Publications by authors named "Huiran Zhang"

47 Publications

MicroRNA-103a regulates the calcification of vascular smooth muscle cells by targeting runt-related transcription factor 2 in high phosphorus conditions.

Exp Ther Med 2021 Sep 19;22(3):1036. Epub 2021 Jul 19.

Department of Nephrology, The Fourth Hospital of Hebei Medical University, Hebei Key Laboratory of Vascular Calcification in Kidney Disease, Hebei Clinical Research Center for Chronic Kidney Disease, Shijiazhuang, Hebei 050011, P.R. China.

Vascular calcification, such as atherosclerosis, is a serious complication of chronic kidney disease that is characterized by tunica media calcification, and has gained increasing attention from researchers. The commonly observed association between vascular calcification and osteoporosis suggests a link between bone and vascular disorders. As microRNAs (miRNAs) have a wide range of gene regulation functions, such as cell proliferation, apoptosis, stress and transdifferentiation, the current study aimed to determine whether miRNAs play a vital role in the calcification and osteoblastic differentiation of rat thoracic aorta vascular smooth muscle cells (VSMCs). Gene expression analysis was performed on seven miRNAs (miR-29a, -30b, -103a, -125b, -133a, -143 and -211) that maybe potentially involved in the differentiation of smooth muscle cells into osteoblastic cells. The results showed that the levels of miR-29a, -30b, -103a, -125b and -143 were markedly reduced in the VSMC calcification model, particularly miR-103a, whereas runt-related transcription factor 2 () expression was increased. Furthermore, it was found that the expression of was significantly decreased following the upregulation of miR-103a, and that the expression of was significantly increased by downregulating miR-103a in VSMCs. Therefore, it was concluded that miR-103a plays a notable role in the transdifferentiation of the VSMCs in high phosphorus-induced calcification by targeting the regulation of , and may therefore constitute a new target for the diagnosis and treatment of vascular calcification.
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http://dx.doi.org/10.3892/etm.2021.10468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343701PMC
September 2021

The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to alkalinization-induced vascular calcification in vitro.

J Clin Lab Anal 2021 Aug 27;35(8):e23854. Epub 2021 Jul 27.

Hebei Clinical Research Center for Chronic Kidney Disease, Hebei Key Laboratory of Vascular Calcification in Kidney Disease, Departments of Nephrology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.

Objective: In order to find new strategies for the prevention of vascular calcification in uremic individuals especially treated by dialysis and develop novel therapeutic targets in vascular calcification, we explore the role of KCa3.1 in alkalinization-induced VSMCs calcification in vitro.

Method: Rat VSMCs calcification model was established by beta-glycerophosphate (β-GP, 10 mM) induction. The pH of Dulbecco's modified Eagle's medium (DMEM) was adjusted every 24 h with 10 mM HCl or 10 mM NaHCO . The mineralization was measured by Alizarin Red staining and O-cresolphthalein complex one method. mRNA and protein expression were detected by RT-PCR and Western blot or immunofluorescence. Ca2+ influx was measured by Elisa.

Result: The results indicated that alkalization induced an increase in Ca2+ influx to enhance VSMCs calcification. Furthermore, the increase of calcification was associated with the expression of KCa3.1 via advanced expression of osteoblastic differentiation markers alkaline phosphatase (ALP) and Runt-related transcription factor 2 (Runx2). Blocking KCa3.1 with TRAM-34 or shRNA vector can significantly lowered the effects of calcification in the activity of ALP and Runx2 expression.

Conclusion: Together all, our studies suggested that alkalinization can promote vascular calcification by upregulating KCa3.1 channel and enhancing osteogenic/chondrogenic differentiation by upregulating Runx2. The specific inhibitor TRAM-34 and KCa3.1-shRNA ameliorated VSMCs calcification by downregulating KCa3.1.
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http://dx.doi.org/10.1002/jcla.23854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373358PMC
August 2021

Novel insights into the role of BRD4 in fine particulate matter induced airway hyperresponsiveness.

Ecotoxicol Environ Saf 2021 Sep 24;221:112440. Epub 2021 Jun 24.

Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China. Electronic address:

Epidemiological research has identified that exposure to fine particulate matter (PM2.5) can increase airway hyperresponsiveness (AHR) which is considered a typical characteristic of asthma. Although the effect of PM2.5 on AHR has been elucidated to a certain degree, its exact mechanism remains unclear. Bromodomain-containing protein 4 (BRD4) is recognized as a member of the bromodomain and extraterminal (BET) family, with the ability to maintain higher-order chromatin configuration and regulate gene expression programs. The primary objective of our study was to examine the role of BRD4 in AHR triggered by PM2.5, and to elucidate its possible molecular mechanism. A mouse model with AHR was established using a nose-only PM2.5 exposure system. We observed that PM2.5 enhanced AHR in the experimental group compared to the control group, and this alteration was accompanied by increased lung inflammation and BRD4 expression in bronchi-lung tissue. However, the BRD4 inhibitor (ZL0420) could alleviate the aforementioned alterations in the mouse model with PM2.5 exposure. To explore the exact molecular mechanism, we further examined the role of BRD4 in human airway smooth muscle cells (hASMCs) after exposure to PM2.5 DMSO extracts. We found that PM2.5 DMSO extracts, which promoted the contraction and migration of hASMCs, was accompanied by an increase in the levels of BRD4, kallikrein 14 (KLK14), bradykinin 2 receptor (B2R), matrix metalloproteinases2(MMP-2), matrix metalloproteinases9(MMP-9), vimentin and bradykinin (BK) secretion, while ZL0420 and BRD4 gene silencing could reverse this response. In summary, these results demonstrate that BRD4 is an important player in AHR triggered by PM2.5, and BRD4 inhibition can ameliorate AHR induced by PM2.5. In addition, PM2.5 DMSO extracts can promote the contraction and migration of hASMCs by increasing BRD4 expression.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112440DOI Listing
September 2021

Identification of a genome-wide serum microRNA expression profile as potential noninvasive biomarkers for chronic kidney disease using next-generation sequencing.

J Int Med Res 2020 Dec;48(12):300060520969481

Department of Nephrology, The Fourth Hospital of Hebei Medical University, Hebei Key Laboratory of Vascular Calcification in Kidney Disease, Hebei Clinical Research Center for Chronic Kidney Disease, Shijiazhuang, China.

Objective: To identify serum microRNAs (miRNAs) as potential non-invasive biomarkers for patients with chronic kidney disease (CKD).

Methods: We collected serum samples from healthy controls, CKD stage 1 (CKD1), and stage 5 (CKD5) patients with primary glomerulonephritis (GN), screened differentially expressed miRNAs (DEMs) using next-generation sequencing (NGS), and confirmed the sequencing data using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR).

