Low concentration flufenamic acid enhances osteogenic differentiation of mesenchymal stem cells and suppresses bone loss by inhibition of the NF-κB signaling pathway

Liu, Xuenan; Li, Zheng; Líu, Hao; Zhu, Yuan; Xia, Dandan; Wang, Siyi; Gu, Ranli; Wu, Wei-Liang; Zhang, Ping; Liu, Yunsong; Zhou, Yongsheng

doi:10.1186/s13287-019-1321-y

Cited by 15 publications

(25 citation statements)

References 38 publications

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“…However, Oil red O staining showed that 200 μM FFA inhibited adipogenesis better than 100 μM FFA. This may be because 200 μM FFA also inhibited the proliferation of hMSCs, which has been documented in our previous study [25]. Human ASCs and hBMMSCs displayed similar results both in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 81%

“…This might be because they are both populations of postnatal tissue-specific stem cells with similar gene expression profiles and display similar characteristics [28]. We found that low concentrations of FFA promote osteogenesis of hMSCs [25], and adipogenic differentiation is generally inhibited when osteogenic differentiation is promoted. The results of our present study are in agreement with our previous report.…”

Section: Discussionmentioning

confidence: 71%

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Flufenamic Acid Inhibits Adipogenic Differentiation of Mesenchymal Stem Cells by Antagonizing the PI3K/AKT Signaling Pathway

Liu¹,

Li²,

Líu³

et al. 2020

Stem Cells International

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Objectives. Flufenamic acid (FFA) is a representative of the fenamic acids, an important group of NSAIDs. In the present study, we study the effects of FFA on adipogenesis of human mesenchymal stem cells (MSCs) and we explore the potential mechanism. Methods. To investigate the effects of FFA on adipogenic differentiation of hMSCs, human adipose-derived stem cells (hASCs) and human bone marrow mesenchymal stem cells (hBMMSCs), representative of hMSCs, were treated with FFA during adipogenic differentiation in vitro. The effects of FFA in vivo were evaluated using a heterotopic adipose formation assay in nude mice as well as ovariectomized (OVX) and aged mice. To explore the mechanism of FFA, Western blot was used to determine activation of the PI3K/AKT signaling pathway. Results. Our results demonstrate that, at certain concentrations, FFA inhibited adipogenesis of human MSCs both in vitro and in vivo. Mechanistically, FFA inhibited adipogenesis of human MSCs by inhibiting the PI3K/AKT pathway. Conclusions. The present study indicated that FFA could be used to inhibit adipogenesis of human MSCs in tissue engineering and diseases related to excessive adipogenic differentiation of MSCs.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 71%

Flufenamic Acid Inhibits Adipogenic Differentiation of Mesenchymal Stem Cells by Antagonizing the PI3K/AKT Signaling Pathway

Liu¹,

Li²,

Líu³

et al. 2020

Stem Cells International

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“…The fibrous glial scar formed by infiltrated inflammatory cells (including microglia, fibroblasts, and reactive astrocytes) limits axon regeneration across the lesion [ 37 , 38 ]. The scar tissue not only exerts a protective effect by limiting the spread of inflammation and secondary damage to adjacent intact tissue but also serves as an inhibitory barrier for axon regeneration [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

hiPSC-derived NSCs effectively promote the functional recovery of acute spinal cord injury in mice

et al. 2021

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Background Spinal cord injury (SCI) is a common disease that results in motor and sensory disorders and even lifelong paralysis. The transplantation of stem cells, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), or subsequently generated stem/progenitor cells, is predicted to be a promising treatment for SCI. In this study, we aimed to investigate effect of human iPSC-derived neural stem cells (hiPSC-NSCs) and umbilical cord-derived MSCs (huMSCs) in a mouse model of acute SCI. Methods Acute SCI mice model were established and were randomly treated as phosphate-buffered saline (PBS) (control group), repaired with 1 × 105 hiPSC-NSCs (NSC group), and 1 × 105 huMSCs (MSC group), respectively, in a total of 54 mice (n = 18 each). Hind limb motor function was evaluated in open-field tests using the Basso Mouse Scale (BMS) at days post-operation (dpo) 1, 3, 5, and 7 after spinal cord injury, and weekly thereafter. Spinal cord and serum samples were harvested at dpo 7, 14, and 21. Haematoxylin-eosin (H&E) staining and Masson staining were used to evaluate the morphological changes and fibrosis area. The differentiation of the transplanted cells in vivo was evaluated with immunohistochemical staining. Results The hiPSC-NSC-treated group presented a significantly smaller glial fibrillary acidic protein (GFAP) positive area than MSC-treated mice at all time points. Additionally, MSC-transplanted mice had a similar GFAP+ area to mice receiving PBS. At dpo 14, the immunostained hiPSC-NSCs were positive for SRY-related high-mobility-group (HMG)-box protein-2 (SOX2). Furthermore, the transplanted hiPSC-NSCs differentiated into GFAP-positive astrocytes and beta-III tubulin-positive neurons, whereas the transplanted huMSCs differentiated into GFAP-positive astrocytes. In addition, hiPSC-NSC transplantation reduced fibrosis formation and the inflammation level. Compared with the control or huMSC transplanted group, the group with transplantation of hiPSC-NSCs exhibited significantly improved behaviours, particularly limb coordination. Conclusions HiPSC-NSCs promote functional recovery in mice with acute SCI by replacing missing neurons and attenuating fibrosis, glial scar formation, and inflammation. Graphical abstract

