Publications by authors named "Ningning Jiang"

11 Publications

  • Page 1 of 1

Role of TGF-β1 in Fluoride-Treated Osteoblasts at Different Stages.

Biol Trace Elem Res 2021 May 24. Epub 2021 May 24.

Department of Regenerative Medical Science, School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, People's Republic of China.

Little attention has been paid to the tolerance of osteoblasts to fluoride in distinct differentiation stages, and the role of TGF-β1 in fluoride-treated osteoblast differentiation of progenitors and precursors was rarely mentioned in previous studies. The present study aimed to clarify how fluoride affected different differentiation stages of osteoblasts, and to elucidate the role of TGF-β1 in this process. We assessed cell migration, proliferation, DNA damage, and apoptosis of early-differentiated osteoblasts derived from bone marrow stem cells (BMSCs) exposed to fluoride with or without TGF-β1. Subsequently, MC3T3-E1 cells cultured with mineral induction medium were treated with fluoride to test fluoride's effect on late-differentiated osteoblasts. The specific fluoride concentrations and treatment times were chosen to evaluate the role of TGF-β1 in fluoride-induced osteoblastic differentiation and function. Results showed early-differentiated osteoblasts treated with a low dose of fluoride grew and moved more rapidly. TGF-β1 promoted cell proliferation and inhibited cell apoptosis in early-differentiated osteoblasts exposed to a low fluoride dose, but enhanced apoptosis at higher fluoride conditions. In the late-differentiated osteoblasts, the fluorine dose range with anabolic effects was narrowed, and the fluoride range with catabolic effects was widened. Treatment with a low fluoride dose stimulated the alkaline phosphatase (ALP) expression. TGF-β1 treatment inhibited Runx2 expression but increased RANKL expression in late-differentiated osteoblasts exposed to fluoride. Meanwhile, TGF-β1 treatments activated Smad3 phosphorylation but blocked Wnt10b expression in osteoblasts. We conclude that TGF-β1 plays an essential role in fluoride-induced differentiation and osteoblast function via activation of Smad3 instead of Wnt10 signaling.
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http://dx.doi.org/10.1007/s12011-021-02686-2DOI Listing
May 2021

Diagnostic value and prognostic significance of CTRP9 combined with pentraxin-3 in acute coronary syndrome.

Exp Ther Med 2021 Mar 25;21(3):254. Epub 2021 Jan 25.

Department of Cardiology, Dongying Hospital of Traditional Chinese Medicine, Dongying, Shandong 257000, P.R. China.

The present study aimed to explore the diagnostic value and prognostic significance of C1q/tumor necrosis factor-related protein 9 (CTRP9) combined with pentraxin-3 (PTX-3) in acute coronary syndrome (ACS). A total of 137 patients with coronary heart disease and chest pain were included. Among them, seventy-nine patients with ACS were allocated into a study group and fifty-eight patients with non-cardiac chest pain (NCCP) were allocated into a control group. The serum CTRP9, PTX-3 levels were quantified by ELISA, and their correlation with other ACS-related indexes, diagnostic value for ACS and predictive significance for poor prognosis were analyzed. In addition, the risk factors of the poor prognosis of ACS patients were studied. CTRP9 was lowly expressed and PTX-3 was highly expressed in the serum of ACS patients. CTRP9 was negatively correlated with cardiac troponin I (cTnI), creatine kinase-MB (CK-MB) and high-sensitivity C-reactive protein (hs-CRP) (P<0.05), while PTX-3 was positively correlated with them (P<0.05). Combined detection of CTRP9 and PTX-3 was of high value in the diagnosis and prognosis of ACS patients. In addition, CTRP9 and PTX-3 were independent risk factors for the poor prognosis of ACS. Patients with ACS had lower CTRP9 expression and higher PTX-3 expression than those without ACS. Moreover, the combined detection of CTRP9 and PTX-3 can better evaluate the diagnosis and prognosis of ACS patients.
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http://dx.doi.org/10.3892/etm.2021.9685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851676PMC
March 2021

Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway.