Results: We identified 20 and 42 DEMs in the CKD1 and CKD5 patients compared with the controls, respectively, and 70 DEMs in the CKD5 compared with the CKD1 patients. The qRT-PCR results showed that miR-483-5p was up-regulated in the CKD1 and CKD5 patients compared with controls (fold change = 2.56 and 18.77, respectively). miR-363-3p was down-regulated in the CKD5 patients compared with the controls and CKD1 patients (fold change = 0.27 and 0.48, respectively).

Conclusion: We identified a genome-wide serum miRNA expression profile in CKD patients, and serum miR-483-5p and miR-363-3p may act as potential diagnostic biomarkers for CKD.
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http://dx.doi.org/10.1177/0300060520969481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739098PMC
December 2020

Antagonism of interleukin 17 protects chronic obstructive pulmonary disease rat lungs from adverse effects of environmental PM.

Am J Transl Res 2020 15;12(9):5808-5817. Epub 2020 Sep 15.

Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University No. 215, Heping West Road, Shijiazhuang 050000, Hebei, China.

Severe air pollution has raised concerns about the adverse effects of particulate matters 2.5 μm in size (PM) on human health. However, the mechanisms elucidating how PM affects lungs, especially in COPD, remain unclear. In this study, we examined the concentration changes of environmental PM from 2013 to 2019 in Shijiazhuang city. PM was collected to study its effects on a COPD lung. Inflammatory factors present in bronchoalveolar lavage fluid (BLF) were examined after exposure. An antagonist of IL-17 was used to reverse PM-induced pathological and functional impairments in COPD rat lungs. Our results show that the degree of air pollution changed significantly (55.873, < 0.001) during the study period in accordance with PM tendency. PM and PM was present in higher concentrations from December 2013 to January 2014 and December 2016 to January 2017, respectively. After COPD rats were exposed to PM for 2 or 4 weeks, all indicators of lung function (FEV0.3, FVC, FEV0.3/FVC, PEF, Rrs) decreased continuously and significantly. The levels of TGF-β1, IL-6, IL-17, and IL-21 in BLF, as well as the expression of IL-17 in lung tissues, were significantly increased after exposure for 2 or 4 weeks. When an IL-17 antagonist was introduced following PM exposure, inflammatory factor levels in BLF and pathological scores of lung tissues decreased significantly. Moreover, lung functions were partially rescued. Collectively, our data demonstrate that IL-17 is a potential therapeutic target for COPD lungs after PM exposure.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540087PMC
September 2020

LRRCA8A and ANO1 contribute to serum-induced VRAC in a Ca-dependent manners.

J Pharmacol Sci 2020 Jul 9;143(3):176-181. Epub 2020 Apr 9.

Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Province, Shijiazhuang, Hebei, China. Electronic address:

The volume-regulated anion channel (VRAC) plays a central role in maintaining cell volume in response to osmotic stress. Leucine-rich repeat-containing 8A (LRRC8A) was recently identified as an essential component of VRAC although other Cl channels were also suggested to contribute to VRAC. VRAC is activated when a cell is challenged with a hypotonic environment or even in isotonic conditions challenged with different stimuli. It is not clear how VRAC is activated and whether activation of VRAC in hypotonic and isotonic conditions share the same mechanism. In this present study, we investigated relative contribution of LRRC8A and anoctamin 1(ANO1) to VRAC currents activated by fetal bovine serum (FBS) in isotonic condition, and studied the role of intracellular Ca in this activation. We used CRISPR/Cas9 gene editing approach, electrophysiology, and pharmacology approaches to show that VRAC currents induced by FBS is mostly mediated by LRRC8A in HEK293 cells, but also with significant contribution from ANO1. FBS induces Ca transients and these Ca signals are required for the activation of VRAC by serum. These findings will help to further understand the mechanism in activation of VRAC.
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http://dx.doi.org/10.1016/j.jphs.2020.04.003DOI Listing
July 2020

Ghrelin ameliorates chronic obstructive pulmonary disease-associated infllammation and autophagy.

Biotechnol Appl Biochem 2021 Apr 19;68(2):356-365. Epub 2020 May 19.

Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China.

Chronic obstructive pulmonary disease (COPD) is a chronic and devastating condition characterized by poor airflow and breath. Smoking and other environmental factors-caused inflammations triggered excessive autophagy of normal lung epithelial cells, eventually leading to impaired lung functions. Previous studies showed that ghrelin exhibited beneficial effects on patients with COPD. However, the mechanisms underlying this impact remained largely unknown. In this study, in vitro and in vivo models of COPD-associated inflammation were established, and we found that inflammation and autophagy were abonormally activated through nuclear factor kappa b (NF-κB) and activator protein-1 (AP-1) signaling pathways. Interestingly, ghrelin could inhibit the excessive inflammation pathways and autophagy induced by particle matter and/or cigarette extract in bronchial epithelial cells. Furthermore, NF-κB and AP-1 signaling were both inhibited while lung functions were significantly improved. Taken together, identification of downstream signaling of ghrelin in inflammation provided a new avenue in the treatment of COPD.
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http://dx.doi.org/10.1002/bab.1933DOI Listing
April 2021

Fine particulate matter increases airway hyperresponsiveness through kallikrein-bradykinin pathway.

Ecotoxicol Environ Saf 2020 Jun 23;195:110491. Epub 2020 Mar 23.

Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China. Electronic address:

Epidemiological studies have reported short-term fine particulate matter (PM2.5) exposure to increase incidence of asthma, related to the increase of airway hyperresponsiveness (AHR); however, the underlying mechanism remains unclear. Aim of this study was to elucidate the role of kallikrein in PM2.5-induced airway hyperresponsiveness and understand the underlying mechanism. Nose-only PM2.5 exposure system was used to generate a mouse model of airway hyperresponsiveness. Compared with the control group, PM2.5 exposure could significantly increase airway resistance, lung inflammation, kallikrein expression of bronchi-lung tissue and bradykinin (BK) secretion. However, these changes could be alleviated by kallikrein inhibitor. In addition,PM2.5 could increase the viability of human airway smooth muscle cells (hASMCs), accompanied by increased expression of kallikrein 14 (Klk14), bradykinin 2 receptor (B2R), bradykinin secretion and cytosol calcium level, while kallikrein 14 gene knockdown could significantly amelioratethe above response induced by PM2.5. Taken together, the data suggested kallikrein to play a key role in PM2.5-induced airway hyperresponsiveness, and that it could be a potential therapeutic target in asthma.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110491DOI Listing
June 2020

CT-Radiomic Approach to Predict G1/2 Nonfunctional Pancreatic Neuroendocrine Tumor.

