HMGB1 Promotes Intraoral Palatal Wound Healing through RAGE-Dependent Mechanisms

Tancharoen, Salunya; Gando, Satoshi; Shrestha, Binita; Nagasato, Tomoka; Kikuchi, Kiyoshi; Nawa, Yuko; Dararat, Pornpen; Yamamoto, Mika; Narkpinit, Somphong; Maruyama, Ikuro

doi:10.3390/ijms17111961

Cited by 25 publications

(20 citation statements)

References 54 publications

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“…Normal human oral mucosa is continuously prone to micro-tissue injury. Several recent studies showed the importance of HMGB1 in normal wound healing in vitro and in vivo, including both the skin and oral contexts (25)(26)(27). HMGB1 is shown to strongly influence sterile scar formation (28).…”

Section: Discussionmentioning

confidence: 99%

Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes

et al. 2019

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Ehlers-Danlos syndromes (EDS) are clinically and genetically heterogeneous disorders characterized by soft connective tissue alteration like joint hypermobility and skin hyper-extensibility. We previously identified heterozygous missense mutations in the C1R and C1S genes, coding for the complement C1 proteases, in patients affected by periodontal EDS, a specific EDS subtype hallmarked by early severe periodontitis leading to premature loss of teeth and connective tissue alterations. Up to now, there is no clear molecular link relating the nominal role of the C1r and C1s proteases, which is to activate the classical complement pathway, to these heterogeneous symptoms of periodontal EDS syndrome. We aim therefore to elucidate the functional effect of these mutations, at the molecular and enzymatic levels. To explore the molecular consequences, a set of cell transfection experiments, recombinant protein purification, mass spectroscopy and N-terminal analyses have been performed. Focusing on the results obtained on two different C1S variants, namely p.Val316del and p.Cys294Arg, we show that HEK293-F cells stably transfected with the corresponding C1s variant plasmids, unexpectedly, do not secrete the full-length mutated C1s, but only a truncated Fg40 fragment of 40 kDa, produced at very low levels. Detailed analyses of the Fg40 fragments purified for the two C1s variants show that they are identical, which was also unexpected. This suggests that local misfolding of the CCP1 module containing the patient mutation exposes a novel cleavage site, between Lys353 and Cys354, which is not normally accessible. The mutation-induced Fg40 fragment contains the intact C-terminal serine protease domain but not the N-terminal domain mediating C1s interaction with the other C1 subunits, C1r, and C1q. Thus, Fg40 enzymatic activity escapes the normal physiological control of C1s activity within C1, potentially providing a loss-of-control. Comparative enzymatic analyses show that Fg40 retains the native esterolytic activity of C1s, as well as its cleavage efficiency toward the ancillary alarmin HMGB1 substrate, for example, whereas the nominal complement C4 activation cleavage is impaired. These new results open the way to further molecular explorations possibly involving subsidiary C1s targets.

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Section: Discussionmentioning

confidence: 99%

Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes

et al. 2019

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“…Sections of 6 μm thickness were obtained. Mallory’s azan staining was used to visualize collagen fibers, and Mayer’s hematoxylin stain was used to examine the parameters of inflammatory cell infiltration, vasodilation, presence of hemorrhagic areas, edema, ulcerations, and abscesses [ 42 ]. Histopathological sections were analyzed under light microscopy.…”

Section: Methodsmentioning

confidence: 99%

“…Cell viability was performed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay according to a method previously described [ 42 ]. Briefly, cells were treated with ANT-rich extracts for 1 mg/mL and 5-FU for 1, 5, and 10 μg/mL for 2 days and incubated with MTT (0.5 mg/mL) for 3 h. Formazan crystal was solubilized by adding DMSO for 16 h.…”

Section: Methodsmentioning

confidence: 99%

Anthocyanins Extracted from Oryza sativa L. Prevent Fluorouracil-Induced Nuclear Factor-κB Activation in Oral Mucositis: In Vitro and In Vivo Studies

