Publications by authors named "Luqing Zhao"

38 Publications

Berberine-Loaded Carboxylmethyl Chitosan Nanoparticles Ameliorate DSS-Induced Colitis and Remodel Gut Microbiota in Mice.

Front Pharmacol 2021 20;12:644387. Epub 2021 Apr 20.

State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, China.

Inflammatory bowel disease (IBD) is a refractory disorder characterized by chronic and recurrent inflammation. The progression and pathogenesis of IBD is closely related to oxidative stress and irregularly high concentrations of reactive oxygen species (ROS). A new oxidation-responsive nano prodrug was constructed from a phenylboronic esters-modified carboxylmethyl chitosan (OC-B) conjugated with berberine (BBR) that degrades selectively in response to ROS. The optimized micelles exhibited well-controlled physiochemical properties and stability in a physiological environment. OC-B-BBR micelles could effectively encapsulate the anti-inflammatory drug berberine and exhibit ideal HO-triggered release behavior as confirmed by drug loading and release studies. The anti-inflammatory effect and regulation of gut microbiota caused by it were explored in mice with colitis induced by dextran sodium sulfate (DSS). The results showed that OC-B-BBR significantly ameliorated colitis symptoms and colon damage by regulating the expression levels of IL-6 and remodeling gut microbiota. In summary, this study exhibited a novel BBR-loaded Carboxylmethyl Chitosan nano delivery system which may represent a promising approach for improving IBD treatment.
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http://dx.doi.org/10.3389/fphar.2021.644387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093821PMC
April 2021

Bu-Zhong-Yi-Qi Granule Enhances Colonic Tight Junction Integrity via TLR4/NF-B/MLCK Signaling Pathway in Ulcerative Colitis Rats.

Evid Based Complement Alternat Med 2021 9;2021:6657141. Epub 2021 Mar 9.

Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.

Background: Bu-zhong-yi-qi granule (BZYQ), a sort of Chinese herbal medicine, has exhibited therapeutic effects on ulcerative colitis (UC). However, the mechanism of BZYQ has not been fully clarified. This study was aimed at investigating the effects of BZYQ on UC rats model and at exploring its potential mechanism.

Methods: The UC rats were established by enema of trinitrobenzene sulfonic acid (TNBS). The therapeutic effects of BZYQ treatment were evaluated by disease activity index (DAI), colon macroscopic damage index (CMDI) scores, and histological observation. The mRNA levels of tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and interleukin-10 (IL-10) were measured by quantitative real time-polymerase chain reaction (qPCR). The expression of tight junction (TJ) proteins, occludin and claudin-1, in the colon was determined by Western blot and immunofluorescence. The expression of toll-like receptors 4 (TLR4), nuclear factor-kappa B (NF-B), p-NF-B, myosin light chain kinase (MLCK), MLC, and p-MLC levels in colon was determined by Western blot or qPCR.

Results: The results showed that BZYQ could attenuate DAI, CMDI, and histological inflammation. TJ proteins expression was decreased in UC rats, but treatment with BZYQ restored the expression of occludin and claudin-1. In addition, BZYQ administration ameliorated UC-associated increase in the production of TNF-, IL-1, and the expression of TLR4, NF-B, p-NF-B, MLCK, MLC, and p-MLC, while BZYQ administration increased the production of IL-10.

Conclusions: The therapeutic effect of BZYQ on UC is at least partially through regulation of the secretion of some inflammatory cytokines and improvement of TJ integrity via TLR4/NF-B/MLCK pathway.
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http://dx.doi.org/10.1155/2021/6657141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963908PMC
March 2021

Smart Responsive Quercetin-Conjugated Glycol Chitosan Prodrug Micelles for Treatment of Inflammatory Bowel Diseases.

Mol Pharm 2021 03 1;18(3):1419-1430. Epub 2021 Feb 1.

State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, P. R. China.

The incidence and progression of inflammatory bowel disease are closely related to oxidative stress caused by excessive production of reactive oxygen species (ROS). To develop an efficacious and safe nanotherapy against inflammatory bowel diseases (IBD), we designed a novel pH/ROS dual-responsive prodrug micelle as an inflammatory-targeted drug, which was comprised by active quercetin () covalently linked to biocompatible glycol chitosan () by aryl boronic ester as a responsive linker. The optimized micelles exhibited well-controlled physiochemical properties and stability in a physiological environment. Time-dependent NMR spectra traced the changes in the polymer structure in the presence of HO, confirming the release of the drug. The drug release studies indicated a low release rate (<20 wt %) in physiological conditions, but nearly complete release (>95 wt % after 72 h incubation) in a pH 5.8 medium containing 10 μM HO, exhibiting a pH/ROS dual-responsive property and sustained release behavior. Importantly, the negligible drug release in a simulated gastric environment in 1 h allowed us to perform intragastric administration, which has potential to achieve the oral delivery by mature enteric-coating modification in future. Further activities and biodistribution experiments found that the micelles tended to accumulate in intestinal inflammation sites and showed better therapeutic efficacy than the free drugs (quercetin and mesalazine) in a colitis mice model. Typical inflammatory cytokines including TNF-α, IL-6, and iNOS were significantly suppressed by micelle treatment. Our work promoted inflammatory-targeted delivery and intestinal drug accumulation for active single drug quercetin and improved the therapeutic effect of IBD. The current study also provided an alternative strategy for designing a smart responsive nanocarrier for a catechol-based drug to better achieve the target drug delivery.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c01245DOI Listing
March 2021

Targeting the signaling in Epstein-Barr virus-associated diseases: mechanism, regulation, and clinical study.

Signal Transduct Target Ther 2021 Jan 12;6(1):15. Epub 2021 Jan 12.

The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.

Epstein-Barr virus-associated diseases are important global health concerns. As a group I carcinogen, EBV accounts for 1.5% of human malignances, including both epithelial- and lymphatic-originated tumors. Moreover, EBV plays an etiological and pathogenic role in a number of non-neoplastic diseases, and is even involved in multiple autoimmune diseases (SADs). In this review, we summarize and discuss some recent exciting discoveries in EBV research area, which including DNA methylation alterations, metabolic reprogramming, the changes of mitochondria and ubiquitin-proteasome system (UPS), oxidative stress and EBV lytic reactivation, variations in non-coding RNA (ncRNA), radiochemotherapy and immunotherapy. Understanding and learning from this advancement will further confirm the far-reaching and future value of therapeutic strategies in EBV-associated diseases.
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http://dx.doi.org/10.1038/s41392-020-00376-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801793PMC
January 2021

Gastro-Protective Effects of Calycosin Against Precancerous Lesions of Gastric Carcinoma in Rats.