Acad Radiol 2020 12 6;27(12):e272-e281. Epub 2020 Feb 6.

Department of Radiology, Changhai Hospital, Changhai Road 168, Shanghai 200434, China. Electronic address:

Rationale And Objectives: Tumor grading of nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) determines the choice of clinical treatment and management. The pathological grade of pancreatic neuroendocrine tumors is usually assessed on postoperative specimens. The goal of our study is to establish a tumor grade (G) prediction model for preoperative G1/2 NF-pNETs using radiomics for multislice spiral CT image analysis.

Materials And Methods: This retrospective study included a primary cohort of 59 patients and an independent validation cohort of 40 consecutive patients; their multislice spiral CT images were collected from October 2012 to October 2016 and October 2016 to June 2018, respectively. All 99 patients were diagnosed with clinicopathologically confirmed NF-pNETs. Most significant radiomic features were selected using the minimum redundancy and maximum relevance algorithm. Support vector machine classifier with a radial basis function-based predictive model was subsequently developed for clinical use.

Results: A total of 585 radiomics features were extracted from every phase for each patient. Six of these radiomics features were identified as most discriminant features for G1 and G2 tumors and used to construct the tumor grade prediction model. The prediction model resulted in the area under the curve values of 0.968 (95% CI: 0.900-0.991) and 0.876 (95% CI: 0.700-0.963) for the training cohort and validation cohort, respectively. Sensitivity and specificity were 96.4% and 83.9%, and 90.9% and 88.9% for the training and validation cohorts, respectively. The decision curves indicated that if the threshold probability is above 0.1, using the rad-score in the current study on G1/2 NF-pNETs is more beneficial than the treat-all-patients scheme or the treat-none scheme.

Conclusion: Radiomics developed with a combination of nonenhanced and portal venous phases can achieve favorable predictive accuracy for histological grade for G1/G2 NF-pNETs.
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http://dx.doi.org/10.1016/j.acra.2020.01.002DOI Listing
December 2020

Hydrogen ameliorates lung injury in a rat model of subacute exposure to concentrated ambient PM2.5 via Aryl hydrocarbon receptor.

Int Immunopharmacol 2019 Dec 9;77:105939. Epub 2019 Nov 9.

Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China. Electronic address:

Background: Ambient fine particulate matter (PM2.5) could induce lung injury. Aryl hydrocarbon receptor (AhR) is involved in the molecular mechanisms of prooxidative and pro-inflammatory effect of PM2.5. Molecular hydrogen has antioxidant properties. The protective effect and mechanism of hydrogen on PM2.5-induced lung injury remain unclear.

Objectives: This study aimed to determine whether hydrogen could alleviate lung injury in a rat model of subacute exposure to concentrated ambient PM2.5, and explore the mechanism related to AhR.

Methods: Male Wastar rats were exposed to either concentrated ambient particles (CAPs) (diameter: ≤2.5 μm, average concentration: 1328 ± 730 μg/m) or filtered air (FA) by nose-only inhalation (5 h/day, 5 days/week for 4 weeks). Hydrogen-treated rats inhaled 66.7% hydrogen from water electrolysis for 2 h after each exposure to CAPs or FA.

Results: CAPs inhalation induced lung injury, as demonstrated by pulmonary function decrease, histopathological damage, mucus hypersecretion [Periodic acid-Schiff (PAS) staining for mucins, immunohistochemistry and quantitative real-time PCR (RT-qPCR) for mucin 5AC (MUC5AC) expression], increased pro-inflammatory cytokines (TNF-α, IL-8 and IL-1β) and oxidative damage indexes [malondialdehyde (MDA) and 8-isoprostane F2α (8-iso-PG)]. While, hydrogen inhalation significantly alleviated the damages mentioned above. In addition, low expression of AhR in lung tissues determined by Western Blot was found after CAPs exposure, whereas hydrogen inhibited AhR decline induced by CAPs.

Conclusions: High concentrations of hydrogen could ameliorate pulmonary dysfunction, airway mucus hypersecretion, oxidation damage, and inflammation response in rats exposed to concentrated ambient PM2.5. Additionally, hydrogen alleviates lung injury induced by PM2.5 possibly through AhR-dependent mechanisms.
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http://dx.doi.org/10.1016/j.intimp.2019.105939DOI Listing
December 2019

Comparison of air pollutant-related hospitalization burden from AECOPD in Shijiazhuang, China, between heating and non-heating season.

Environ Sci Pollut Res Int 2019 Oct 28;26(30):31225-31233. Epub 2019 Aug 28.

Department of Respiratory and Critical Care Medicine, The Second Hospital of HeBei Medical University, No. 215 Heping West Road, Shijiazhuang, Hebei Province, China.

Few researches have been investigated on the effects of ambient air pollutants from coal combustion on acute exacerbation of chronic obstructive pulmonary disease (AECOPD) hospitalizations. The whole time series was split into heating season and non-heating season. We used a quasi-Poisson generalized linear regression model combined with distributed lag non-linear models (DLNMs) to estimate the relative cumulative risk and calculate the air pollutant hospitalization burden of AECOPD for lag 0-7 days in heating season and non-heating season. There were higher PM, PM, NO, SO, and CO concentrations in heating seasons than non-heating season in Shijiazhuang; however, O was higher in non-heating season than heating season. The AECOPD-associated relative cumulative risks for PM, PM, NO, and SO for lag 0-7 days were significantly positively associated with hospitalization in heating and non-heating season; we found that the cumulative relative risk of NO was the greatest in every 1 unit of air pollutants during the heating season and the cumulative relative risk of SO was the greatest during the non-heating season. The results showed that 17.8%, 12.9%, 1.7%, 16.7%, and 10.5% of AECOPD hospitalizations could be attributable to PM, PM, SO, NO, and CO exposure in heating season, respectively. However, the results showed that 19.5%, 22.4%, 15%, 8.3%, and 10.4% of AECOPD hospitalizations could be attributable to PM, PM, SO, NO and O exposure in non-heating season, respectively. The attributable burden of AECOPD hospitalization in heating season and non-heating season are different. PM, PM, NO, and CO are the main factors of heating season, while PM, PM, SO, and O are the main factors of non-heating season. In conclusions, the centralized heating can change the influence of attributable risk. When government departments formulate interventions to reduce the risk of acute hospitalization of chronic obstructive pulmonary disease (COPD), the influence of heating on disease burden should be considered.
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http://dx.doi.org/10.1007/s11356-019-06242-3DOI Listing
October 2019

The hospitalization attributable burden of acute exacerbations of chronic obstructive pulmonary disease due to ambient air pollution in Shijiazhuang, China.

