KR-12-a5 Reverses Adverse Effects of Lipopolysaccharides on HBMSC Osteogenic Differentiation by Influencing BMP/Smad and P38 MAPK Signaling Pathways

Li, Hui; Zhang, Shutao; Nie, Bin’en; Long, Teng; Qu, Xinhua; Yue, Bing

doi:10.3389/fphar.2019.00639

Cited by 14 publications

(10 citation statements)

References 66 publications

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“…A multitude of signaling pathways regulates the intricate osteoblast precursor cells differentiation network, such as Wnt, Notch, and MAPK signaling pathways [28,29]. Many osteogenesis-related extracellular signaling pathways such as BMP/Smad, TGF, and TNF are transduced through cascades of multilevel protein kinases in MAPK pathway to trigger intracellular biological responses [30][31][32][33]. Low expression of Mir24-2-5p promoted the phosphorylation of JNK and p38, but not ERK in MAPK signaling; On the contrary, low expression of Gnai3 inhibited the phosphorylation of JNK and p38, but not ERK in MAPK.…”

Section: Discussionmentioning

confidence: 99%

Mir24-2-5p suppresses the osteogenic differentiation with Gnai3 inhibition presenting a direct target via inactivating JNK-p38 MAPK signaling axis

Li¹,

Yuan²,

Ni³

et al. 2021

Int. J. Biol. Sci.

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Background: Congenital anomalies are increasingly becoming a global pediatric health concern, which requires immediate attention to its early diagnosis, preventive strategies, and efficient treatments. Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3 (Gnai3) gene mutation has been demonstrated to cause congenital small jaw deformity, but the functions of Gnai3 in the disease-specific microRNA (miRNA) upregulations and their downstream signaling pathways during osteogenesis have not yet been reported. Our previous studies found that the expression of Mir24-2-5p was significantly downregulated in the serum of young people with overgrowing mandibular, and bioinformatics analysis suggested possible binding sites of Mir24-2-5p in the Gnai3 3'UTR region. Therefore, this study was designed to investigate the mechanism of Mir24-2-5p-mediated regulation of Gnai3 gene expression and explore the possibility of potential treatment strategies for bone defects. Methods: Synthetic miRNA mimics and inhibitors were transduced into osteoblast precursor cells to regulate Mir24-2-5p expression. Dual-luciferase reporter assay was utilized to identify the direct binding of Gnai3 and its regulator Mir24-2-5p. Gnai3 levels in osteoblast precursor cells were downregulated by shRNA (shGnai3). Agomir, Morpholino Oligo (MO), and mRNA were microinjected into zebrafish embryos to control mir24-2-5p and gnai3 expression. Relevant expression levels were determined by the qRT-PCR and Western blotting. CCK-8 assay, flow cytometry, and transwell migration assays were performed to assess cell proliferation, apoptosis, and migration. ALP, ARS and Von Kossa staining were performed to observe osteogenic differentiation. Alcian blue staining and calcein immersions were performed to evaluate the embryonic development and calcification of zebrafish. Results: The expression of Mir24-2-5p was reduced throughout the mineralization process of osteoblast precursor cells. miRNA inhibitors and mimics were transfected into osteoblast precursor cells. Cell proliferation, migration, osteogenic differentiation, and mineralization processes were measured, which showed a reverse correlation with the expression of Mir24-2-5p. Dual-luciferase reporter gene detection assay confirmed the direct interaction between Mir24-2-5p and Gnai3 mRNA. Moreover, in osteoblast precursor cells treated with Mir24-2-5p inhibitor, the expression of Gnai3 gene was increased, suggesting that Mir24-2-5p negatively targeted Gnai3. Silencing of Gnai3 inhibited osteoblast precursor cells proliferation, migration, osteogenic differentiation, and mineralization. Promoting effects of osteoblast precursor cells proliferation, migration, osteogenic differentiation, and mineralization by low expression of Mir24-2-5p was partially rescued upon silencing of Gnai3. In vivo, mir24-2-5p Agomir microinjection into zebrafish embryo resulted in shorter body length, smaller and retruded mandible, decreased cartilage development, and vertebral calcification, which was partially resc...

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Section: Discussionmentioning

confidence: 99%

Mir24-2-5p suppresses the osteogenic differentiation with Gnai3 inhibition presenting a direct target via inactivating JNK-p38 MAPK signaling axis

Li¹,

Yuan²,

Ni³

et al. 2021

Int. J. Biol. Sci.