Drug Des Devel Ther 2020 9;14:2207-2219. Epub 2020 Jun 9.

Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.

Aim: Gastric cancer is a leading cause of cancer death worldwide. In-depth research of precancerous lesions of gastric carcinoma (PLGC) with malignant transformation potential is a key measure to prevent the development of gastric carcinoma. Recently, calycosin has been shown to have anticancer effects in vitro and in vivo. The molecular mechanism by which calycosin affects PLGC, however, has not yet been elucidated. The purpose of this study was to evaluate the effect and mechanism of calycosin in -methyl-'-nitro--nitrosoguanidine (MNNG)-induced PLGC rats.

Methods: The effects of calycosin in the gastric mucosa of rats with PLGC were evaluated using histopathology and transmission electron microscopy (TEM). For further characterization, the expression levels of integrin β1, nuclear factor kappa B (NF-κB), p-NF-κB, DARPP-32 and signal transducer and activator of transcription 3 (STAT3) were determined by Western blot assay and immunohistochemistry.

Results: Hematoxylin-eosin and high iron diamine-Alcian blue-periodic acid-Schiff (HID-AB-PAS) staining showed that intestinal metaplasia and dysplasia were significantly ameliorated in the calycosin intervention groups compared with the model group. Further, TEM results showed that calycosin intervention tempered microvascular abnormalities and cell morphology of primary and parietal cells in PLGC tissues. The results suggested that calycosin had gastro-protective effects in MNNG-induced PLGC rats. Western blot and immunohistochemistry analysis showed that the increased protein expression levels of NF-κB, p-NF-κB, DARPP-32 and STAT3 in the model group were downregulated by calycosin. The upregulation of integrin β1 expression induced by MNNG was decreased in the calycosin groups.

Conclusion: Collectively, calycosin protected against gastric mucosal injury in part via regulation of the integrin β1/NF-κB/DARPP-32 pathway and suppressed the expression of STAT3 in PLGC. The elucidation of this effect and mechanism of calycosin in PLGC provides a potential therapeutic strategy for treatment of gastric precancerous lesions.
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http://dx.doi.org/10.2147/DDDT.S247958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294567PMC
March 2021

Long non-coding RNA TUSC8 inhibits breast cancer growth and metastasis via miR-190b-5p/MYLIP axis.

Aging (Albany NY) 2020 02 9;12(3):2974-2991. Epub 2020 Feb 9.

Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.

The lncRNA tumor suppressor candidate 8 (TUSC8) plays a critical role in the development of several cancers. However, the biological functions and underlying molecular mechanisms of TUSC8 with respect to breast cancer remain largely unclear. Here, we found that TUSC8 was significantly down-regulated in breast cancer tissues and its high expression predicted better prognosis of breast cancer patients. Functionally, knock-down of TUSC8 drastically promoted the proliferation, migration and invasion of breast cancer cells and facilitated tumorigenicity and metastasis . Mechanistically, the results of luciferase reporter, RIP and RNA pull-down assays proved that TUSC8 functioned as molecular sponge for miR-190b-5p. Furthermore, we showed that TUSC8 served as a competing endogenous RNA (ceRNA) of myosin regulatory light chain interacting protein (MYLIP) through competitively binding with miR-190b-5p and suppressed breast cancer metastasis through regulating the expression of epithelial-mesenchymal transition (EMT) related markers. Clinically, the receiver operating characteristic curve (ROC) analyses revealed that the combination usage of TUSC8 and MYLIP might become novel promising diagnostic biomarkers for breast cancer. Taken together, these results suggested that TUSC8 inhibited breast cancer growth and metastasis via miR-190b-5p/MYLIP axis, providing us new insights into developing potential therapeutic targets for breast cancer patients.
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http://dx.doi.org/10.18632/aging.102791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041739PMC
February 2020

Diagnostic performance of magnetic resonance imaging for colorectal liver metastasis: A systematic review and meta-analysis.

Sci Rep 2020 02 6;10(1):1969. Epub 2020 Feb 6.

Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

The prognosis of colorectal cancer (CRC) is largely dependent on the early detection of hepatic metastases. With the advantages of nonradioactivity and the availability of multiple scanning sequences, the efficacy of magnetic resonance imaging (MRI) in the detection of colorectal liver metastases (CRLM) is not yet clear. We performed this meta-analysis to address this issue. PubMed, Embase, and the Cochrane Library were searched for studies reporting diagnostic performance of MRI for CRLM. Descriptive and quantitative data were extracted. The study quality was evaluated for the identified studies and a random effects model was used to determine the integrated diagnosis estimation. Meta-regression and subgroup analyses were implemented to investigate the potential contributors to heterogeneity. As a result, seventeen studies were included for analysis (from the year 1996 to 2018), comprising 1121 patients with a total of 3279 liver lesions. The pooled sensitivity, specificity, and diagnostic odds ratio were 0.90 (95% confidence intervals (CI): 0.81-0.95), 0.88 (0.80-0.92), and 62.19 (23.71-163.13), respectively. The overall weighted area under the curve was 0.94 (0.92-0.96). Using two or more imaging planes and a quantitative/semiquantitative interpretation method showed higher diagnostic performance, although only the latter demonstrated statistical significance (P < 0.05). Advanced scanning sequences with DWI and liver-specific contrast media tended to increase the sensitivity for CRLM detection. We therefore concluded that contemporary MRI has high sensitivity and specificity for screening CRLM, especially for those with advanced scanning sequences. Using two or more imaging planes and adopting a quantitative/semiquantitative imaging interpretation may further improve diagnosis. However, the MRI results should be interpreted with caution because of substantial heterogeneity among studies.
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http://dx.doi.org/10.1038/s41598-020-58855-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005325PMC
February 2020

Modified Liu-Jun-Zi decoction alleviates visceral hypersensitivity in functional dyspepsia by regulating EC cell-5HT3r signaling in duodenum.

J Ethnopharmacol 2020 Mar 10;250:112468. Epub 2019 Dec 10.

Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China. Electronic address:

Ethnopharmacological Relevance: Modified Liu-Jun-Zi (MLJZ) is derived from one of the most famous traditional Chinese prescription Liu-Jun-Zi. It exhibits therapeutic effects in functional dyspepsia (FD), but the underlying mechanisms remain not well understood. Enterochromaffin (EC) cells contribute to the pathogeneses of visceral hypersensitivity in functional gastrointestinal disorders. But whether and how EC cells in duodenum participate in the mechanism of FD remain unsettled.