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“…MDA expression was increased and SOD expression was decreased in CLP‐ or LPS‐induced sepsis rats and FFA down‐regulated the MDA expression and up‐regulated the SOD expression in this study. FFA could also improve the osteogenic differentiation and Vibrio cholerae ‐induced diarrhea by inhibiting the NF‐κB signaling pathway (Liu et al, 2019; Pongkorpsakol et al, 2017). We speculate that FFA alleviate the lung injury induced by sepsis through NF‐κB signaling pathway, which might be investigated in the further study.…”

Section: Discussionmentioning

confidence: 99%

“…In mice, FFA played an antidiarrheic role by inhibiting the inflammatory response mediated by NF‐κB (Pongkorpsakol et al, 2017). A study reported that low concentration of FFA promoted osteogenic differentiation of mesenchymal stem cells and inhibited bone loss by inhibiting the NF‐κB signaling pathway (Liu et al, 2019). Through the prediction of STITCH website, the FFA‐related protein, AKR1C3, was found.…”

Section: Introductionmentioning

confidence: 99%

Flufenamic acid alleviates sepsis‐induced lung injury by up‐regulating CBR1

Jiang

Chen

Jiang

2020

Drug Development Research

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Investigate the effect of flufenamic acid (FFA) on lung injury of sepsis rats. Rat sepsis model was established using cecal ligation and puncture (CLP). The pathomorphology of lung tissue was detected by Hematoxylin–eosin (H&E) staining. The expression levels of tumor necrosis factor alpha (TNF‐α), interleukin‐6 (IL‐6), and high mobility group box‐1 (HMGB‐1) in serum and TNF‐α, IL‐6, malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) in lung tissues. The viability of RLE‐6TN cells was detected by CCK‐8 assay. The expression of carbonyl reductase 1 (CBR1) in RLE‐6TN cells was analyzed by Western blot analysis and reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) analysis. The inflammatory response was obviously enhanced in CLP‐constructed sepsis rats and alleviated by FFA treatment. Sepsis induced the increase of W/D ratio, promoted the levels of TNF‐α, IL‐6, HMGBR1, and MDA and inhibited the levels of SOD and GSH. FFA could effectively alleviate the sepsis‐induced lung injury. The viability of RLE‐6TN cells induced by LPS was improved with the treatment of FFA. CBR1 expression in LPS‐induced RLE‐6TN cells was decreased and FFA could up‐regulate the CBR1 expression. In addition, LPS‐induced lung injury promoted the inflammatory response in lung tissues, increased the W/D ratio and levels of TNF‐α, IL‐6, HMGBR1, and MDA while inhibited the levels of SOD and GSH. FFA could effectively improve the LPS‐induced lung injury while the effect of FFA on LPS‐induced lung injury was alleviated by CBR1 interference. FFA may alleviate sepsis‐induced lung injury by up‐regulating CBR1.

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Low concentration flufenamic acid enhances osteogenic differentiation of mesenchymal stem cells and suppresses bone loss by inhibition of the NF-κB signaling pathway

Cited by 15 publications

References 38 publications

Flufenamic Acid Inhibits Adipogenic Differentiation of Mesenchymal Stem Cells by Antagonizing the PI3K/AKT Signaling Pathway

Flufenamic Acid Inhibits Adipogenic Differentiation of Mesenchymal Stem Cells by Antagonizing the PI3K/AKT Signaling Pathway

hiPSC-derived NSCs effectively promote the functional recovery of acute spinal cord injury in mice

Flufenamic acid alleviates sepsis‐induced lung injury by up‐regulating CBR1

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