Environ Sci Pollut Res Int 2019 Oct 24;26(30):30866-30875. Epub 2019 Aug 24.

Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, Hebei Province, China.

Few studies have investigated the acute exacerbations of chronic obstructive pulmonary disease (AECOPD)-associated attributable burden under exposure to high levels of air pollution among Asians. Data on hospitalization for AECOPD, air pollution and meteorological factors from 1 January 2013 to 31 December 2016 were collected in Shijiazhuang, China. We used a Poisson generalized linear regression model combined with a distributed lag nonlinear model (DLNM) to evaluate the relative cumulative risk for a lag of 0-7 days and examined the potential effect modifications by age and sex via stratification analyses, controlling for long-term trends, seasonal patterns, meteorological factors, and other possible confounders. Then, we computed hospitalization percentages attributable to air pollutants. The AECOPD-associated relative cumulative risks for PM, PM, NO, SO, and CO for a lag of 0-7 days were significantly positively correlated with hospitalization. The associations were stronger in females and retired patients. The NO Cum RR of AECOPD admission was the greatest. A 10μg/m increase in daily NO concentration was associated with 6.7% and 5.7% increases in COPD hospitalizations in the retired and female groups, respectively. The results showed that 13%, 9.4%, 1.7%, 9.7%, and 8.8% of AECOPD hospitalizations were attributable to exposure to PM, PM, SO, NO, and CO, respectively. If the air pollutant concentration was reduced to the 24-h average grade II levels of NAAQS of China, the AECOPD attributable percentage for PM and PM would decrease by 80%. The air pollutants PM, PM, SO, NO, and CO were significantly relevant to AECOPD-associated hospitalization. The associations differed by individual characteristics. The retired and female populations were highly vulnerable.
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http://dx.doi.org/10.1007/s11356-019-06244-1DOI Listing
October 2019

Novel insights into the role of LRRC8A in ameliorating alveolar fluid clearance in LPS induced acute lung injury.

Eur J Pharmacol 2019 Oct 14;861:172613. Epub 2019 Aug 14.

Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. Electronic address:

Leucine-rich repeat-containing 8A (LRRC8A) protein was recently identified as an essential component of volume-regulated anion channel which plays a central role in maintaining cell volume. The aim of this study was to elucidate the role of LRRC8A in alveolar fluid clearance (AFC) and the effect of inflammatory cytokines on LRRC8A and the underlying mechanism. Lipopolysaccharide (LPS) was used to generate a rat acute lung injury model. The results showed that the concentrations of IL-1β, TNF-α and IL-6 in bronchoalveolar lavage fluid increased significantly, but the expression of LRRC8A in the lung tissue decreased dramatically in the acute lung injury group followed by a decline in the AFC rate. Additionally, LRRC8A knockdown reduced AFC in normal rats. However, specific overexpression of LRRC8A in the lung could increase AFC. Furthermore, we observed the effects of LPS, IL-1β, TNF-α and IL-6 on the LRRC8A current in alveolar type II (ATII) cells, and IL-1β showed the greatest inhibition among them, which was involved in phospho-p38 activation. Overall, LRRC8A plays an essential role in the progression of AFC in LPS-induced acute lung injury, and chronic treatment with IL-1β or TNF-α could inhibit the function of LRRC8A in ATII cells by targeting phospho-p38. All of the findings suggested that LRRC8A could be a new partner in AFC and a potential target for the treatment of acute lung injury.
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http://dx.doi.org/10.1016/j.ejphar.2019.172613DOI Listing
October 2019

Volume-regulated Cl current: contributions of distinct Cl channels and localized Ca signals.

Am J Physiol Cell Physiol 2019 09 26;317(3):C466-C480. Epub 2019 Jun 26.

Department of Pharmacology, Hebei Medical University, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, China.

The swelling-activated chloride current () is induced when a cell swells and plays a central role in maintaining cell volume in response to osmotic stress. The major contributor of is the volume-regulated anion channel (VRAC). Leucine-rich repeat containing 8A (LRRC8A; SWELL1) was recently identified as an essential component of VRAC, but the mechanisms of VRAC activation are still largely unknown; moreover, other Cl channels, such as anoctamin 1 (ANO1), were also suggested to contribute to . In this present study, we investigated the roles of LRRC8A and ANO1 in activation of ; we also explored the role of intracellular Ca in activation. We used a CRISPR/Cas9 gene editing approach, electrophysiology, live fluorescent imaging, selective pharmacology, and other approaches to show that both LRRC8A and ANO1 can be activated by cell swelling in HEK293 cells. Yet, both channels contribute biophysically and pharmacologically distinct components to , with LRRC8A being the major component. Cell swelling induced oscillatory Ca transients, and these Ca signals were required to activate both the LRRC8A- and ANO1-dependent components of . Both components required localized rather than global Ca for activation. Interestingly, while intracellular Ca was necessary and sufficient to activate ANO1, it was necessary but not sufficient to activate LRRC8A-mediated currents. Finally, Ca transients linked to the activation were mediated by the G protein-coupled receptor-independent PLC isoforms.
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http://dx.doi.org/10.1152/ajpcell.00507.2018DOI Listing
September 2019

The effect and burden modification of heating on adult asthma hospitalizations in Shijiazhuang: a time-series analysis.

Respir Res 2019 Jun 14;20(1):122. Epub 2019 Jun 14.

The Second Hospital of Hebei Medical University, Shijiazhuang city, Hebei province, China.

Background: Previous studies have found associations between asthma morbidity and air pollution especially in young population, (PLoS One 12:e0180522, 2017; Can J Public Health 103:4-8, 2012; Environ Health Perspect 118:449-57, 2010; Am J Respir Crit Care Med 182:307-16, 2010; J Allergy Clin Immunol 104:717-22, 2008; J Allergy Clin Immunol 104:717-22, 1999; Environ Res 111:1137-47, 2011) but most of them were conducted in areas with relatively low air pollutant level. Moreover, very few studies have investigated the effect and burden modification of heating season during which the ambient air pollution level is significantly different from that during non-heating season in north China.

Objectives: This study aimed to evaluate the effect and burden modification of heating on short-term associations between adult asthma hospitalizations and ambient air pollution in the north China city of Shijiazhuang.

Methods: Generalized additive models combined with penalized distributed lag nonlinear models were used to model associations between daily asthma hospitalizations and ambient air pollutants from 1 January 2013 to 16 December 2016 in Shijiazhuang city, adjusting for long-term and seasonality trend, day of week, statutory holiday, daily mean air pressure and temperature. Attributable risks were calculated to evaluate the burden of asthma hospitalizations due to air pollutants exposure. The effect of pollutants on hospitalization and the attributable measures were estimated in heating and non-heating season separately and the comparisons between the two seasons were conducted.