Anticancer Agents Med Chem 2021 Jan 31. Epub 2021 Jan 31.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061. China.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/β-catenin signaling pathway remains unclear.

Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/βcatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/β-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro.

Results: Wnt/β-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of β-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro.

Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.2174/1871520621666210201095613DOI Listing
January 2021

Effect of fluoride on osteocyte-driven osteoclastic differentiation.

Toxicology 2020 04 7;436:152429. Epub 2020 Mar 7.

Department of Regenerative Medical Science, School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, People's Republic of China. Electronic address:

Excessive systemic uptake of inorganic fluorides causes disturbances of bone homeostasis. The mechanism of skeletal fluorosis is still uncertain. This study aimed to study the effect of fluoride on osteocyte-driven osteoclastogenesis and probe into the role of PTH in this process. IDG-SW3 cells seeded in collagen-coated constructs were developed into osteocyte-like cells through induction of mineral agents. Then, osteocyte-like cells were exposed to fluoride in the presence or absence of parathyroid hormone (PTH). Cell viability and their capacity to produce receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and sclerostin (SOST) were detected by MTT and Western blot assays, respectively. Finally, a transwell coculture system using osteocyte-like cells seeded in the low compartment, and osteoclast precursors added in the inserts was developed to observe the osteocyte-driven osteoclasogenesis response to fluoride with or without PTH, and the expression of molecules involved in this mechanism were measure by real time RT-PCR. Results showed that osteocytes withstood a toxic dose of fluoride, and yet PTH administration significantly reduced osteocytes viability. PTH amplified the effect of fluoride on the expression of osteoclastogenesis-related molecules in osteocyte, but did not enlarged the stimulating effect of fluoride on osteoclastogenesis drove by osteocyte coculture. Gene expression levels of TRAP, RANK, JNK and NFAtc1 significantly increased in fluoride affected osteoclast precursor cocultured with osteocyte-like cells. The impact of fluoride on osteocyte-driven osteoclast differentiation was stronger than that of PTH. In conclusion, osteocyte played a pivotal role on the mechanism underlying fluoride-affected osteoclastogenesis in which RANK-JNK-NFATc1 signaling pathway was involved, and PTH had a significant impact in this process.
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http://dx.doi.org/10.1016/j.tox.2020.152429DOI Listing
April 2020

The antiresoptive effects of recombinant Lingzhi-8 protein against retinoic acid-induced osteopenia.

Eur J Pharmacol 2019 Nov 19;863:172669. Epub 2019 Sep 19.

China-Japan Union Hospital, Jilin University, Changchun, 130033, People's Republic of China. Electronic address:

The antiresorptive agents still are the mainstay of osteoporosis treatment. This study aimed to investigate the efficacy of recombinant Lingzhi-8 (rLZ-8) on osteoclast in vitro and bone resorption in vivo. The rLZ-8 protein was derived from Ganoderma lucidum transformation and produced by a genetic system. Receptor activator of nuclear factor kappa-Β ligand induced RAW 264.7 cells to differentiate into osteoclastic cells in vitro. Cells were exposed to different doses of rLZ-8 for 7 days to measure differences of osteoclastic differentiation, apoptosis rate and gene expression. rLZ-8 was labeled with Alexa Fluor 568 to observe its intracellular distribution under super-resolution light microscopy. In addition, retinoic acid was administered to female rats for 14 days to develop osteopenia changes. Different doses of rLZ-8 were simultaneously administered to rats treated with retinoic acid to observe changes of bone mineral density, biochemical parameters and organ weight ratio. Results indicated that rLZ-8 regulated receptor activator of nuclear factor kappa-Β (RANK) - tumor necrosis factor receptor-associated factor 6 (TRAF6) - c-Jun N-terminal kinase (JNK) signaling pathway, by which rLZ-8 inhibited osteoclastic differentiation and promoted osteoclastic apoptosis. Through 3D-structured illumination microscopy, it was observed that rLZ-8 entered RAW264.7 cells and accumulated gradually into the cytoplasm but little into nucleus. Administration with rLZ-8 reversed loss of bone mass and improved ALP activity in osteoporotic rats. Low-to high-dose rLZ-8 treatments displayed little toxic effects on rat organs and did not seem to impact their overall health. All data suggested that rLZ-8 has possible action against osteoporosis.
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http://dx.doi.org/10.1016/j.ejphar.2019.172669DOI Listing
November 2019

Different Effects of Fluoride Exposure on the Three Major Bone Cell Types.