Aim Of The Study: To detect the crucial factors related to EC cells, and to evaluate the therapeutic effect of MLJZ and to determine whether MLJZ relieves visceral hypersensitivity in FD by regulating EC cell-5-hydroxytryptamine 3 receptor (5HT3r) signaling.

Materials And Methods: FD rats were established by iodoacetamide gavage combined with tail clamping method. The verification of FD model and the evaluation of the therapeutic effect of MLJZ was taken place by hematoxylin-eosin (HE) staining and visceral sensitivity measurement. The expression of EC cells and 5-hydroxytryptamine (5HT) in duodenum was detected by Immunohistochemistry (IHC) staining and enzyme-linked immunosorbent assay (ELISA). IHC staining and quantitative polymerase chain reaction (qPCR) were applied to measure the expression of tryptophan hydroxylase-1 (TPH1), paired box gene 4 (PAX4), transient receptor potential A1 (TRPA1), transient receptor potential C4 (TRPC4) and 5HT3r. Duodenum sections were stained by double immunofluorescence (IF) to study the synthesis of 5HT in EC cells.

Results: The gastric sensitivity increased in FD rats while MLJZ decoction significantly attenuated visceral hypersensitivity. The duodenum of FD rats displayed increased expressions of EC cells, 5HT, TPH1, PAX4 and 5HT3r. And the overexpression was reduced in response to MLJZ decoction treatment.

Conclusions: EC cell-5HT3r signaling pathway is abnormally active in FD with visceral hypersensitivity. And MLJZ decoction can alleviates visceral hypersensitivity in FD by regulating EC cell-5HT3r signaling in duodenum.
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http://dx.doi.org/10.1016/j.jep.2019.112468DOI Listing
March 2020

Reactive oxygen species-responsive amino acid-based polymeric nanovehicles for tumor-selective anticancer drug delivery.

Mater Sci Eng C Mater Biol Appl 2020 Jan 3;106:110159. Epub 2019 Sep 3.

State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, PR China. Electronic address:

Stimuli-triggered drug delivery systems have been recognized as a crucial strategy to achieve on-demand drug release at the tumor for improving therapeutic efficacy. In this work, novel biocompatible and biodegradable reactive oxygen species (ROS)-responsive amino acid- based polymeric micelles were developed for tumor-specific drug release triggered by high ROS levels in cancer cells, which were composed of amphiphilic poly(aspartic acid) (PASP) derivatives (PASP-BSer) with phenylborate serine (BSer) side groups as the ROS-responsive unit. A series of PASP-BSer conjugates with different degree of substitution (DS) were synthesized, and their self-assembly and HO-responsive behaviors were investigated to optimize the structure of PASP-BSer. In vitro drug loading and release studies confirmed that the optimized PASP-BSer micelles could effectively encapsulate the model anticancer drug doxorubicin (Dox) and exhibit desirable HO-triggered release behaviors. More importantly, Dox-loaded PASP-BSer micelles showed high selective cytotoxicity against A549 cancer cells than L929 normal cells. Accordingly, PASP-BSer micelles have significant potential as on-demand drug carriers for anticancer therapy.
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http://dx.doi.org/10.1016/j.msec.2019.110159DOI Listing
January 2020

Sini San ameliorates duodenal mucosal barrier injury and low‑grade inflammation via the CRF pathway in a rat model of functional dyspepsia.

Int J Mol Med 2020 Jan 4;45(1):53-60. Epub 2019 Nov 4.

Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, P.R. China.

The gut‑brain interaction is associated with impaired duodenal mucosal integrity and low‑grade inflammation, which have been proven to be important pathological mechanisms of functional dyspepsia (FD). Sini San (SNS) is a classical Chinese medicine used to treat FD, but its underlying mechanisms are poorly understood. The aim of the present study was to evaluate the effects of SNS on duodenal mucosal barrier injury and low‑grade inflammation with FD, and to assess its potential molecular mechanisms on the brain‑gut axis. FD rats were established using the iodoacetamide and tail‑squeezed methods. The expression of corticotropin‑releasing factor (CRF), CRF receptor 1 (CRF‑R1) and CRF‑R2, were determined by western blot analysis and/or immunohistochemistry (IHC). In addition, mast cell (MC) migration was assessed by IHC with an anti‑tryptase antibody, and histamine concentration was quantified using ELISA. The mRNA expression levels of tryptase and protease‑activated receptor 2 (PAR‑2) were quantified using reverse transcription‑quantitative PCR, and the protein expression levels of zona occludens protein 1 (ZO‑1), junctional adhesion molecule 1 (JAM‑1), β‑catenin and E‑cadherin were determined via western blot analysis. It was demonstrated that the expression level of CRF was downregulated in the central nervous system and duodenum following SNS treatment, and that SNS modulated the expression of both CRF‑R1 and CRF‑R2. In addition, SNS suppressed MC infiltration and the activity of the tryptase/PAR‑2 pathway in the duodenum. Furthermore, treatment with SNS restored the normal expression levels of ZO‑1, JAM‑1 and β‑catenin in FD rats. These findings suggested that the therapeutic effects of SNS on FD were achieved by restoring mucosal barrier integrity and suppressing low‑grade inflammation in the duodenum, which was at least partially mediated via the CRF signaling pathway.
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http://dx.doi.org/10.3892/ijmm.2019.4394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889936PMC
January 2020

[An artificial neural network model for glioma grading using image information].

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2018 Dec;43(12):1315-1322

Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008; Postdoctoral Research Workstation of Clinical Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.

Objective: To explore the feasibility and efficacy of artificial neural network for differentiating high-grade glioma and low-grade glioma using image information.
 Methods: A total of 130 glioma patients with confirmed pathological diagnosis were selected retrospectively from 2012 to 2017. Forty one imaging features were extracted from each subjects based on 2-dimension magnetic resonance T1 weighted imaging with contrast-enhancement. An artificial neural network model was created and optimized according to the performance of feature selection. The training dataset was randomly selected half of the whole dataset, and the other half dataset was used to verify the performance of the neural network for glioma grading. The training-verification process was repeated for 100 times and the performance was averaged.
 Results: A total of 5 imaging features were selected as the ultimate input features for the neural network. The mean accuracy of the neural network for glioma grading was 90.32%, with a mean sensitivity at 87.86% and a mean specificity at 92.49%. The area under the curve of receiver operating characteristic curve was 0.9486.
 Conclusion: As a technique of artificial intelligence, neural network can reach a relatively high accuracy for the grading of glioma and provide a non-invasive and promising computer-aided diagnostic process for the pre-operative grading of glioma.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2018.12.006DOI Listing
December 2018

Design and Evaluation of Potent EGFR Inhibitors through the Incorporation of Macrocyclic Polyamine Moieties into the 4-Anilinoquinazoline Scaffold.