Results: All pollutants demonstrated positive and significant impacts on asthma hospitalizations both in heating season and non-heating season, except for O in heating season where a negative association was observed. However, the differences of the pollutant-specific effects between the two seasons were not significant. SO and NO exposure were associated with the heaviest burden among all pollutants in heating season; meanwhile, PM and PM were associated with the heaviest burden in heating season.

Conclusions: In conclusion, we found evidence of the effect of ambient air pollutants on asthma hospitalizations in Shijiazhuang. The central heating period could modify the effects in terms of attributable risks. The disease burden modification of heating should be taken into consideration when planning intervention measures to reduce the risk of asthma hospitalization.
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http://dx.doi.org/10.1186/s12931-019-1092-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570879PMC
June 2019

Fine particulate matter (PM) enhances airway hyperresponsiveness (AHR) by inducing necroptosis in BALB/c mice.

Environ Toxicol Pharmacol 2019 May 12;68:155-163. Epub 2019 Mar 12.

Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China. Electronic address:

Objective: To observe the effects of prolonged exposure to high concentrations of PM on the trachea and lungs of mice and to determine whether the damages to the trachea and lung are induced by necroptosis.

Methods: Six- to eight-week-old female Balb/C mice of PM group were restrained in an animal restraining device using a nose-only "PM online enrichment system" for 8 weeks, in Shijiazhuang, Hebei, China. Anti -Fas group was exposed to PM inhalation and anti-Fas treatment via intranasal instillation. The mice in the control group inhaled filtered clean air. PM sample was collected and analyzed. Airway Hyperresponsiveness (AHR) was tested. Lung tissue and bronchoalveolar lavage fluid (BALF) were analyzed for Hematoxylin and eosin (HE) staining, electron microscopy, cellular inflammation, cytokines, Tunel, Fas, RIPK3 and MLKL expression.

Results: Compared to the other two groups, PM group displayed significantly increased AHR, neutrophils in BALF, significant bronchitis and alveolar epithelial hyperplasia and inflammation and necroptosis which were indicated by increased TUNEL, Fas, RIPK3 and MLKL measure.

Conclusion: Our findings suggest that PM can enhance AHR and these changes are induced by necroptosis-related inflammation.
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http://dx.doi.org/10.1016/j.etap.2019.03.013DOI Listing
May 2019

Natural and synthetic flavonoids, novel blockers of the volume-regulated anion channels, inhibit endothelial cell proliferation.

Pflugers Arch 2018 10 30;470(10):1473-1483. Epub 2018 Jun 30.

Department of Pharmacology, Hebei University of Chinese Medicine, No. 326 South Xinshi Road, Shijiazhuang, 050091, Hebei, China.

Natural flavonoids are ubiquitous in dietary plants and vegetables and have been proposed to have antiviral, antioxidant, cardiovascular protective, and anticancer effects. Volume-regulated anion channels (VRACs), which are essential for cell volume regulation, have been proposed to play a key role in cell proliferation and migration, apoptosis, transepithelial transport, and cancer development. In this study, we screened a group of 53 structurally related natural flavonoids and three synthetic flavonoids for their inhibitory activities on VRAC currents. A whole-cell patch technique was used to record VRAC currents in the human embryonic kidney (HEK) 293 and human umbilical vein endothelial (HUVEC) cells. The 5'-bromo-2-deoxyuridine (BrdU) assay technique was used to investigate cell proliferation. At 100 μM, 34 of 53 compounds significantly inhibited hypotonic extrasolution-induced VRAC currents by > 50% in HEK293 cells. Among these compounds, luteolin, baicalein, eupatorin, galangin, quercetin, fisetin, karanjin, Dh-morin, genistein, irisolidone, and prunetin exhibited the highest efficacy for VRAC blockade (the mean inhibition > 80%) with ICs of 5-13 μM and Es of about 87-99%. We also studied the effects of three synthetic flavonoids on VRAC currents in HEK293 cells. Flavoxate showed high inhibition efficacy toward VRAC currents (IC = 2.3 ± 0.3 μM; E = 91.8% ± 2.7%). Finally, these flavonoids inhibited endogenous VRAC currents and cell proliferation in endothelial cells. This study demonstrates that natural and synthetic flavonoids are potent VRAC current inhibitors, and VRAC inhibition by flavonoids might be responsible for their anti-angiogenic effects.
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http://dx.doi.org/10.1007/s00424-018-2170-8DOI Listing
October 2018

Extracellular acidosis suppresses calcification of vascular smooth muscle cells by inhibiting calcium influx via L-type calcium channels.

Clin Exp Hypertens 2018 8;40(4):370-377. Epub 2018 Feb 8.

a Departments of Nephrology , The Fourth Hospital of Hebei Medical University , Shijiazhuang , P. R. China.

Vascular calcification such as arteriosclerosis, which is characterized by a calcification of the tunica media, is a severe complication of chronic kidney disease (CKD), contributing to the high prevalence of cardiovascular morbidity and mortality in patients with CKD. An essential step during the development of arteriosclerosis is the transdifferentiation/calcification of vascular smooth muscle cells (VSMCs), resembling osteogenesis. Metabolic acidosis, a common clinical manifestation in CKD, is known to decrease vascular calcification. To understand the underlying regulatory mechanisms of acidosis, we investigated whether the acidosis-decreased VSMC calcification involves altered signaling of the LTCC/Ca/Runx2 pathway. Vascular calcifications, calcium content, runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), L-type calcium channel (LTCC) β subunits, and calcium influx were measured in vivo or in vitro. Calcified nodules and calcium content increased either in aorta sections of vascular calcified rats or in VSMCs induced by β-GP. The expression of Runx2 and ALP activity markedly rose, accompanied by the increasing expression of LTCC β subunits and calcium influx. However, acidosis supplementation successfully attenuated VC and VSMC calcification and inhibited Runx2, ALP, LTCC β subunits, and calcium influx. In conclusion, acidosis significantly attenuated vascular calcification in association with downregulation of the LTCC/Ca/Runx2 pathway.
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http://dx.doi.org/10.1080/10641963.2017.1384482DOI Listing
August 2018

miR-502-mediated histone methyltransferase expression is associated with clear cell renal cell carcinoma risk.

Oncol Lett 2017 Dec 2;14(6):7131-7138. Epub 2017 Oct 2.

Department of Nephrology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.