Biol Trace Elem Res 2020 Jan 14;193(1):226-233. Epub 2019 Mar 14.

School of Pharmaceutical Sciences, Jilin University, 1163 Xinmin Street, Changchun, Jilin Province, 130021, People's Republic of China.

Fluoride accumulates and is toxic to bones. Clinical bone lesions occur in a phased manner, being less severe early in the natural course of skeletal fluorosis. Previous research rarely focused on osteocyte, osteoclast, and osteoblast at the same time, although these three types of cells are involved in the process of fluorosis. In this study, commitment of bone cells was performed according to their respective characteristics. Osteocyte-like cells were verified by protein expression of sclerostin (SOST) in IDG-SW3 cell culture with mineral medium. Positive tartrate-resistant acid phosphatase (TRACP) staining, characteristic of osteoclasts, is observed in RAW264.7 cells after administration of RANKL. We successfully purified a high percentage (94%) of bone mesenchymal stem cells (BMSCs) co-expressing CD34 and CD44. Parallel studies were performed to observe cell viability and apoptosis rates in osteocyte, osteoclast, and osteoblast like cells by using MTT and Annexin V FITC assays. Our results demonstrated that osteocytes have a strong tolerance to high fluoride concentrations, while osteoclasts are more sensitive to changes of fluoride dose. The range of anabolic action of fluoride concentration on osteoblast was narrow. Notably, fluoride exposure aggravated apoptosis of osteocyte and osteoclast induced by administration of PTH and TGF-β, respectively. In short, three types of bone cells display disparate responses to fluoride exposure and to PTH- and TGF-β-induced apoptosis.
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http://dx.doi.org/10.1007/s12011-019-01684-9DOI Listing
January 2020

Requirement of TGFβ Signaling for Effect of Fluoride on Osteoblastic Differentiation.

Biol Trace Elem Res 2019 Feb 16;187(2):492-498. Epub 2018 May 16.

School of Pharmaceutical Sciences, Jilin University, 1163 Xinmin Street, Changchun, Jilin Province, 130021, People's Republic of China.

Research focused on transforming growth factor β (TGFβ) signaling in osteoblast is gradually increasing, whereas literature is rare in terms of fluorosis. This work aimed to investigate how TGFβ signaling participated in regulation of the osteoblast by different doses of fluoride treatment. Bone marrow stem cells (BMSCs) were developed into osteoblastic cells and exposed to 1, 4, and 16 mg/L F with and without 10 ng/mL of TGFβ. Cell viability and differentiation state of osteoblast under different settings were measured by means of cell counting kit and analysis of alkaline phosphatase (ALP) activity as well as formation of mineral nodules. Real-time PCR was utilized to test expression of ALP and Runt-related transcription factor 2 (Runx2) at gene level. The gene expression of TGFβ signaling effectors was also investigated, such as TGFβ receptors (TβRs), smad3, and mitogen-activated protein kinases (MAPK). Results demonstrated that fluoride treatment exhibited action on osteoblast viability and osteogenic differentiation and upregulated expression of TβR2, smad3, and MAPK in this process. Administration of TGFβ strengthened ALP activity but attenuated formation of mineral nodules. Co-treatment of TGFβ and low-dose fluoride increased ALP activity compared to same dose of single fluoride treatment, whereas it inhibited mineral nodule formation. Administration of TGFβ reversed the suppression of high-dose fluoride on osteogenic differentiation of BMSCs. Taken together, studies revealed that TβR2 acted as a target for fluoride and TGFβ treatment on BMSCs, and smad3 and MAPK were involved in the mechanism of fluoride regulating osteogenic differentiation. Together, our data indicated that TGFβ receptor-mediated signaling through smad3 and MAPK was required for modulation of fluoride on osteoblast viability and differentiation, and activating TβR2-smad3 signaling pathway reversed suppression of osteoblasts differentiation by high dose of fluoride treatment.
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http://dx.doi.org/10.1007/s12011-018-1387-xDOI Listing
February 2019