J Med Chem 2018 12 14;61(24):11372-11383. Epub 2018 Dec 14.

State Key Laboratory of Chemical Resource Engineering , Beijing University of Chemical Technology , Beijing 100029 , P. R. China.

Adenosine triphosphate (ATP)-competitive inhibitors of the epidermal growth factor receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, some marketed drugs affect a transient beneficial response in EGFR mutant NSCLC patients. We reported a series of potential EGFR inhibitors through incorporation of macrocyclic polyamine into 4-anilinoquinazoline scaffold. It is expected that anilinoquinazoline part effectively bind to EGFR domain, while ATP molecules are captured by a macrocyclic polyamine moiety. In vitro experiments exhibited that most of tested compounds suppressed tumor cell proliferation more strongly than Gefitinib and Lapatinib (dual inhibitor of EGFR/HER2) as controls. In kinase assays, the compound 1f showed excellent dual inhibition activity toward EGFR (IC = 1.4 nM) and HER2 (IC = 2.1 nM). In vivo pharmacology evaluation of 1f showed significant antitumor activity (TGI = 44.2%) in A549 xenografts mice. The current work provided a feasible solution to optimize anilinoquinazoline-based inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01612DOI Listing
December 2018

Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα-dependent manner.

FASEB J 2019 03 13;33(3):3549-3561. Epub 2018 Nov 13.

Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

Excessive iron increases the incidence of diabetes and worsens diabetic complications. Reciprocally, diabetes induces iron loading, partially attributable to elevated intestinal iron export according to a recent report. Herein, we show that iron uptake and the mRNA expression of iron importer divalent metal transporter 1 (DMT1) were significantly increased in the duodenum of streptozotocin-induced diabetic mice. Immunofluorescence staining of human intestinal biopsies revealed increased brush border membrane (BBM) and decreased cytoplasmic DMT1 expression in patients with diabetes, suggesting translocation of DMT1. This pattern of DMT1 regulation was corroborated by immunoblotting results in diabetic mice showing that BBM DMT1 expression was increased by 210%, in contrast to a 60% increase in total DMT1. PKC mediates many diabetic complications, and PKCα activity was increased in diabetic mouse intestine. Intriguingly, diabetic mice with PKCα deficiency did not show increases in iron uptake and BBM DMT1 expression. High-glucose treatment increased plasma membrane DMT1 expression via the activation of PKCα in cultured IECs. Inhibition of PKCα potentiated the ubiquitination and degradation of DMT1 protein. We further showed that high glucose suppressed membrane DMT1 internalization. These findings demonstrate that PKCα promotes microvillus membrane DMT1 expression and intestinal iron uptake, contributing to diabetic iron loading.-Zhao, L., Bartnikas, T., Chu, X., Klein, J., Yun, C., Srinivasan, S., He, P. Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα-dependent manner.
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http://dx.doi.org/10.1096/fj.201801855RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404579PMC
March 2019

The functional pathway analysis and clinical significance of miR-20a and its related lncRNAs in breast cancer.

Cell Signal 2018 11 6;51:152-165. Epub 2018 Aug 6.

Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address:

Background: miR-20a is a critical molecule in various biological processes and cancer progression procedures. However, its relationships with lncRNAs and their functional pathway analysis in breast tumorigenesis are less intensively studied.

Methods: The expression data from TCGA database and multiple bioinformatics resources were used to check the expression levels, survival curves, interactions and functional illustrations of miR-20a and its related lncRNAs (XIST, H19 and MALAT1) in breast cancer patients. The luciferase reporter assays and Pearson's correlation analyses were utilized to verify the direct regulatory relationship between miR-20a and three lncRNAs (XIST, H19 and MALAT1). In vitro cell proliferation, migration and invasion assays, were performed to check the biological effects of miR-20a and XIST in different breast cancer cell lines. The receiver operating characteristic curve (ROC) analyses were done for evaluating diagnostic values of serum miR-20a and XIST in breast cancer patients.

Results: The miR-20a expression was significantly up-regulated in both breast cancer samples and serum samples, and correlated with poor survival rate in breast cancer patients. LncRNAs (XIST, H19 and MALAT1) directly bound to hsa-miR-20a and were negatively correlated with hsa-miR-20a expression in breast cancer patient samples. For functional illustrations and downstream signaling pathways analysis, XIST, H19 and MALAT1 mainly shared their regulatory functions in cell motility and interleukin signaling in breast cancer progression. Additionally, over-expression of miR-20a and inhibition of XIST promoted breast cancer cell growth, migration and invasion in vitro, and serum miR-20a and XIST served as potential diagnostic biomarkers for breast cancer with the area under ROC curve (AUC) of 0.87 (95% CI = 0.78 to 0.97), and 0.78 (95% CI = 0.67 to 0.89) respectively.

Conclusions: Taken together, these findings provide us novel insights and avenues for utilizing miR-20a and its related lncRNAs as potential diagnostic biomarkers and promising therapeutic targets for breast cancer treatment.
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http://dx.doi.org/10.1016/j.cellsig.2018.08.004DOI Listing
November 2018

Effects of Fengliao-Changweikang in Diarrhea-predominant Irritable Bowel Syndrome Rats and Its Mechanism Involving Colonic Motility.

J Neurogastroenterol Motil 2018 Jul;24(3):479-489

Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China.

Background/aims: This study was designed to investigate the effect of Fengliao-Changweikang (FLCWK) in diarrhea-predominant irritable bowel syndrome (IBS-D) rats and explore its underlying mechanisms.

Methods: IBS-D model rats were induced by neonatal maternal separation (NMS) combined with restraint stress (RS). In in vivo experiments, the model rats were randomly divided into 5 groups: NMS + RS, FLCWK (low dose, middle dose, and high dose), and pinaverium bromide. The normal control (no handling) rats were classified as the NH group. The therapeutic effect of FLCWK was evaluated by fecal characteristics, electromyographic response and abdominal withdrawal reflex scores. In in vitro experiments, the model rats were randomly divided into 2 groups: NMS + RS, FLCWK (middle dose), and no handling rats were used as the NH group. The differences in basic tension and ACh-induced tension of isolated colonic longitudinal smooth muscle strips (CLSMs) among the 3 groups were observed. In addition, different inhibitors (nifedipine, TMB-8, L-NAME, methylene blue, and 4-AP) were pretreated to explore the underlying mechanisms.