Genetic variants may affect the interactions between microRNAs (miRNAs/miRs) and their target genes by modulating their binding affinity or by creating, or destroying a miRNA-binding site. SET domain containing (lysine methyltransferase) 8 (SET8) is the sole lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20, and is associated with tumor growth, invasion and metastasis. In the present study, the rs16917496 polymorphism within the miR-502 binding site of the SET8 mRNA 3' untranslated region (3'UTR) in patients with clear cell renal cell carcinoma (ccRCC) and healthy controls was genotyped. The CC genotype was associated with a decreased ccRCC risk compared with the CT [P=0.003; odds ratio (OR)=0.318; 95% confidence interval (CI), 0.146-0.691], TT (P=0.011; OR=0.402; 95% CI, 0.197-0.819) and CT+TT (P=0.004; OR=0.370; 95% CI, 0.186-0.736) genotypes. The CC genotype was associated with reduced SET8 expression based on immunostaining of ccRCC tissue. Low SET8 protein levels were negatively associated with tumor-node-metastasis staging in patients with ccRCC according to the size of tumor and lymph node metastases. -knockdown inhibited renal carcinoma 786-O cell proliferation, migration and invasion. c-Myc and matrix metalloproteinase-7 mRNA expression were downregulated upon -knockdown in renal carcinoma 786-O cells. These data indicated that SET8 may be a functional tumor promoter and that its activation, which is partially regulated by changing the miR-502 and 3'UTR binding affinity, may serve an important role in ccRCC development.
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http://dx.doi.org/10.3892/ol.2017.7115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727589PMC
December 2017

Inhibition of transmembrane member 16A calcium-activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects.

Br J Pharmacol 2017 Jul 7;174(14):2334-2345. Epub 2017 Jun 7.

Department of Pharmacology, Institution of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, China.

Background And Purpose: Natural flavonoids are ubiquitous in dietary plants and vegetables and have been proposed to have antiviral, antioxidant, cardiovascular protective and anticancer effects. Transmembrane member 16A (TMEM16A)-encoded Ca -activated Cl channels play a variety of physiological roles in many organs and tissues. Overexpression of TMEM16A is also believed to be associated with cancer progression. Therefore, inhibition of TMEM16A current may be a potential target for cancer therapy. In this study, we screened a broad spectrum of flavonoids for their inhibitory activities on TMEM16A currents.

Experimental Approach: A whole-cell patch technique was used to record the currents. The BrdU assay and transwell technique were used to investigate cell proliferation and migration.

Key Results: At a concentration of 100 μM, 10 of 20 compounds caused significant (>50%) inhibition of TMEM16A currents. The four most potent compounds - luteolin, galangin, quercetin and fisetin - had IC values ranging from 4.5 to 15 μM). To examine the physiological relevance of these findings, we also studied the effects of these flavonoids on endogenous TMEM16A currents in addition to cell proliferation and migration in LA795 cancer cells. Among the flavonoids tested, we detected a highly significant correlation between TMEM16A current inhibition and cell proliferation or reduction of migration.

Conclusions And Implications: This study demonstrates that flavonoids inhibit TMEM16A currents and suggests that flavonoids could have anticancer effects via this mechanism.
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http://dx.doi.org/10.1111/bph.13841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481650PMC
July 2017

Characterization and structure-activity relationship of natural flavonoids as hERG K channel modulators.

Int Immunopharmacol 2017 Apr 21;45:187-193. Epub 2017 Feb 21.

Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China. Electronic address:

Objectives: Flavonoids are present in varying concentrations in plant foods and have been reported to have numerous pharmacological activities, such as anti-cancer, antioxidant, anti-inflammatory, hepatoprotective, and vasodilator effects. We found that quercetin, fisetin, and some related flavonoid derivatives could inhibit human ether-à-go-go-related gene (hERG) K channels.

Key Findings: In this study, we tested the effects of a series of flavonoids on the hERG K channel expressed in HEK293 cells. For the first time, we demonstrate that quercetin and fisetin (Fise) are potent hERG current blockers. The 50% inhibiting concentration (IC) and maximum efficacy (E) of quercetin were 11.8±0.9μM and 82±2%, while those of fisetin were 38.4±6μM and 100±6%, respectively. Luteolin (Lute) was a less potent inhibitor of hERG current (48±1% at 100μM). Galangin, kaempferol, and isorhamnetin (100μM) showed weaker activity on the hERG currents.

Conclusion: These results suggest that quercetin, fisetin, and luteolin are potent hERG K channel inhibitors and reveal the structure-activity relationship of natural flavonoids.
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http://dx.doi.org/10.1016/j.intimp.2017.02.012DOI Listing
April 2017

Increased TMEM16A Involved in Alveolar Fluid Clearance After Lipopolysaccharide Stimulation.

Inflammation 2016 Apr;39(2):881-90

Department of Respirology, The Second Hospital of Hebei Medical University, No. 215, West Heping Road, Shijiazhuang, Hebei, 050000, China.

Unlabelled: Transmembrane protein 16A (TMEM16A) regulates a wide variety of cellular activities, including epithelial fluid secretion and maintenance of ion homeostasis. Lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria, is one of the major causes of acute lung injury (ALI). In this study, we investigated the effects of LPS on the expression of TMEM16A in LA795 cells and mouse lung tissue and the potential mechanism.

Result: We detected the expression of TMEM16A in LA795 cells and mouse lung tissue by RT-PCR, Western blot, and RNA interference techniques. TMEM16A expression was significantly increased by LPS stimulation in LA795 cells and in mouse lung tissue. Moreover, the LPS-induced TMEM16A expression enhancement in lung tissue was much more prominent in the alveolar epithelial region than in bigger airway epithelial cells. The typical TMEM16A current was recorded, and LPS treatment significantly enhances the current amplitude in LA795 cells. TMEM16A shRNA or TMEM16A inhibitor (T16Ainh-A01) did not affect alveolar fluid clearance (AFC), while co-application of T16Ainh-A01 induced a stronger AFC inhibition than LPS alone. LPS notably and synchronously enhanced Akt phosphorylation (p-Akt) and TMEM16A expression in a time-dependent manner in LA795 cells. Taken together, our results suggest that TMEM16A maybe plays an important role in pathological conditions of LPS-induced ALI as a protective protein.
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http://dx.doi.org/10.1007/s10753-016-0320-8DOI Listing
April 2016

Magnesium prevents β-glycerophosphate-induced calcification in rat aortic vascular smooth muscle cells.

Biomed Rep 2015 Jul 27;3(4):593-597. Epub 2015 May 27.

Department of Nephrology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.