PTH (1-34) affects bone turnover governed by osteocytes exposed to fluoride.

Toxicol Lett 2018 May 12;288:25-34. Epub 2018 Feb 12.

School of pharmaceutical Sciences, Jilin University, Changchun, 130021, China, China. Electronic address:

Exposure to fluoride from environmental sources remains an overlooked, but serious public health risk. In this study, we looked into the role osteocytes play on the mechanism underlying fluoride induced osteopathology. We analyzed bone formation and resorption related genes generated by osteocytes that were exposed to varied doses of fluoride with and without PTH in vitro. Correspondingly, osteogenesis and osteoclastogenesis related genes were also investigated in rats exposed to fluoride for 8 weeks, and the PTH(1-34)was applied at the last 3 weeks to observe its role in regulating bone turnover upon fluoride treatment. The data in vitro indicated that fluoride treatment inhibited Sost expression of mRNA and protein and stimulated RANKL mRNA protein expression as well as the RANKL/OPG ratio in the primary osteocytes. Single PTH treatment played the similar role on expression of these genes and proteins. The PTH combined administration enhanced the action of fluoride treatment on RNAKL/OPG and SOST/Sclerostin. The up-regulation of RANKL and decreasing of Sost induced by fluoride and/or PTH treatment was validated in vivo and suggests that osteocytes are a major source of RANKL and Sost, both of which play essential roles in fluoride affecting osteogenesis and osteoclastogenesis. Expression of Wnt/β-catenin was up-regulated in both in vitro osteocytes treated with high dose of fluoride and bone tissue of rats in the presence of fluoride and PTH. In vivo, fluoride and single PTH stimulated bone turnover respectively, furthermore, PTH combined with low dose of fluoride treatment reinforced the osteogenesis and osteoclastogenesis genes expression, however, co-treatment of PTH reversed the effect of high dose of fluoride on osteogenesis and osteoclastogenensis related factors. In conclusion, this study demonstrated that osteocytes play a key role in fluoride activated bone turnover, and PTH participates in the process of fluoride modulating SOST/Sclerostin and RANKL expression.
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http://dx.doi.org/10.1016/j.toxlet.2018.02.014DOI Listing
May 2018

The role of TGFβ receptor 1-smad3 signaling in regulating the osteoclastic mode affected by fluoride.

Toxicology 2018 01 7;393:73-82. Epub 2017 Nov 7.

Department of Regenerative Medical Science, School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, People's Republic of China. Electronic address:

Studies that have focused on the role TGFβ signaling plays in osteoclast activity are gradually increasing; however, literature is rare in terms of fluorosis. The aim of this study is to observe the role the TβR1/Smad3 pathway plays in fluoride regulating cellsosteoclast-like cells that are under the treatment of TGFβ receptor 1 kinase. The RANKL-mediated osteoclast-like cells from RAW264.7 cells were used as osteoclast precursor model. The profile of miRNA expression in fluoride-treated osteoclast-like cells exhibited 303 upregulated miRNAs, 61 downregulated miRNAs, and further drew 37 signaling pathway maps by KEGG and Biocarta pathway enrichment analysis. TGFβ and its downstream effectors were included among them. Osteoclast viability, formation and function were detected via MTT method, bone resorption pit and tartrate-resistant acid phosphatase (TRACP) staining, respectively. Results demonstrated that different doses of fluoride exhibited a biphasic effect on osteoclast cell viability, differentiation, formation and function. It indicated that a low dose of fluoride treatment stimulated them, but high dose inhibited them. SB431542 acted as TβR1 kinase inhibitor and blocked viability, formation and function of osteoclast-like cells regulated by fluoride. The expression of the osteoclast marker, RANK, and TβR1/Smad3 at gene and protein level was analyzed under fluoride with and without SB431542 treatment. Fluoride treatment indicated little effect on the RANK protein expression; however it significantly influenced TRACP expression in osteoclast-like cells. The stimulation of fluoride on the expression of Smad3 gene and phosphorylated Smad3 protein exhibited dose-dependent manner. SB431542 significantly impeded phosphorylation of Smad3 protein and TRACP expression in osteoclast-like cells that were exposed to fluoride. Our work demonstrated that TGFβ signaling played a key role in fluoride regulating osteoclast differentiation, formation and function. It elucidated that TβR1/Smad3 pathway participated in the mechanism of biphasic modulation of osteoclast mode regulated by fluoride.
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http://dx.doi.org/10.1016/j.tox.2017.11.009DOI Listing
January 2018

[The relationship between expression of mitogen-activated protein kinase kinase 4 and metastasis in oral squamous cell carcinoma].

Hua Xi Kou Qiang Yi Xue Za Zhi 2011 Oct;29(5):555-8

Dept. of Pathology, Stomatological Hospital of Guangxi Medical University, Nanning 530021, China.

Objective: To explore the correlation between expression of mitogen-activated protein kinase kinase 4 (MKK4) and metastasis of oral squamous cell carcinoma (OSCC).

Methods: Expression levels of MKK4 mRNA and protein were examined in surgically resected oral squamous cell carcinoma specimens and corresponding lymph nodes by semi-quantitative reverse Transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry.

Results: The expression of MKK4 in 48 cases of metastasis of lymph node group was significantly higher than 27 cases of without metastasis of lymph node group in 75 cases of paraffin-embedded OSCC samples (P < 0.05). The expression of MKK4 in 48 cases of metastatic lymph node lesions was higher than 48 cases of primary site of OSCC (P < 0.05). There was no correlation between the expression of MKK4 and primary site, size of tumor, histological grade ( P > 0.05). The expression of MKK4 mRNA in 16 cases of metastasis of lymph node group was significantly higher than 22 cases of without metastasis of lymph node group in 38 cases of fresh OSCC samples (P < 0.01). The expression of MKK4 in 6 cases of matched metastatic lymph node lesions was higher than 16 cases of primary tumour (P < 0.05)

Conclusion: The up-regulation of MKK4 protein and mRNA may be related with the invasion and metastasis of OSCC. MKK4 maybe played a promoting role in the progression and metastasis of OSCC.
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October 2011

Robust joint analysis allowing for model uncertainty in two-stage genetic association studies.

BMC Bioinformatics 2011 Jan 7;12. Epub 2011 Jan 7.

Department of Statistics, Yunnan University, Kunming 650091, PR China.

Background: The cost efficient two-stage design is often used in genome-wide association studies (GWASs) in searching for genetic loci underlying the susceptibility for complex diseases. Replication-based analysis, which considers data from each stage separately, often suffers from loss of efficiency. Joint test that combines data from both stages has been proposed and widely used to improve efficiency. However, existing joint analyses are based on test statistics derived under an assumed genetic model, and thus might not have robust performance when the assumed genetic model is not appropriate.

Results: In this paper, we propose joint analyses based on two robust tests, MERT and MAX3, for GWASs under a two-stage design. We developed computationally efficient procedures and formulas for significant level evaluation and power calculation. The performances of the proposed approaches are investigated through the extensive simulation studies and a real example. Numerical results show that the joint analysis based on the MAX3 test statistic has the best overall performance.

Conclusions: MAX3 joint analysis is the most robust procedure among the considered joint analyses, and we recommend using it in a two-stage genome-wide association study.
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http://dx.doi.org/10.1186/1471-2105-12-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027114PMC
January 2011
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