Results: In in vivo experiments, fecal characteristics, electromyographic response, and abdominal withdrawal reflex scores significantly improved in the FLCWK group, compared with the NMS + RS group. In in vitro experiments, the basic tension and ACh-induced tension of CLSMs in IBS-D rats were significantly inhibited by FLCWK. After pre-treatment with different inhibitors, the ACh-induced tension of CLSMs in each group showed no significant difference.

Conclusions: FLCWK manifested curative effect in IBS-D rats by inhibiting colonic contraction. The underlying mechanisms may be related to regulatory pathway of nitric oxide/cGMP/Ca²⁺ and specific potassium channels.
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http://dx.doi.org/10.5056/jnm17093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034674PMC
July 2018

Mechanistic Understanding of Herbal Therapy in Inflammatory Bowel Disease.

Curr Pharm Des 2017 ;23(34):5173-5179

Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA 30322, United States.

The incidence and prevalence of inflammatory bowel diseases (IBD), which comprise ulcerative colitis and Crohn's disease, are increasing dramatically worldwide. Immunomodulators and biological agents can help but cause severe side effects in long-term use. As such, complementary and alternative medicine, in particular herbal remedy, is becoming more and more popular in the treatment of IBD patients. Many natural compounds have been used in clinical trials and some have been proven promising in IBD treatment. To achieve a better understanding of herbal therapy, researchers focus on understanding the underlying mechanisms by using experimental rodent models. The mechanism of the pathogenesis of IBD is complex involving both environmental and genetic factors. IBD is considered as a consequence of impaired epithelial barrier function, gut microbiota dysbiosis, and aberrant immune response. Studies have demonstrated that herbal medicine can improve epithelial proliferation and barrier integrity, restore microbiota homeostasis, and suppress hyper-immune reaction. This review is to summarize current understanding of the molecular basis of herbal treatment of IBD at the levels of epithelial, microbial, and immune regulation.
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http://dx.doi.org/10.2174/1381612823666171010124414DOI Listing
April 2019

miR-19b promotes breast cancer metastasis through targeting MYLIP and its related cell adhesion molecules.

Oncotarget 2017 Sep 17;8(38):64330-64343. Epub 2017 Jul 17.

Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

miR-19b is a key molecule for cancer development, however its crucial roles in breast cancer metastasis are rarely studied right now. In this study, using several bioinformatics databases to predict the downstream targets for miR-19b, we verified that a novel target gene, myosin regulatory light chain interacting protein (MYLIP), could be directly down-regulated by miR-19b through its 3'-UTR region. MYLIP belongs to the cytoskeletal protein clusters and is involved in the regulation of cell movement and migration. We further explored that miR-19b was highly expressed and negatively correlated with MYLIP expression in breast cancer patient samples from the TCGA database. And the over-expression of miR-19b or inhibition of MYLIP facilitated the migration and metastasis of breast cancer cells, through conducting the wound healing assay and transwell invasion assay. Additionally, miR-19b could obviously promote breast tumor growth in mouse models and affect the expressions of cell adhesion molecules (including E-Cadherin, ICAM-1 and Integrin β1) by down-regulating E-Cadherin expression and up-regulating ICAM-1 and Integrin β1 expressions and . Meanwhile, miR-19b effectively activated the Integrin β downstream signaling pathways (such as the Ras-MAPK pathway and the PI3K-AKT pathway) and elevated the expression levels of essential genes in these two pathways. Taken together, these findings comprehensively illustrate the regulatory mechanisms ofmiR-19b in breast cancer metastasis, and provide us new insights for exploring MYLIP and its related cell adhesion molecules as promising therapeutic targets to interfere breast cancer development.
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http://dx.doi.org/10.18632/oncotarget.19278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610006PMC
September 2017

Sini-san improves duodenal tight junction integrity in a rat model of functional dyspepsia.

BMC Complement Altern Med 2017 Aug 30;17(1):432. Epub 2017 Aug 30.

Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China.

Background: Recent reports have demonstrated that impaired barrier function and local microinflammation in the duodenal mucosa contribute to the pathogeneses of functional dyspepsia (FD). Thus, restoring normal barrier integrity becomes a potential therapeutic strategy in the treatment of FD. Sini-San (SNS) is a traditional Chinese prescription that exhibits therapeutic effects in FD, but the underlying mechanisms remain not well understood.

Methods: FD rats were established by tail clamping method and the therapeutic effect of SNS was evaluated by measuring the visceral sensitivity and gastric compliance. Transepithelial electrical resistance (TEER) that reveals epithelial barrier integrity was measured by Ussing chamber. The expression of tight junction (TJ) proteins, occludin and claudin-1, in the duodenum was determined by Western blot and immunofluorescence. The amount of tumor necrosis factor alpha (TNF-α) and interferon gamma (INF-γ) in duodenal mucosa was detected by enzyme-linked immune sorbent assay (ELISA). The mRNA level of transient receptor potential vanilloid type 1 (TRPV1) was measured by quantitative real time-polymerase chain reaction (qPCR).

Results: SNS could improve gastric compliance and attenuate visceral hypersensitivity (VH) in FD rats. TEER was decreased in FD rats, but treatment with SNS restored normal level of TEER and the expression of occludin and claudin-1 in FD rats. In addition, SNS administration ameliorated FD-associated increase in the production of TNF-α, IFN-γ and the expression of TRPV1.

Conclusions: The therapeutic effect of SNS on FD is at least partially through improvement of TJ integrity and attenuation of FD-associated low-grade inflammation in the duodenum. Our findings highlight the molecular basis of SNS-based treatment of FD in human patients.
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http://dx.doi.org/10.1186/s12906-017-1938-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577804PMC
August 2017

DDX3X promotes the biogenesis of a subset of miRNAs and the potential roles they played in cancer development.

Sci Rep 2016 09 2;6:32739. Epub 2016 Sep 2.

School of Computer Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510640, China.

DDX3X, located on the X-chromosome, belongs to the DEAD-box RNA helicase family and acts as a key RNA-binding protein to exert its regulatory functions in various biological processes. In this paper, knock-down the expression of DDX3X can affect a subset of miRNA expression levels, especially for miR-1, miR-141, miR-145, miR-19b, miR-20a and miR-34a. Through adopting the immunoprecipitation (IP), RNA immunoprecipitation (RIP), dual luciferase reporter assays, we illustrate that DDX3X could interact with Drosha/DGCR8 complex, elevate the processing activity of Drosha/DGCR8 complex on pri-miRNAs, and increase mature miRNA expression levels. For the studies of potential roles and biological functions of DDX3X-dependent miRNAs and their downstream target genes in multiple cancers, we use the primary data from The Cancer Genome Atlas (TCGA), Ingenuity Pathway Analysis (IPA) and several miRNA target prediction databases, to systematically analyze the expression levels of DDX3X-dependent miRNAs in almost 14 kinds of cancers versus normal tissues, and the essential biological functions for their putative downstream target genes. All these findings will provide us novel insights and directions for thoroughly exploring the regulatory mechanisms of miRNA biogenesis, and shed light on effectively searching the clinical significances and biological roles of DDX3X-dependent miRNAs and their target genes in cancer development.
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http://dx.doi.org/10.1038/srep32739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009351PMC
September 2016

Effect of Aurantii Fructus Immaturus Flavonoid on the Contraction of Isolated Gastric Smooth Muscle Strips in Rats.