Vascular calcification (VC), in which high serum phosphate plays a critical role, is one major problem in patients with chronic kidney disease. Clinical studies report that magnesium has a protective effect on VC. However, the studies regarding the impact of high serum magnesium on VC at a cellular level are few and require further investigation. Therefore, the present study explored the effect of magnesium on calcification induced by β-glycerophosphate (BGP) in rat aortic vascular smooth muscle cells (RAVSMCs). In the present study, the addition of magnesium decreased calcium deposition, which was increased by BGP. Higher magnesium levels inhibited BGP-induced alkaline phosphatase (ALP) activity and decreased the expression of core-binding factor α-1 (Cbfα1). In conclusion, higher magnesium levels prevented BGP-induced calcification in RAVSMCs and inhibited the expression of Cbfα1 and ALP. Thus, magnesium is influencing the expression of Cbfα1 and ALP associated with VC and may have the potential to serve as a role for VC in clinical situations.
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http://dx.doi.org/10.3892/br.2015.473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486886PMC
July 2015

Single-nucleotide polymorphism of the promoter is associated with the outcome of chronic kidney disease patients.

Biomed Rep 2015 Jul 26;3(4):588-592. Epub 2015 May 26.

Department of Nephrology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.

Uromodulin (UMOD) is the most abundant protein secreted in urine and the mutated form of the gene is associated with UMOD-associated kidney disease (UAKD). Although UMOD accumulates in the kidney of UAKD patients, it is unclear whether this also occurred in the chronic kidney disease (CKD) patients. Therefore, the association of single-nucleotide polymorphisms (SNPs) in the promoter region of gene with the kidney survival time of CKD was investigated. The promoter region of the gene was sequenced for 111 CKD patients. The Kaplan-Meier method was used to identify the disease outcome associated with SNPs in the promoter region of the gene in CKD patients. The Cox proportional hazard model was used to identify risk factors for the kidney survival time of CKD. SNPs in reference to GenBank accession NG-000016 were detected at 23 sites of the 481-bp in the UMOD promoter region from the CKD patients and the healthy controls. The 6 SNPs with minor allele frequency >5% in the CKD patients or controls were used for disease risk and outcome analysis. The frequent allele rs13333226AA was associated with a shorter period of kidney survival time in CKD patients (P=0.005). The length of kidney survival time in CKD patients with the rs13333226AA genotype was significantly shorter than that of patients with the frequent allele rs13333226AG+GG (relative risk, 0.361; 95% confidence interval, 0.171-0.761; P=0.007). In conclusion, analysis of genetic polymorphisms in may help to identify the CKD patient subgroups at a high risk for a disease outcome, thereby helping to refine therapeutic decisions in CKD patients.
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http://dx.doi.org/10.3892/br.2015.471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487055PMC
July 2015

Tannic acid modulates excitability of sensory neurons and nociceptive behavior and the Ionic mechanism.

Eur J Pharmacol 2015 Oct 30;764:633-642. Epub 2015 Jun 30.

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China. Electronic address:

M/Kv7 K(+) channels, Ca(2+)-activated Cl(-) channels (CaCCs) and voltage gated Na(+) channels expressed in dorsal root ganglia (DRG) play an important role in nociception. Tannic acid has been proposed to be involved in multiple beneficial health effects; tannic acid has also been described to be analgesic. However the underlying mechanism is unknown. In this study, we investigated the effects of tannic acid on M/Kv7 K(+), Na(+) currents and CaCCs, and the effects on bradykinin-induced nociceptive behavior. A perforated patch technique was used. The bradykinin-induced rat pain model was used to assess the analgesic effect of tannic acid. We demonstrated that tannic acid enhanced M/Kv7 K(+) currents but inhibited bradykinin-induced activation of CaCC/TMEM16A currents in rat small DRG neurons. Tannic acid potentiated Kv7.2/7.3 and Kv7.2 currents expressed in HEK293B cells, with an EC50 of 7.38 and 5.40 µM, respectively. Tannic acid inhibited TTX-sensitive and TTX-insensitive currents of small DRG neurons with IC50 of 5.25 and 8.43 µM, respectively. Tannic acid also potently suppressed the excitability of small DRG neurons. Furthermore, tannic acid greatly reduced bradykinin-induced pain behavior of rats. This study thus demonstrates that tannic acid is an activator of M/Kv7 K(+) and an inhibitor of voltage-gated Na(+) channels and CaCC/TMEM16A, which may underlie its inhibitory effects on excitability of DRG neurons and its analgesic effect. Tannic acid could be a useful agent in treatment of inflammatory pain conditions such as osteoarthritis, rheumatic arthritis and burn pain.
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http://dx.doi.org/10.1016/j.ejphar.2015.06.048DOI Listing
October 2015

Grey matter morphological anomalies in the caudate head in first-episode psychosis patients with delusions of reference.

Psychiatry Res 2015 Jul 12;233(1):57-63. Epub 2015 May 12.

Mental Health Institute of The Second Xiangya Hospital, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, Hunan, China.

Delusions of reference (DOR) are theoretically linked with aberrant salience and associative learning. Previous studies have shown that the caudate nucleus plays a critical role in the cognitive circuits of coding prediction errors and associative learning. The current study aimed at testing the hypothesis that abnormalities in the caudate nucleus may be involved in the neuroanatomical substrate of DOR. Structural magnetic resonance imaging of the brain was performed in 44 first-episode psychosis patients (with diagnoses of schizophrenia or schizophreniform disorder) and 25 healthy controls. Patients were divided into three groups according to symptoms: patients with DOR as prominent positive symptom; patients with prominent positive symptoms other than DOR; and patients with minimal positive symptoms. All groups were age-, gender-, and education-matched, and patient groups were matched for diagnosis, duration of illness, and antipsychotic treatment. Voxel-based morphometric analysis was performed to identify group differences in grey matter density. Relationships were explored between grey matter density and DOR. Patients with DOR were found to have reduced grey matter density in the caudate compared with patients without DOR and healthy controls. Grey matter density values of the left and right caudate head were negatively correlated with DOR severity. Decreased grey matter density in the caudate nucleus may underlie DOR in early psychosis.
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http://dx.doi.org/10.1016/j.pscychresns.2015.04.011DOI Listing
July 2015

Alteration of type I collagen in the radial artery of patients with end-stage renal disease.

Am J Med Sci 2015 Apr;349(4):292-7

Department of Nephrology (YB, JZ, JX, LC, HZ, SZ), The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.

Background: Cardiovascular disease is the leading cause of death in chronic kidney disease. Extracellular matrix remodeling is implicated in atherosclerosis development. This study investigated the effects and possible mechanism of type I collagen expression on radial artery elasticity in patients with end-stage renal disease (ESRD).

