relationship between secondary metabolism and fungal morphogenesis.
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http://dx.doi.org/10.1016/j.funbio.2020.10.010DOI Listing
March 2021

FOXO1-Mediated Downregulation of RAB27B Leads to Decreased Exosome Secretion in Diabetic Kidneys.

Diabetes 2021 07 17;70(7):1536-1548. Epub 2021 Feb 17.

Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.

Exosomes have been implicated in diabetic kidney disease (DKD), but the regulation of exosomes in DKD is largely unknown. Here, we have verified the decrease of exosome secretion in DKD and unveiled the underlying mechanism. In Boston University mouse proximal tubule (BUMPT) cells, high-glucose (HG) treatment led to a significant decrease in exosome secretion, which was associated with specific downregulation of RAB27B, a key guanosine-5'-triphosphatase in exosome secretion. Overexpression of RAB27B restored exosome secretion in HG-treated cells, suggesting a role of RAB27B downregulation in the decrease of exosome secretion in DKD. To understand the mechanism of RAB27B downregulation, we conducted bioinformatics analysis that identified FOXO1 binding sites in the Rab27b gene promoter. Consistently, HG induced phosphorylation of FOXO1 in BUMPT cells, preventing FOXO1 accumulation and activation in the nucleus. Overexpression of nonphosphorylatable, constitutively active FOXO1 led to the upregulation of RAB27B and an increase in exosome secretion in HG-treated cells. In vivo, compared with normal mice, diabetic mice showed increased FOXO1 phosphorylation, decreased RAB27B expression, and reduced exosome secretion. Collectively, these results unveil the mechanism of exosome dysfunction in DKD where FOXO1 is phosphorylated and inactivated in DKD, resulting in RAB27B downregulation and the decrease of exosome secretion.
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http://dx.doi.org/10.2337/db20-1108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336008PMC
July 2021

Investigation on the potential of circulating tumor DNA methylation patterns as prognostic biomarkers for lung squamous cell carcinoma.

Transl Lung Cancer Res 2020 Dec;9(6):2356-2366

Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Background: Aberrant epigenetic modifications play a key role in lung tumorigenesis. In our study, we aimed to explore the clinical implications of baseline circulating tumor DNA (ctDNA) somatic and methylation profiles in patients with lung squamous cell carcinoma (LUSC).

Methods: A total of 26 patients with LUSC of various stages were included in this study. Somatic mutations and methylation levels were profiled from the plasma-derived ctDNA obtained at the time of diagnosis using unique molecular identifier (UMI)-based targeted sequencing and bisulfite sequencing, respectively. The correlation between baseline ctDNA mutation and methylation profile, and overall survival (OS), were analyzed.

Results: Somatic mutations were detected in 80.8% (20/26) of the patients. Patients harboring somatic mutations with maximum allelic fraction (maxAF) of >5% had significantly shorter OS compared to those with maxAF ≤5% (7.1 54.6 months; P=0.020). ctDNA methylation level was found to be strongly correlated with maxAF (Pearson correlation =0.934; P<0.001). Consistent with maxAF, higher methylation levels were also associated with poorer OS (hazard ratio =2.377; 95% CI: 1.283-4.405; P=0.006). Moreover, a total of 1,956 ctDNA methylation blocks were differentially methylated in patients with maxAF >0 (P<0.05). Least absolute shrinkage and selection operator (LASSO) regression analysis revealed a significant correlation between methylation signatures from 5 methylation blocks and OS (hazard ratio =183.20, 95% CI: 2.74-12,243.32; P=0.015). These 5 methylation blocks could serve as an alternative to maxAF and can be explored as prognostic biomarkers.

Conclusions: Our study identified several ctDNA methylation blocks that can potentially predict the prognosis of LUSC at the time of diagnosis.
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http://dx.doi.org/10.21037/tlcr-20-1070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815356PMC
December 2020

CHIP protects against MPP/MPTP-induced damage by regulating Drp1 in two models of Parkinson's disease.

Aging (Albany NY) 2021 01 2;13(1):1458-1472. Epub 2021 Jan 2.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.

Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). Carboxyl terminus of Hsp70-interacting protein (CHIP) is a key regulator of mitochondrial dynamics, and mutations in CHIP or deficits in its expression have been associated with various neurological diseases. This study explores the protective role of CHIP in cells and murine PD models. In SH-SY5Y cell line, overexpression of CHIP improved the cell viability and increased the ATP levels upon treatment with 1-methyl-4-phenylpyridinium (MPP). To achieve CHIP overexpression in animal models, we intravenously injected mice with AAV/BBB, a new serotype of adeno-associated virus that features an enhanced capacity to cross the blood-brain barrier. We also generated gene knock-in mice that overexpressed CHIP in neural tissue. Our results demonstrated that CHIP overexpression in mice suppressed 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage, including movement impairments, motor coordination, and spontaneous locomotor activity, as well as loss of dopaminergic neurons. and experiments showed that overexpression of CHIP inhibited the pathological increase in Drp1 observed in the PD models, suggesting that CHIP regulates Drp1 degradation to attenuate MPP/MPTP-induced injury. We conclude that CHIP plays a protective role in MPP/MPTP-induced PD models. Our experiments further revealed that CHIP maintains the integrity of mitochondria.
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http://dx.doi.org/10.18632/aging.202389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834979PMC
January 2021

Critical immunosuppressive effect of MDSC‑derived exosomes in the tumor microenvironment.

Oncol Rep 2021 03 14;45(3):1171-1181. Epub 2021 Jan 14.

Laboratory of Tumor Angiogenesis, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA.

Myeloid‑derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME). Along with the role of MDSC immunosuppression and antitumor immunity, MDSCs facilitate tumor growth, differentiation, and metastasis in several ways that are yet to be explored. Like any other cell type, MDSCs also release a tremendous number of exosomes, or nanovesicles of endosomal origin, that participate in intercellular communications by dispatching biological macromolecules. There have been no investigational studies conducted to characterize the role of MDSC‑derived exosomes (MDSC exo) in modulating the TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant level of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed a higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those in the spleen or bone marrow. Our in vitro data suggest that MDSC exo are capable of hyper‑activating or exhausting CD8 T‑cells and induce reactive oxygen species production that elicits activation‑induced cell death. We confirmed the depletion of CD8 T‑cells in vivo by treating mice with MDSC exo. We also observed a reduction in pro‑inflammatory M1‑macrophages in the spleen of those animals. Our results indicate that the immunosuppressive and tumor‑promoting functions of MDSCs are also implemented by MDSC‑derived exosomes which would open up a new avenue of MDSC research and MDSC‑targeted therapy.
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http://dx.doi.org/10.3892/or.2021.7936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860000PMC
March 2021

Sex-Specific Differences in Extracellular Vesicle Protein Cargo in Synovial Fluid of Patients with Osteoarthritis.

Life (Basel) 2020 Dec 10;10(12). Epub 2020 Dec 10.

Department of Pathology, Augusta University, Augusta, GA 30912, USA.

Women are at a significantly higher risk of developing osteoarthritis (OA) compared to males. The pathogenesis of osteoarthritis (OA) in women is poorly understood. Extracellular vesicles (EVs) have been shown to play an essential role in numerous signaling processes during the pathogenesis of age-related diseases via paracrine signaling. Molecular profiling of the synovial fluid-derived EVs cargo in women may help in the discovery of novel biomarkers and therapeutics for the treatment of OA in women. Previously, we reported that synovial fluid-derived EV miRNA cargo differs in a sex-specific manner. This study aims to characterize synovial fluid-derived EV protein cargo in OA patients. Our data showed sex-specific EVs protein content in OA. We found haptoglobin, orosomucoid, and ceruloplasmin significantly up-regulated, whereas apolipoprotein down-regulated in female OA EVs. In males, we discovered β-2-glycoprotein, and complement component 5 proteins significantly up-regulated and Spt-Ada-Gcn5 acetyltransferase (SAGA)-associated factor 29 down-regulated in male OA EVs. Database for Annotation, Visualization, and Integrated Discovery (DAVID) and QuickGO analysis revealed OA-specific protein involvement in several biological, molecular, and cellular pathways, specifically in inflammatory processes. In conclusion, synovial fluid EV protein content is altered in a sex-specific manner with OA, explaining the increased prevalence and severity of OA in women.
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http://dx.doi.org/10.3390/life10120337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763294PMC
December 2020

Optimal timing for activation of sigma 1 receptor in the Pde6b/J (rd10) mouse model of retinitis pigmentosa.

Exp Eye Res 2021 01 9;202:108397. Epub 2020 Dec 9.

Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, United States; Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA, United States. Electronic address:

Sigma 1 Receptor (Sig1R), a pluripotent modulator of cell survival, is a promising target for treatment of retinal degenerative diseases. Previously, we reported that administration of the high-affinity, high-specificity Sig1R ligand (+)-pentazocine, ((+)-PTZ) beginning at post-natal day 14 (P14) and continuing every other day improves visual acuity and delays loss of photoreceptor cells (PRCs) in the Pde6βrd10/J (rd10) mouse model of retinitis pigmentosa. Whether administration of (+)-PTZ, at time points concomitant with (P18) or following (P21, P24) onset of PRC death, would prove neuroprotective was investigated in this study. Rd10 mice were administered (+)-PTZ intraperitoneally [0.5 mg/kg], starting at either P14, P18, P21 or P24. Injections continued every other day through P42. Visual acuity was assessed using the optokinetic tracking response (OKR). Rd10 mice treated with (+)-PTZ beginning at P14 retained visual acuity for the duration of the study (~0.33 c/d at P21, ~0.38 c/d at P28, ~0.32 c/d at P35, ~0.32 c/d at P42), whereas mice injected beginning at P18, P21, P24 showed a decline in acuity when tested at P35 and P42. Their acuity was only slightly better than rd10-non-treated mice. Electrophysiologic function was assessed using scotopic and photopic electroretinography (ERG) to assess rod and cone function, respectively. Photopic a- and b-wave amplitudes were significantly greater in rd10 mice treated with (+)-PTZ beginning at P14 compared with non-treated mice and those in the later-onset (+)-PTZ injection groups. Retinal architecture was visualized in living mice using spectral domain-optical coherence tomography (SD-OCT) allowing measurement of the total retinal thickness, the inner retina and the outer retina (the area most affected in rd10 mice). The outer retina measured ~35 μm in rd10 mice treated with (+)-PTZ beginning at P14, which was significantly greater than mice in the later-onset (+)-PTZ injection groups (~25 μm) and non-treated rd10 mice (~25 μm). Following the visual function studies performed in the living mice, eyes were harvested at P42 for histologic analysis. While the inner retina was largely intact in all (+)-PTZ-injection groups, there was a marked reduction in the outer retina of non-treated rd10 mice (e.g. in the outer nuclear layer there were ~10 PRCs/100 μm retinal length). The rd10 mice treated with (+)-PTZ beginning at P14 had ~20 PRCs/100 μm retinal length, whereas the mice in groups beginning P18, P21 and P24 had ~16 PRCs/100 μm retinal length. In conclusion, the data indicate that delaying (+)-PTZ injection past the onset of PRC death in rd10 mice - even by a few days - can negatively impact the long-term preservation of retinal function. Our findings suggest that optimizing the administration of Sig1R ligands is critical for retinal neuroprotection.
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http://dx.doi.org/10.1016/j.exer.2020.108397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808329PMC
January 2021

Cytochrome P450 Mediated Bioactivation of Rutaevin, a Bioactive and Potentially Hepatotoxic Component of .

Chem Res Toxicol 2020 12 11;33(12):3054-3064. Epub 2020 Dec 11.

Department of Internal Medicine, Yantai Municipal Government Hospital, No. 16 Yuhuangding West Road, Yantai 264000, Shandong Province, China.

Rutaevin is one of the major bioactive constituents isolated from , a well-known herbal medicine that has been widely prescribed for the treatment of gastrointestinal disorders in China. However, oral administration of rutaevin has been shown to cause hepatotoxicity in mice. Bioactivation was suggested to be involved in rutaevin-induced hepatotoxicity. The aim of this study was to investigate the bioactivation of rutaevin in rat and human liver microsomes fortified with NADPH. Rutaevin was metabolized into the reactive intermediate -butene-1,4-dial (BDA) that was dependent on NADPH. The rutaevin-derived BDA intermediate was trapped by nucleophiles such as glutathione (GSH), -acetyl-lysine (NAL), and methoxylamine (MOA) in the microsomal incubation system. A total of 10 conjugates resulting from the conjugation of the intermediate with GSH, NAL, or MOA were detected and structurally characterized by liquid chromatography combined with high-resolution tandem mass spectrometry. M1, structurally confirmed by NMR spectroscopic analysis, was identified as a cyclic mono(GSH) conjugate of the BDA intermediate, which was also found in the biliary samples of rutaevin-treated rats. Further inhibitory experiments suggested that ketoconazole showed strong inhibitory effect on the formation of the rutaevin-derived BDA intermediate. CYP3A4 was demonstrated to be the major enzyme responsible for rutaevin bioactivation by using cDNA-expressed human recombinant cytochrome P450 enzymes. Additionally, it was found that rutaevin was a mechanism-based inactivator of CYP3A4, with inactivation parameters of = 15.98 μM, = 0.032 min, and = 21.65 min. In summary, these findings are of great significance in understanding the bioactivation mechanism of rutaevin, the potential mechanism of rutaevin-caused hepatotoxicity, and the drug-drug interactions associated with rutaevin mainly via CYP3A4 inactivation.
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http://dx.doi.org/10.1021/acs.chemrestox.0c00475DOI Listing
December 2020
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