Evid Based Complement Alternat Med 2016 27;2016:5616905. Epub 2016 Jun 27.

Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing 100010, China.

This study was designed to investigate the effect of Aurantii fructus immaturus flavonoid (AFIF) on the contraction of isolated gastric smooth muscle in rats and explore its underlying mechanisms. Isolated antral longitudinal smooth muscle strip (ALSMS) and pyloric circular smooth muscle strip (PCSMS) of rats were suspended in tissue chambers. The responses of ALSMS and PCSMS to administration of AFIF were observed. Cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG) levels of PCSMS were measured by ELISA kits. In this study, AFIF showed no significant effect on ALSMS contraction, but it dose-dependently reduced the mean contraction amplitude of PCSMS. When the concentration of AFIF reached 3000 μg/mL, 6000 μg/mL, and 10000 μg/mL, its inhibitory effect on PCSMS contraction was significant. This effect of AFIF was weakened in Ca(2+)-rich environment. And Nω-nitro-L-arginine methyl (L-NAME), the inhibitor of nitric oxide synthase (NOS), significantly inhibited AFIF's action in comparison with control (P < 0.05). After incubation with AFIF for 30 min, levels of cGMP and PKG in PCSMS were significantly increased compared with control (P < 0.05). Our results suggest that AFIF has a dose-dependent diastolic effect on PCSMS in rats, which may be related to the regulatory pathway of NO/cGMP/PKG/Ca(2+).
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http://dx.doi.org/10.1155/2016/5616905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939329PMC
July 2016

Effect of TongXie-YaoFang on Cl(-) and HCO3 (-) Transport in Diarrhea-Predominant Irritable Bowel Syndrome Rats.

Evid Based Complement Alternat Med 2016 14;2016:7954982. Epub 2016 Jun 14.

Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing 100010, China.

TongXie-YaoFang (TXYF) can effectively alleviate the symptoms of diarrhea-predominant irritable bowel syndrome (D-IBS) patients. However, the curative mechanism has not been fully clarified. The study was designed to investigate the effect of TXYF on the colonic ion transport induced by serotonin (5-HT) in D-IBS rats. A method of multiple stress (neonatal maternal separation (NMS) combined with restraint stress (RS)) was used to induce the D-IBS model. The model rats were randomly divided into two groups: NMS + RS group and TXYF-formula group, and the normal control (no handling) rats were classified as NH group. In the NMS + RS group, the change of short-circuit current (ΔI sc) induced by 5-HT was lower than that in the NH and TXYF-formula groups. After removing of the extracellular Cl(-) or HCO3 (-) or basolateral Na(+) or blocking the cystic fibrosis transmembrane conductance regulator (CFTR), Na(+)-K(+)-2Cl(-) cotransporter (NKCC), Na(+)-HCO3 (-) cotransporter, Cl(-)/HCO3 (-) exchanger, K(+) channel, or Na(+)/K(+)-ATPase, respectively, there was no difference in 5-HT-induced ΔI sc among the three groups. These data suggest that TXYF can regulate 5-HT-induced Cl(-) and HCO3 (-) secretion, possibly mediated by the combined action of CFTR, NKCC, Na(+)-HCO3 (-) cotransporter, Cl(-)/HCO3 (-) exchanger, K(+) channel, and Na(+)/K(+)-ATPase.
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http://dx.doi.org/10.1155/2016/7954982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923577PMC
July 2016

The NHERF1 PDZ1 domain and IRBIT interact and mediate the activation of Na+/H+ exchanger 3 by ANG II.

Am J Physiol Renal Physiol 2016 08 8;311(2):F343-51. Epub 2016 Jun 8.

Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Atlanta Veterans Affairs Medical Center, Decatur, Georgia; and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.

Na(+)/H(+) exchanger (NHE)3, a major Na(+) transporter in the luminal membrane of the proximal tubule, is subject to ANG II regulation in renal Na(+)/fluid absorption and blood pressure control. We have previously shown that inositol 1,4,5-trisphosphate receptor-binding protein released with inositol 1,4,5-trisphosphate (IRBIT) mediates ANG II-induced exocytosis of NHE3 in cultured proximal tubule epithelial cells. In searching for scaffold protein(s) that coordinates with IRBIT in NHE3 trafficking, we found that NHE regulatory factor (NHERF)1, NHE3, and IRBIT proteins were coexpressed in the same macrocomplexes and that loss of ANG II type 1 receptors decreased their expression in the renal brush-border membrane. We found that NHERF1 was required for ANG II-mediated forward trafficking and activation of NHE3 in cultured cells. ANG II induced a concomitant increase of NHERF1 interactions with NHE3 and IRBIT, which were abolished when the NHERF1 PDZ1 domain was removed. Overexpression of a yellow fluorescent protein-NHERF1 construct that lacks PDZ1, but not PDZ2, failed to exaggerate the ANG II-dependent increase of NHE3 expression in the apical membrane. Moreover, exogenous expression of PDZ1 exerted a dominant negative effect on NHE3 activation by ANG II. We further demonstrated that IRBIT was indispensable for the ANG II-provoked increase in NHERF1-NHE3 interactions and that phosphorylation of IRBIT at Ser(68) was necessary for the assembly of the NHEF1-IRBIT-NHE3 complex. Taken together, our findings suggest that NHERF1 mediates ANG II-induced activation of renal NHE3, which requires coordination between IRBIT and the NHERF1 PDZ1 domain in binding and transporting NHE3.
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http://dx.doi.org/10.1152/ajprenal.00247.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189742PMC
August 2016

EBV-LMP1 suppresses the DNA damage response through DNA-PK/AMPK signaling to promote radioresistance in nasopharyngeal carcinoma.

Cancer Lett 2016 09 30;380(1):191-200. Epub 2016 May 30.

Key Laboratory of Carcinogenesis of Chinese Ministry of Public Health, Xiangya School of Medicine, Central South University, Changsha, China; Key Laboratory of Chinese Ministry of Education, Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China; Molecular Imaging Center, Central South University, Changsha, China. Electronic address:

We conducted this research to explore the role of latent membrane protein 1 (LMP1) encoded by the Epstein-Barr virus (EBV) in modulating the DNA damage response (DDR) and its regulatory mechanisms in radioresistance. Our results revealed that LMP1 repressed the repair of DNA double strand breaks (DSBs) by inhibiting DNA-dependent protein kinase (DNA-PK) phosphorylation and activity. Moreover, LMP1 reduced the phosphorylation of AMP-activated protein kinase (AMPK) and changed its subcellular location after irradiation, which appeared to occur through a disruption of the physical interaction between AMPK and DNA-PK. The decrease in AMPK activity was associated with LMP1-mediated glycolysis and resistance to apoptosis induced by irradiation. The reactivation of AMPK significantly promoted radiosensitivity both in vivo and in vitro. The AMPKα (Thr172) reduction was associated with a poorer clinical outcome of radiation therapy in NPC patients. Our data revealed a new mechanism of LMP1-mediated radioresistance and provided a mechanistic rationale in support of the use of AMPK activators for facilitating NPC radiotherapy.
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http://dx.doi.org/10.1016/j.canlet.2016.05.032DOI Listing
September 2016

Multifunctional DDX3: dual roles in various cancer development and its related signaling pathways.

Am J Cancer Res 2016 15;6(2):387-402. Epub 2016 Jan 15.

Department of Dermatology, Xiangya Hospital, Central South University Changsha 410008, Hunan, China.

DEAD-box RNA helicase 3 (DDX3) is a highly conserved family member of DEAD-box protein, which is a cluster of ATP-dependent and the largest family of RNA helicase. DEAD-box family is characterized by the regulation of ATPase and helicase activities, the modulation of RNA metabolism, and the actors of RNA binding proteins or molecular chaperones to interact with other proteins or RNA. For DDX3, it exerts its multifaceted roles in viral manipulation, stress response, hypoxia, radiation response and apoptosis, and is closely related to cancer development and progression. DDX3 has dual roles in different cancer types and can act as either an oncogene or tumor suppressor gene during cancer progression. In the present review, we mainly provide an overview of current knowledge on dual roles of DDX3 in various types of cancer, including breast cancer, lung cancer, colorectal cancer, hepatocellular carcinoma, oral squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme and gallbladder carcinoma, and illustrate the regulatory mechanisms for leading these two controversial biological effects. Furthermore, we summarize the essential signaling pathways that DDX3 participated, especially the Wnt/β-catenin signaling and EMT related signaling (TGF-β, Notch, Hedgehog pathways), which are crucial to DDX3 mediated cancer metastasis process. Thoroughly exploring the dual roles of DDX3 in cancer development and the essential signaling pathways it involved, it will help us open new perspectives to develop novel promising targets to elevate therapeutic effects and facilitate the "Personalized medicine" or "Precision medicine" to come into clinic.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859668PMC
May 2016

Role of multifaceted regulators in cancer glucose metabolism and their clinical significance.

Oncotarget 2016 May;7(21):31572-85

Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Aberrant glucose metabolism, "aerobic glycolysis" or "Warburg effect", is a hallmark of human cancers. There is a cluster of "multifaceted regulators", which plays a pivotal role in the regulation of glucose metabolism. They can not only modulate the activities of specific enzymes, but also act as transcriptional activators to regulate the expression of metabolism related genes. Additionally, they can crosstalk with other key factors involved in glucose metabolism and work together to initiate multiple oncogenic processes. These "multifaceted regulators", especially p53, HIF-1, TIGAR and microRNA, will be focused in this review. And we will comprehensively illustrate their regulatory effects on cancer glucose metabolism, and further elaborate on their clinical significance. In-depth elucidation the role of "multifaceted regulators" in cancer glucose metabolism will provide us novel insights in cancer research field and offer promising therapeutic targets for anti-cancer therapies.
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http://dx.doi.org/10.18632/oncotarget.7765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058779PMC
May 2016

Deletion of Na+/H+ exchanger regulatory factor 2 represses colon cancer progress by suppression of Stat3 and CD24.

Am J Physiol Gastrointest Liver Physiol 2016 04 11;310(8):G586-98. Epub 2016 Feb 11.

Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Winship Cancer Institute, Emory University, Atlanta, Georgia; and

The Na(+)/H(+) exchanger regulatory factor (NHERF) family of proteins is scaffolds that orchestrate interaction of receptors and cellular proteins. Previous studies have shown that NHERF1 functions as a tumor suppressor. The goal of this study is to determine whether the loss of NHERF2 alters colorectal cancer (CRC) progress. We found that NHERF2 expression is elevated in advanced-stage CRC. Knockdown of NHERF2 decreased cancer cell proliferation in vitro and in a mouse xenograft tumor model. In addition, deletion of NHERF2 in Apc(Min/+) mice resulted in decreased tumor growth in Apc(Min/+) mice and increased lifespan. Blocking NHERF2 interaction with a small peptide designed to bind the second PDZ domain of NHERF2 attenuated cancer cell proliferation. Although NHERF2 is known to facilitate the effects of lysophosphatidic acid receptor 2 (LPA2), transcriptome analysis of xenograft tumors revealed that NHERF2-dependent genes largely differ from LPA2-regulated genes. Activation of β-catenin and ERK1/2 was mitigated in Apc(Min/+);Nherf2(-/-) adenomas. Moreover, Stat3 phosphorylation and CD24 expression levels were suppressed in Apc(Min/+);Nherf2(-/-) adenomas. Consistently, NHERF2 knockdown attenuated Stat3 activation and CD24 expression in colon cancer cells. Interestingly, CD24 was important in the maintenance of Stat3 phosphorylation, whereas NHERF2-dependent increase in CD24 expression was blocked by inhibition of Stat3, suggesting that NHERF2 regulates Stat3 phosphorylation through a positive feedback mechanism between Stat3 and CD24. In summary, this study identifies NHERF2 as a novel oncogenic protein and a potential target for cancer treatment. NHERF2 potentiates the oncogenic effects in part by regulation of Stat3 and CD24.
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http://dx.doi.org/10.1152/ajpgi.00419.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836134PMC
April 2016

Comparing Cerebralcare Granule and aspirin for neurological dysfunction in acute stroke in real-life practice.

Psychogeriatrics 2017 Jan 12;17(1):3-8. Epub 2016 Jan 12.

Department of Neurology, People's Hospital of Shanxi Province, Shanxi Medical University, Taiyuan, China.

Background: Cerebralcare Granule (CG) is a polyherbal Chinese medicine that has been shown to have neuroprotective effects in experimental models of stroke. We compared the efficacy and safety of CG with aspirin in patients with acute stroke.

Methods: For this open-label, controlled trial, we recruited patients with angiographically confirmed strokes and US National Institutes of Health Stroke Scale (NIHSS) scores of 4-22 within 2 weeks of symptom onset; recruitment was performed at 55 sites in China. Patients received CG or aspirin. The primary efficacy end-point was neurological function. Analyses were done by intention to treat. Patients were measured for NIHSS, Montreal Cognitive Assessment, and Mini-Mental State Examination scores and Barthel index at baseline and at 4, 8, and 12 weeks after treatment.

Results: Between January 2013 and January 2014, we treated 1963 patients with CG and 1288 patients with aspirin. Baseline NIHSS, Mini-Mental State Examination, and Montreal Cognitive Assessment scores were comparable between the two groups. Patients in the CG group had a greater improvement than the aspirin group in terms of NIHSS (P < 0.01) and Barthel index at 4, 8, and 12 weeks. At 12 weeks, patients in the CG group had a greater improvement than the aspirin group in terms of Mini-Mental State Examination (P < 0.01) and Montreal Cognitive Assessment (P < 0.05). Adverse reactions were similar between the two groups.

Conclusions: This large-scale, controlled trial indicated that CG may be a useful treatment in the management of post-stroke patients.
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http://dx.doi.org/10.1111/psyg.12180DOI Listing
January 2017

Restoration of Na+/H+ exchanger NHE3-containing macrocomplexes ameliorates diabetes-associated fluid loss.

J Clin Invest 2015 Sep 10;125(9):3519-31. Epub 2015 Aug 10.

Diarrhea is one of the troublesome complications of diabetes, and the underlying causes of this problem are complex. Here, we investigated whether altered electrolyte transport contributes to diabetic diarrhea. We found that the expression of Na+/H+ exchanger NHE3 and several scaffold proteins, including NHE3 regulatory factors (NHERFs), inositol trisphosphate (IP₃) receptor-binding protein released with IP₃ (IRBIT), and ezrin, was decreased in the intestinal brush border membrane (BBM) of mice with streptozotocin-induced diabetes. Treatment of diabetic mice with insulin restored intestinal NHE3 activity and fluid absorption. Molecular analysis revealed that NHE3, NHERF1, IRBIT, and ezrin form macrocomplexes, which are perturbed under diabetic conditions, and insulin administration reconstituted these macrocomplexes and restored NHE3 expression in the BBM. Silencing of NHERF1 or IRBIT prevented NHE3 trafficking to the BBM and insulin-dependent NHE3 activation. IRBIT facilitated the interaction of NHE3 with NHERF1 via protein kinase D2-dependent phosphorylation. Insulin stimulated ezrin phosphorylation, which enhanced the interaction of ezrin with NHERF1, IRBIT, and NHE3. Additionally, oral administration of lysophosphatidic acid (LPA) increased NHE3 activity and fluid absorption in diabetic mice via an insulin-independent pathway. Together, these findings indicate the importance of NHE3 in diabetic diarrhea and suggest LPA administration as a potential therapeutic strategy for management of diabetic diarrhea.
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http://dx.doi.org/10.1172/JCI79552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588303PMC
September 2015

miR-504 mediated down-regulation of nuclear respiratory factor 1 leads to radio-resistance in nasopharyngeal carcinoma.

Oncotarget 2015 Jun;6(18):15995-6018

Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.

microRNAs (miRNAs) are involved in the various processes of DNA damage repair and play crucial roles in regulating response of tumors to radiation therapy. Here, we used nasopharyngeal carcinoma (NPC) radio-resistant cell lines as models and found that the expression of miR-504 was significantly up-regulated. In contrast, the expression of nuclear respiratory factor 1 (NRF1) and other mitochondrial metabolism factors, including mitochondrial transcription factor A (TFAM) and oxidative phosphorylation (OXPHOS) complex III were down-regulated in these cell lines. At the same time, the Seahorse cell mitochondrial stress test results indicated that the mitochondrial respiratory capacity was impaired in NPC radio-resistant cell lines and in a miR-504 over-expressing cell line. We also conducted dual luciferase reporter assays and verified that miR-504 could directly target NRF1. Additionally, miR-504 could down-regulate the expression of TFAM and OXPHOS complexes I, III, and IV and impaired the mitochondrial respiratory function of NPC cells. Furthermore, serum from NPC patients showed that miR-504 was up-regulated during different weeks of radiotherapy and correlated with tumor, lymph nodes and metastasis (TNM) stages and total tumor volume. The radio-therapeutic effect at three months after radiotherapy was evaluated. Results indicated that patients with high expression of miR-504 exhibited a relatively lower therapeutic effect ratio of complete response (CR), but a higher ratio of partial response (PR), compared to patients with low expression of miR-504. Taken together, these results demonstrated that miR-504 affected the radio-resistance of NPC by down-regulating the expression of NRF1 and disturbing mitochondrial respiratory function. Thus, miR-504 might become a promising biomarker of NPC radio-resistance and targeting miR-504 might improve tumor radiation response.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599252PMC
http://dx.doi.org/10.18632/oncotarget.4138DOI Listing
June 2015

[An epidemiologic study of restless leg syndrome among retired military elders in Shanxi Province].

Zhonghua Yi Xue Za Zhi 2015 Feb;95(5):382-5

Objective: To explore the prevalence, diagnosis and treatment of restless leg syndrome (RLS) among military elders.

Methods: A cross-sectional study was conducted among retired military elders in Shanxi Province from 2010 to 2011. According to age, they were divided into 4 groups to compare the prevalence of RLS and evaluate the severity of symptoms as "mild, moderate and severe". And the compositions of symptom severity were compared among different age groups. Also the rate of correct diagnosis of RLS was examined. Univariate analyses were conducted with SPSS 13. 0.

Results: There were 559 RLS patients in 3 472 elder subjects. The prevalence of RLS was 16. 1% and 15. 8% in male elders. The prevalence of RLS in male elders increased significantly with advancing age (P <0. 05). No significant difference existed in the compositions of symptom severity among different age groups of RLS patients (P > 0. 05). Only 3. 22% RLS patients were previously diagnosed and none received a proper therapy.

Conclusion: The prevalence of RLS among military elders is higher than that of their foreign counterparts. The prevalence of RLS in male elders increases significantly with advancing age. Symptom severity of RLS has no obvious relationship with advancing age. Since the rate of correct diagnosis and therapy is rather low for RLS elders in China, we should pay greater attention to the knowledge of RLS.
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February 2015