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“…The osteogenic differentiation of rBMSCs cultured on each PEEK sample was investigated by measuring the osteogenic differentiation markers, such as alkaline phosphatase (ALP) activity, collagen secretion, and ECM‐mineralization 21 . ALP activity is determined using ALP staining and an ALP activity assay.…”

Section: Methodsmentioning

confidence: 99%

Hydrofluoric acid and nitric acid cotreatment for biofunctionalization of polyetheretherketone in M2 macrophage polarization and osteogenesis

Huo

Meng

Zhang

et al. 2020

J Biomedical Materials Res

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Due to its excellent mechanical and low‐friction properties, polyetheretherketone (PEEK) has been widely investigated for use in orthopedic applications over the past decade. However, the bioinertness and poor osteogenic properties of PEEK have hampered its clinical application. In this study, the surface of PEEK was modified by co‐treatment with hydrofluoric acid and nitric acid (AFN). The microstructures of the modified PEEK surfaces were investigated using scanning electron microscopy. The water contact angles of the surfaces were also measured. To evaluate their cytocompatibility, PEEK samples were used as substrates to culture rat bone mesenchymal stem cells, and cell adhesion, viability, and expression of specific marker genes were measured. Treatment of PEEK with AFN (PEEK‐AFN) was found to enable better osteoblast adhesion, spreading, and proliferation; the activity of alkaline phosphatase (an early osteogenic differentiation marker) was also found to be enhanced post‐treatment. Furthermore, PEEK‐AFN was able to modulate macrophage polarization and down regulated the expression of proinflammatory factors via inhibiting the NF‐κB pathway. Thus, treatment of PEEK with AFN could promote M2 polarization of the macrophages and stimulate the differentiation of osteoblasts. These results provide valuable information that could facilitate the use of PEEK‐based composites as bone implant materials.

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“…Hybridization of this tag sequence to a membrane-lytic short peptide, GNU-7, was shown to improve the antimicrobial efficacy of parent GNU-7 by 16-fold toward P. aeruginosa both in in vitro and in vivo model systems. LPS-targeting GNU-7 variants were also developed through hybridization with lactoferrin (28-34), BPI (84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99), and de novo sequence (125). Chimeric bactericidal peptides targeted to E. faecalis (123) and S. mutans (124) were also developed based on the species-specific pheromones.…”

Section: Hybridizationmentioning

confidence: 99%

“…Specifically, KE-18 showed anti-biofilm activity even at sub-killing concentration against yeast and bacteria (81). Further variants of KR-12 were also reported and the less cationic analogs, a5 and a6, were shown to possess potent immunomodulatory, antibiofilm, antimicrobial, and osteogenic properties (82)(83)(84)(85). Variants of LL-23, corresponding to 23 N-terminal residues of LL-37, were generated through substitution of Ser→ Ala and Ser→ Val at the 9th position.…”

Section: Introductionmentioning

confidence: 98%

Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

et al. 2020

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The golden era of antibiotics, heralded by the discovery of penicillin, has long been challenged by the emergence of antimicrobial resistance (AMR). Host defense peptides (HDPs), previously known as antimicrobial peptides, are emerging as a group of promising antimicrobial candidates for combatting AMR due to their rapid and unique antimicrobial action. Decades of research have advanced our understanding of the relationship between the physicochemical properties of HDPs and their underlying antimicrobial and non-antimicrobial functions, including immunomodulatory, anti-biofilm, and wound healing properties. However, the mission of translating novel HDP-derived molecules from bench to bedside has yet to be fully accomplished, primarily attributed to their intricate structure-activity relationship, toxicity, instability in host and microbial environment, lack of correlation between in vitro and in vivo efficacies, and dwindling interest from large pharmaceutical companies. Based on our previous experience and the expanding knowledge gleaned from the literature, this review aims to summarize the novel strategies that have been employed to enhance the antimicrobial efficacy, proteolytic stability, and cell selectivity, which are all crucial factors for bench-to-bedside translation of HDP-based treatment. Strategies such as residues substitution with natural and/or unnatural amino acids, hybridization, L-to-D heterochiral isomerization, C-and N-terminal modification, cyclization, incorporation with nanoparticles, and "smart design" using artificial intelligence technology, will be discussed. We also provide an overview of HDP-based treatment that are currently in the development pipeline.

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KR-12-a5 Reverses Adverse Effects of Lipopolysaccharides on HBMSC Osteogenic Differentiation by Influencing BMP/Smad and P38 MAPK Signaling Pathways

Cited by 14 publications

References 66 publications

Mir24-2-5p suppresses the osteogenic differentiation with Gnai3 inhibition presenting a direct target via inactivating JNK-p38 MAPK signaling axis

Mir24-2-5p suppresses the osteogenic differentiation with Gnai3 inhibition presenting a direct target via inactivating JNK-p38 MAPK signaling axis

Hydrofluoric acid and nitric acid cotreatment for biofunctionalization of polyetheretherketone in M2 macrophage polarization and osteogenesis

Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

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