Methods: Sixty-five patients receiving forearm arteriovenous fistula in the Fourth Hospital of Hebei Medical University from January 2010 to December 2012 were enrolled in the study. The echo-tracking technique was used to measure radial artery 1-point pulse wave velocity (PWVβ), and immunohistochemical staining was used to detect the expression of type I collagen and transcription factor CBFA1, a marker for calcification, in the radial artery. Uremic serum and serum from healthy volunteers of different concentrations were then used to treat the rat aortic vascular smooth muscle cells (VSMCs), reverse transcription polymerase chain reaction (PCR) was used to measure COL1A1 and CBFA1 transcription and a Western blot was performed to detect type I collagen expression in the rat aortic VSMCs.

Results: In patients with ESRD, increased COL1A1 expression was an independent risk factor for radial artery PWVβ (P < 0.05) and was positively associated with that of CBFA1 (r = 0.573, P < 0.001). In the rat aortic VSMCs, serum from patients with ESRD upregulated COL1A1 and CBFA1 transcription as well as type I collagen expression in a concentration-dependent manner (P < 0.05).

Conclusions: Type I collagen expression is an essential factor for radial artery elasticity dysfunction in patients with ESRD. Uremic toxins apparently induced a phenotypic transition of the rat aortic VSMCs, leading to increased type I collagen secretion and subsequent extracellular matrix remodeling.
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http://dx.doi.org/10.1097/MAJ.0000000000000408DOI Listing
April 2015

Magnesium modulates the expression levels of calcification-associated factors to inhibit calcification in a time-dependent manner.

Exp Ther Med 2015 Mar 26;9(3):1028-1034. Epub 2015 Jan 26.

Department of Nephrology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.

Vascular calcification, a common complication in patients with chronic kidney disease, involves a variety of mechanisms associated with the regulation of calcification-associated factors. Previous clinical studies have indicated that magnesium is involved in the reduction of vascular calcification; however, the mechanism underlying this process remains unknown. The aim of the present study was to investigate the effects of magnesium on β-glycerophosphate (β-GP)-induced calcification and the underlying mechanisms. Primary rat vascular smooth muscle cells (VSMCs) were exposed to 10 mM β-GP in medium with or without the addition of 3 mM magnesium or 2-aminoethoxy-diphenylborate (2-APB; an inhibitor of magnesium transport), for a 14-day period. Calcium deposition and alkaline phosphatase (ALP) activity were measured by Alizarin red staining, quantification of calcium and enzyme-linked immunosorbent assay. The expression levels of core-binding factor α-1 (Cbfα1), matrix Gla protein (MGP) and osteopontin (OPN) were determined by reverse transcription-polymerase chain reaction or western blot analysis, following incubation for 0, 3, 6, 10 and 14 days with the different media. VSMC calcification and ALP activity was reduced significantly in the high-magnesium medium compared with the calcification medium, during the 14-day incubation. The magnesium-induced changes in the VSMCs included a β-GP-induced downregulation of Cbfα1 by day 3 of incubation, an effect that was gradually enhanced over the 14-day period. By contrast, magnesium produced notable increases in MGP and OPN expression levels, with an opposite pattern to that observed in the Cbfα1 expression levels. However, the addition of 2-APB appeared to inhibit the protective effect of magnesium on the VSMCs. Therefore, magnesium was able to effectively reduce β-GP-induced calcification in rat VSMCs by regulating the expression levels of calcification-associated factors in a time-dependent manner.
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http://dx.doi.org/10.3892/etm.2015.2215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4316900PMC
March 2015

Single nucleotide polymorphisms in the D-loop region of mitochondrial DNA is associated with the kidney survival time in chronic kidney disease patients.

Ren Fail 2015 Feb 3;37(1):108-12. Epub 2014 Nov 3.

Departments of Nephrology, The Fourth Hospital of Hebei Medical University , Shijiazhuang , PR China and.

Background: The mitochondrial displacement loop (D-loop) is known to accumulate mutations and SNPs at a higher frequency than other regions of mitochondrial DNA (mtDNA). We had identified chronic kidney disease (CKD) risk-associated SNPs in the D-loop of CKD patients previously. In this study, we investigated the association of SNPs in the D-loop of mtDNA with the kidney survival of CKD.

Methods: The D-loop region of mtDNA was sequenced for 119 CKD patients from the inpatient of the Fourth Hospital of Hebei Medical University. The Kaplan-Meier method was used to identify disease outcome-associated SNPs in the D-loop of CKD patients. The Cox proportional hazards model was used to identify risk factors for the kidney survival of CKD.

Results: In the present study, we identified 20 SNPs with a frequency higher than 5% and assessed the relationship of these SNPs with kidney survival time in CKD patients, a SNP of 146 was identified by log-rank test for statistically significant prediction of the kidney survival time. In an overall multivariate analysis, allele 146 was identified as an independent predictor of kidney survival time in CKD patients. The survival time of kidney in the CKD patients with 146C was significantly shorter than that of kidney in CKD patients with 146T (relative risk, 2.336; 95% CI, 1.319-3.923; p = 0.001).

Conclusion: SNPs in the D-loop can predict the kidney survival of CKD patients. Analysis of genetic polymorphisms in the mitochondrial D-loop can help to identify CKD patient subgroup at high risk of a poor disease outcome.
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http://dx.doi.org/10.3109/0886022X.2014.976132DOI Listing
February 2015

The 9-bp deletion at position 8272 in region V of mitochondrial DNA is associated with renal cell carcinoma outcome.

Mitochondrial DNA A DNA Mapp Seq Anal 2016 05 20;27(3):1973-5. Epub 2014 Oct 20.

a Departments of Nephrology and.

Mitochondrial DNA (mtDNA) is considered a mutation hotspot in various types of tumors, and mitochondrial DNA microsatellite instability (mtMSI) is associated with various cancers. We had previously identified cancer risk-associated MSIs in the D-loop region of mtDNA in renal cell carcinoma (RCC) patients. In the present study, we further investigated the association of MSIs in the non-D-loop region of mtDNA with cancer risk and outcome of RCC. Six microsatellite loci (5892, 8272, 8280, 8281, 8289, 9777) in the non-D-loop of mtDNA were assessed. The CCCCCTCTA at position 8272 was associated with cancer outcome in an overall multivariate analysis (relative risk, 1.599; 95%CI, 1.365-1.872; p < 0.001). mtMSI at position 8272 can therefore be used as an independent prognostic marker for RCC patients.
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http://dx.doi.org/10.3109/19401736.2014.971312DOI Listing
May 2016
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