Tancharoen

Shakya

Narkpinit

et al. 2018

IJMS

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This study aims to investigate the immunomodulatory effect of anthocyanins (ANTs) from Oryza sativa L. extracts on 5-fluorouracil (5-FU)-induced oral mucositis, using a rat model and oral keratinocytes. ANTs were detected by high-performance liquid chromatography (HPLC)-electrospray ionization mass spectrometry. Animals were randomly given varying doses of ANT-rich extract treatment (500 mg/kg and 1000 mg/kg) in the absence or presence of 5-FU-induced mucositis. Buccal mucosae were photographed and scored for macroscopic analysis and incisional biopsies of cheek pouches were collected for microscopic examination of oral mucositis. 5-FU caused marked hemorrhage, extensive ulcerations and abscesses compared to non-treated animals with slight erythema. Histologically, a loss of collagen bundles and inflammatory cell infiltrates was observed. After 29 days of ANT treatment, lesions resolved, and abundant collagen fibers were evident in the lamina propria. Buccal mucosa of 5-FU-injected rats showed increased Nuclear factor-kappa B (NF-κB) p50 and p65 in oral keratinocytes. The administration of ANT reduced NF-κB-positive cells in 5-FU rats (p < 0.001) compared to the non-treatment group. In oral keratinocytes, ANT treatment significantly restored 5-FU-induced growth inhibition and impaired the nuclear accumulation of NF-κB p50 and p65. Our study demonstrated that ANT from Oryza sativa L. exhibited effective anti-inflammatory properties against 5-FU-induced oral mucositis by inhibiting NF-κB activation.

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“…It has been reported that several receptors are implicated in HMGB1-mediated functions including receptor for advanced glycation end products (RAGE) [19]. Recent studies indicated that HMGB1 promotes intraoral palatal wound healing through RAGE-dependent mechanisms [20]. It is found that HMGB1 enhances recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and the signaling pathway is via CXCR4 [19].…”

Section: Discussionmentioning

confidence: 99%

A novel full-reduced HMGB1 and kartogenin-containing bio-active scaffold for meniscus regeneration

Zhi-hong

Zou

et al. 2020

Preprint

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43 44 A novel bio-active scaffold for enhancing wounded meniscus healing has been developed by 45 combination of High mobility group box 1 protein (HMGB1) and kartogenin (KGN) with 46 alginate gel. The properties of the bio-active scaffold were also investigated using an in vitro cell 47 culture model and in vivo rat wounded meniscus healing model. This HMGB1-KGN-containing 48 bioactive scaffold released HMGB1 and KGN into wound area and kept high concentrations of 49 HMGB1 and KGN in the system for more than two weeks. This HMGB1-KGN-containing 50 bioactive scaffold also activated rat bone marrow stem cells (BMSCs) from G0 to GAlert stage and 51 promoted cell proliferation as evidenced by 5-bromo-2-deoxyuridine (BrdU) incorporation 52 testing. Our results also demonstrated that the HMGB1-KGN-containing bioactive scaffold 53 induced cell migration in vitro and recruited the cells to wound area to promote wounded rat 54 meniscus healing in vivo. 55 56 57 58 59 60 61 62 63 64 4 65 66 67The menisci are C-shaped fibrocartilage located between the femoral condyles and tibial plateau 68 to transmit the load across the joint space [1]. Menisci play an important role in joint 69 stabilization, proprioception, lubrication and protection of articular cartilage [2]. Such 70 environment and function lead to meniscus easily injury and damaged meniscus can cause the 71 progression of cartilage degeneration and result in osteoarthritis [3]. Clinical studies have found 72 that it is difficult to regenerate the meniscus due to the specific structural and functional 73 properties of the meniscus tissue [1]. 74 75Histology studies have shown that meniscus is a geometrically and biochemically complex tissue. 76Its outer 1/3 tissue is formed by collagen type I produced by fibroblast-like cells, while its inner 77 2/3 tissue is formed by collagen II and proteoglycan produced by chondrocyte-like cells [4]. 78 Vascularization in meniscus is of high relevance. The meniscus is fully vascularized during fetal 79 development though blood supply diminishes over time, receding to the peripheral 20-30% by 10 80 years of age [4], [1]. 81 82The injury in the avascular zone of the meniscus is generally more complex and broad, and is 83 often associated with a poor prognosis following repair [5]. Promoting the healing process in the 84 avascular zone of the meniscus is an ongoing challenge for both clinical medical doctors and 85 orthopedic researchers [6]. Recently, tissue engineering approaches that involve the use of adult 86 tissue-derived multi-potent stem cells and biomaterial scaffolds have gained increasing attention 87 5 for enhancing the wounded meniscus healing. However, the isolation and culture of stem cells 88 not only need the donor tissue obtained by additional surgical procedure but also take long time 89 and increase contamination risk. Therefore, recruiting stem cells to wound area to enhance 90 wound healing is still a new challenge for orthopedic researchers. 91 92 High mobility group box 1 protein (HMGB1) is a ubiquitously...

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HMGB1 Promotes Intraoral Palatal Wound Healing through RAGE-Dependent Mechanisms

Cited by 25 publications

References 54 publications

Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes

Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes

Anthocyanins Extracted from Oryza sativa L. Prevent Fluorouracil-Induced Nuclear Factor-κB Activation in Oral Mucositis: In Vitro and In Vivo Studies

A novel full-reduced HMGB1 and kartogenin-containing bio-active scaffold for meniscus regeneration

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