scholarly journals The Process of Acclimation to Chronic Hypoxia Leads to Submandibular Gland and Periodontal Alterations: An Insight on the Role of Inflammatory Mediators

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Antonela Romina Terrizzi ◽  
María Inés Conti ◽  
María Pilar Martínez ◽  
Javier Fernández-Solari
Keyword(s):  
Bone Loss ◽  
Molecular Mechanisms ◽  
Salivary Secretion ◽  
Gingival Tissue ◽  
Prostaglandin E ◽  
Bone Resorption Marker ◽  
Mrna Levels ◽  
Hypoxic Acclimation ◽  
Hypoxia Acclimation

The exposition to hypoxia is a stressful stimulus, and the organism develops acclimation mechanisms to ensure homeostasis, but if this fails, it leads to the development of pathological processes. Considering the large number of people under hypoxic conditions, it is of utmost importance to study the mechanisms implicated in hypoxic acclimation in oral tissues and the possible alteration of some important inflammatory markers that regulate salivary and periodontal function. It is the aim of the present study to analyze submandibular (SMG) and periodontal status of animals chronically exposed to continuous (CCH) or intermittent (CIH) hypoxia in order to elucidate the underlying molecular mechanisms that may lead to hypoxic acclimation. Adult Wistar rats were exposed to CCH or CIH simulating 4200 meters of altitude during 90 days. Salivary secretion was decreased in animals exposed to hypoxia, being lower in CIH, together with increased prostaglandin E2 (PGE2) content, TBARS concentration, and the presence of apoptotic nuclei and irregular secretion granules in SMG. AQP-5 mRNA levels decreased in both hypoxic groups. Only the CCH group showed higher HIF-1α staining, while CIH alone exhibited interradicular bone loss and increased concentration of the bone resorption marker CTX-I. In summary, animals exposed to CIH show a worse salivary secretion rate, which related with higher levels of PGE2, suggesting a negative role of this inflammatory mediator during hypoxia acclimation. We link the weak immunorreactivity of HIF-1α in CIH with improper hypoxia acclimation, which is necessary to sustaining SMG physiology under this environmental condition. The alveolar bone loss observed in CIH rats could be due mainly to a direct effect of PGE2, as suggested by its higher content in gingival tissue, but also to the indirect effect of hyposalivation. This study may eventually contribute to finding therapeutics to treat the decreased salivary flow, improving in that way oral health.

scholarly journals Periodontitis Vaccine Decreases Local Prostaglandin E2 Levels in a Primate Model

2004 ◽  
Vol 72 (2) ◽  
pp. 1166-1168 ◽  
Author(s):  
Frank A. Roberts ◽  
Laura S. Houston ◽  
Sheila A. Lukehart ◽  
Lloyd A. Mancl ◽  
G. Rutger Persson ◽  
...  
Keyword(s):  
Bone Loss ◽  
Gingival Crevicular Fluid ◽  
Prostaglandin E ◽  
Primate Model ◽  
Necrosis Factor Alpha ◽  
Periodontal Destruction ◽  
Factor Alpha ◽  
Crevicular Fluid ◽  
Necrosis Factor

ABSTRACT Interleukin-1β, tumor necrosis factor alpha, prostaglandin E2 (PGE2), and Porphyromonas gingivalis-specific immunoglobulin G levels in gingival crevicular fluid were measured in primates immunized with a P. gingivalis vaccine followed by ligature-induced periodontitis. Only PGE2 levels were dramatically suppressed (P < 0.0001) in immunized animals versus controls. A significant correlation (P < 0.027) was also found between PGE2 levels and decreased bone loss scores. This study presents the first evidence of a potential mechanism involved in periodontitis vaccine-induced suppression of bone loss in a nonhuman primate model and offers insight into the role of PGE2 in periodontal destruction.

scholarly journals Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression

2017 ◽  
Vol 6 (3) ◽  
pp. 121-128 ◽  
Author(s):  
Xuhua Mao ◽  
Hucheng Chen ◽  
Junmin Tang ◽  
Liangliang Wang ◽  
Tingting Shu
Keyword(s):  
High Glucose ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Mrna Levels ◽  
Β Cell ◽  
Min6 Cells ◽  
Hepcidin Expression ◽  
Insulin Synthesis

Objective Gluco-toxicity is a term used to convey the detrimental effect of hyperglycemia on β-cell function through impaired insulin synthesis. Although it is known that the expression and activity of several key insulin transcription regulators is inhibited, other molecular mechanisms that mediate gluco-toxicity are poorly defined. Our objective was to explore the role of hepcidin in β-cell gluco-toxicity. Design We first confirmed that high glucose levels inhibited hepcidin expression in the mouse insulinoma cell line, MIN6. The downregulation of hepcidin decreased Pdx-1 expression, which reduced insulin synthesis. Methods MIN6 cells were exposed to high glucose concentrations (33.3 mmol/L). Glucose-stimulated insulin secretion (GSIS) and serum hepcidin levels were measured by ELISA. The mRNA levels of insulin1, insulin2, Pdx-1 and hepcidin were measured by real-time polymerase chain reaction. Western blot analysis was used to detect the changes in PDX-1 expression. