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Ke B.,The Third Hospital of Nanchang | Fan C.,Nanchang University | Yang L.,Jiangxi Cancer Hospital | Fang X.,Nanchang University
Frontiers in Physiology | Year: 2017

Matrix metalloproteinase-7 (MMP-7) is a secreted zinc- and calcium-dependent endopeptidase that degrades a broad range of extracellular matrix substrates and additional substrates. MMP-7 playsa crucial role in a diverse array of cellular processes and appears to be a key regulator of fibrosis in several diseases, including pulmonary fibrosis, liver fibrosis, and cystic fibrosis. In particular, the relationship between MMP-7 and kidney fibrosis has attracted significant attention in recent years. Growing evidence indicates that MMP-7 plays an important role in the pathogenesis of kidney fibrosis. Here, we summarize the recent progress in the understanding of the role of MMP-7 in kidney fibrosis. In particular, we discuss how MMP-7 contributes to kidney fibrotic lesions via the following three pathways: epithelial-mesenchymal transition (EMT), transforming growth factor-beta (TGF-β) signaling, and extracellular matrix (ECM) deposition. Further dissection of the crosstalk among and regulation of these pathways will help clinicians and researchers develop effective therapeutic approaches for treating chronic kidney disease. © 2017 Ke, Fan, Yang and Fang.

Yu Y.,Nanchang University | Yu Y.,The Third Hospital of Nanchang | Cai W.,Nanchang University | Pei C.-G.,Nanchang University | Shao Y.,Nanchang University
Biochemical and Biophysical Research Communications | Year: 2015

Abstract Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer therapy. The identification of new drugs from natural products has a long and successful history. In this study, we described a novel VEGFR2 inhibitor, rhamnazin, which inhibits tumor angiogenesis and growth. Rhamnazin significantly inhibited proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in vitro as well as inhibited sprouts formation of rat aorta ring. In addition, it inhibited vascular endothelial growth factor (VEGF)-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVECs. Moreover, rhamnazin could directly inhibit proliferation of breast cancer cells MDA-MB-231 in vitro and in vivo. Oral administration of rhamnazin at a dose of 200 mg/kg/day could markedly inhibited human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that rhamnazin inhibits angiogenesis and may be a promising anticancer drug candidate. © 2015 Elsevier Inc. All rights reserved.

PubMed | Nanchang University and The Third Hospital of Nanchang
Type: | Journal: Molecular medicine reports | Year: 2016

Adenosine monophosphate-activated protein kinase (AMPK) is a principal regulator of metabolism and the conservation of energy in cells, and protects them from exposure to various stressors. AMPK activators may exhibit therapeutic potential as suppressors of cell growth; however, the molecular mechanism underlying this phenomenon in various cancer cells remains to be fully elucidated. The present study investigated the effects of AMPK activators on breast cancer cell growth and specified the underlying molecular mechanism. In the present study, the AMPK activator metformin impaired breast cancer cell growth by reducing dishevelled segment polarity protein3 (DVL3) and catenin levels. Western blotting and immunohistochemistry demonstrated that DVL3 was recurrently upregulated in breast cancer cells that were not treated with metformin, and was significantly associated with enhanced levels of catenin, cMyc and cyclinD1. Overexpression of DVL3 resulted in upregulation of catenin and amplification of breast cancer cell growth, which confirmed that Wnt/catenin activation via DVL3 is associated with breast cancer oncogenesis. To elucidate the underlying mechanism of these effects, the present study verified that metformin resulted in a downregulation of DVL3 and catenin in a dosedependent manner, and induced phosphorylation of AMPK. Compound C is an AMPK inhibitor, which when administered alongside metformin, significantly abolished the effects of metformin on the reduction of DVL3 and activation of the phosphorylation of AMPK. Notably, the effects of metformin on the mRNA expression levels of DVL3 remain to be fully elucidated; however, a possible interaction with DVL3 at the posttranscriptional level was observed. It has previously been suggested that the molecular mechanism underlying AMPK activatorinduced suppression of breast cancer cell growth involves an interaction with, and impairment of, DVL3 proteins. The results of the present study are of future clinical importance and advocate the use of metformin as a potential therapeutic agent against breast cancer.

Tu P.,The Third Hospital of Nanchang | Duan P.,The Third Hospital of Nanchang | Zhang R.-S.,The Third Hospital of Nanchang | Xu D.-B.,The Third Hospital of Nanchang | And 4 more authors.
Osteoporosis International | Year: 2014

Summary: Association between 22 single nucleotide polymorphisms (SNPs) in the TNFSF11, TNFRSF11A, and TNFRSF11B genes in the RANKL/RANK/OPG pathway with bone mineral density (BMD) in 881 post-menopausal women. Our results suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women.Introduction: The aim of this study was to assess the relationship of polymorphisms in the TNFSF11, TNFRSF11A, and TNFRSF11B genes in the RANKL/RANK/OPG pathway with bone mineral density (BMD) in a cohort of Chinese post-menopausal women.Methods: A cross-sectional study was conducted in 881 post-menopausal women aged 50–89 years. All participants underwent lumbar spinal (LS) and femoral neck (FN) BMD evaluation by dual-energy X-ray absorptiometry. Twenty-two TNFSF11, TNFRSF11A, and TNFRSF11B SNPs were genotyped. We tested whether a single SNP or a haplotype was associated with BMD variations.Results: Two SNPs in the TNFSF11 gene (rs2277439 and rs2324851) and one in the TNFRSF11A gene (rs7239261) were found to be significantly associated with FN BMD (p = 0.014, 0.013, and 0.047, respectively). Haplotype TGACGT of TNFSF11 rs9525641-rs2277439-rs2324851-rs2875459-rs2200287-rs9533166 was a genetic risk factor toward a lower FN BMD (beta = −0.1473; p = 0.01126). In contrary, haplotype TAGCGT of TNFSF11 rs9525641-rs2277439-rs2324851-rs2875459-rs2200287-rs9533166 was genetic protective factor for LS BMD (beta = 0.3923; p = 0.04917).Conclusions: Our findings suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women. This contributes to the understanding of the role of genetic variation in this pathway in determining bone health. © 2014, International Osteoporosis Foundation and National Osteoporosis Foundation.

Zong Y.,The Third Hospital of Nanchang | Duan P.,The Third Hospital of Nanchang
Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] | Year: 2014

OBJECTIVE: To investigate the impact of self-efficacy theory health education in patients of diabetic osteoporosis.METHODS: We used SPSS 19.0 software to generate random numbers and 260 diabetic osteoporosis patients were randomly divided into an observation group and a control group. There was 130 patients in observation group, 130 in control group. The self-efficacy theory health education was carried out in observation group, and routine health education in control group. SF-36 questionnaire was used to assess the quality of life. Osteoporosis self-efficacy scale (OSES) was used to assess self-efficacy. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry. Blood glucose was detected by glucose oxidase method. Glycosylated hemoglobin was detected by high efficiency liquid chromatography to estimate the index change before intervention and after one year's follow up.RESULTS: The number of patients that had completed follow-up was 104 in control group and 107 in observation group. The self-efficacy scores, movement efficiency scores and calcium intake efficiency scores were all higher in intervention group ((82.25 ± 13.54) , (79.26 ± 15.37) , (84.39 ± 17.09) points) than which in the control group ((71.14 ± 14.19), (63.89 ± 19.87), (75.24 ± 10.70) points) after one year's follow up, there were significant differences in two groups (t values were 6.04, 7.95, 5.77, all P values<0.05). The scores of quality of life in the dimension of general health, vitality, social function, role emotional and mental health were all higher in intervention group ((75.29 ± 14.90) , (68.61 ± 17.38) , (75.74 ± 18.50) , (71.22 ± 17.93) , (73.69 ± 14.40 ) points) than in the control group ( (44.25 ± 11.01) , (47.39 ± 18.90) , (63.54 ± 15.95), (49.04 ± 19.36), (55.15 ± 19.74) points), there were significant differences in two groups (t values were 8.45, 8.83, 6.92, 8.79, 8.05, all P values<0.05) . Fasting blood-glucose 2 hour postprandial blood glucose and glycosylated hemoglobin were all lower in intervention group ((7.29 ± 1.81) mmol/L, (8.21 ± 2.37) mmol/L, (6.59 ± 0.92) %) than in the control group ((8.53 ± 1.66) mmol/L, (9.41 ± 3.30) mmol/L, (7.66 ± 1.50) %) , there were significant differences in two groups (t values were 5.33, 4.67, 5.49, all P values<0.05). There were 1 (0.93%) fracture case in observation group and 7 (6.73%) cases in control group during one year's follow up, there are significant difference in two groups (χ(2) = 4.86, P = 0.028).CONCLUSIONS: The self-efficacy theory health education may improve the quality of life and decreased fracture risk of diabetic osteoporosis patients.

PubMed | The Third Hospital of Nanchang and Southern Medical University
Type: Journal Article | Journal: Genetic testing and molecular biomarkers | Year: 2016

Receptor activator of nuclear factor-kappa B ligand (RANKL), its receptor activator of nuclear factor-kappa B (RANK), and decoy receptor osteoprotegerin (OPG) are three major proteins of the RANKL/RANK/OPG signaling pathway encoded by TNFSF11, TNFRSF11A, and TNFRSF11B, respectively. This pathway plays a critical role in bone remodeling and may have a role in the pathogenesis of type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the relationship between gene polymorphisms in the RANKL/RANK/OPG pathway and T2DM in Southern Han Chinese women.A total of 1233 participants, including 514 T2DM patients and 719 healthy control subjects, were enrolled in this case-control study. Twenty-one single-nucleotide polymorphisms (SNPs) of TNFSF11, TNFRSF11A, and TNFRSF11B were genotyped using an improved multiplex ligation detection reaction technique.Two SNPs of TNFRSF11B (rs11573819 and rs2073618) were significantly associated with T2DM (p=0.04 and p=0.009, respectively). Subjects with the GA genotype of rs11573819 had a lower risk of T2DM (odds ratio [OR]=0.67, 95% confidence interval [CI]=0.51-0.88, p=0.005) compared with subjects with the GG genotype. The GG genotype of rs2073618 was associated with increased risk for T2DM (OR=1.94, 95% CI=1.14-3.30, p=0.01) compared with the CC genotype.This study suggests that TNFRSF11B but not TNFSF11 and TNFRSF11A genetic polymorphisms are associated with T2DM in Southern Han Chinese women. These findings provide preliminary support for the potential role of the RANKL/RANK/OPG pathway in T2DM.

PubMed | The Third Hospital of Nanchang
Type: Journal Article | Journal: Oncoscience | Year: 2017

The discrepancy of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) statuses in breast cancers has been reported. Available systemic therapy for patients with breast cancer is based on the molecular subtypes as identified by IHC and/or FISH. However, these biomarkers may change throughout tumor progression.We report a relatively uncommon case of a 39-year-old Chinese woman with local advanced breast cancer (LABC) treated with 6 cycles of docetaxel, doxorubicin and cyclophosphamide (TAC) regimen neoadjuvant chemotherapy, and subsequently mastectomy, intensity-modulated radiation therapy (IMRT) and tamoxifen followed as regularly. Brain metastatic event appeared in 6 months after mastectomy. Treatment for brain metastasis was surgical resection and followed by whole brain radiotherapy (WBRT) approved by multidisciplinary team (MDT). Initial pathological diagnosis was IDC, cT4N1M0, luminal B (ER+ 90%, PR+90%, HER2 0, Ki67+ 70%) based on ultrasound-guided core needle biopsy. Surgical pathology revealed IDC, pT2N3M0 luminal B (ER+ 20%, PR+20%, HER2 0, Ki67+ 20%). Histological response to neoadjuvant chemotherapy is grade 3 according to the Miller/Payne grading system. Final pathology of brain metastasis showed a HER2 overexpression metastatic breast cancer luminal B (ER+ 70%, PR+ 70%, HER2 2+, Ki67+ 30%), FISH confirmed HER2 overexpression. Weekly paclitaxel plus trastuzumab was given for 12 weeks, then trastuzumab every 3 weeks for a whole year. Patient follow-up is still ongoing, no new events appear yet.The determination of hormone receptors and HER2 status should be routinely performed in all involved tissues, if possible, and systemic therapy should be tailored following the latest finding.

PubMed | the Third Hospital of Nanchang
Type: Journal Article | Journal: Zhonghua yi xue za zhi | Year: 2016

To explore the impact of lifestyle and quantitative nutrition intervention on individuals with prediabetes.A total of 214 prediabetic patients from epidemiologic survey in Ximazhuang and Guangrunmen community centers in Nanchang from January 2011 to January 2012 were enrolled in the study. All the participants were randomly divided into two groups: the intervention group and the control group, with 107 patients in each group. Intensified lifestyle and quantitative nutrition interventions were carried out in the intervention group, and routine lifestyle intervention was carried out in control group. Height and weight were measured, and the body mass index (BMI) was calculated. Blood glucose was tested by glucose oxidase method, and glycosylated hemoglobin (HbA1c) was detected by high performance liquid chromatography. Various parameter changes were compared between two groups after two years follow-up, and the outcome data of patients was collected. The study was approved by the Ethics Committee of the Third Hospital of Nanchang.There were no significant differences in each parameter between two groups before intervention (all P>0.05). No obvious change was found for the parameters in the control group after two years follow-up (all P>0.05), but weight, BMI, fasting blood glucose, postprandial two-hour blood glucose and HbA1c decreased in the intervention group (P<0.05). There were 11 (13.1%) diabetic cases and 1 (1.2%) participant with normal glucose tolerance in the control group, and 3 (3.4%) diabetic cases and 7 (8.0%) participants with normal glucose tolerance in the intervention group (P<0.05). The risk of diabetes in two groups was performed using cox regression model analysis, and the primary end-point was the incidence of diabetes. The risk of diabetes in the control group was significantly higher than that in the intervention group [HR=3.903, 95% CI: 1.089-13.992, P=0.037].The lifestyle and quantitative nutrition interventions may improve the blood glucose control and delay the progression of diabetes in prediabetes patients.

PubMed | The Third Hospital of Nanchang
Type: | Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie | Year: 2016

During the past two decades, cytokines have emerged as key molecules to modulate innate and adaptive immunity and mediate anti-tumor activity. Although multiple cytokine types are implicated for such anti-tumor activity in several cancer types, it remains largely unknown in breast cancer. In this study, cytokines that are prior known for antitumor activity in different cancer types were examined against breast cancer using a 4T1 cells based xenograft-model. Our results showed Interleukin-12 (IL-12) (500ng/mouse) significantly suppressed the growth of tumors, while other cytokines showed minimal suppression. Subsequent molecular analysis by flow cytometry and immunohistochemistry confirmed the CD8

PubMed | Fudan University and The Third Hospital of Nanchang
Type: Journal Article | Journal: International journal of oncology | Year: 2016

Despite the great progress in breast cancer research and treatment, measures for efficient targeting of triplenegative breast cancer(TNBC) are still lacking. The wellestablished dependency of cancer cells on their microenvironment suggests that targeting the tumor niche might form a novel therapeutic approach. We identified the tumorassociated macrophage(TAM) infiltration in breast cancer tissues by immunohistochemistry, and analyzed overall survival(OS). U937 cocultures with MDAMB231, MDAMB468 and MCF7, respectively, to simulate invivo cellular interactions were assessed. In hormoneindependent breast cancer cell conditioned media(CM), U937 differentiates into M2 macrophage as identified by morphological changes and expression of specific surface antigens CD163 and CD204. Moreover, MDAMB231 recruits U937, and colonystimulating factor1(CSF1) level in MDAMB231 and MDAMB468 CM is much higher than that of MCF7. Overexpression of CSF1 in MCF7 fails to rebuild its aggressiveness both invitro and invivo since CSF1 was not found extracellularly, while genetic inhibition of CSF1 in MDAMB231 abrogates TAM infiltration and consequently reduces tumorigenesis in nonobese diabetic/severe combined immunodeficient(NOD/SCID) mice. Using various strategies we demonstrate that CSF1induced TAMs specifically support breast cancer progression. Importantly, our results may reveal the efficacy of using targeted therapy against tumor niche and indicate that CSF1 inhibition may limit some breast cancer progression.

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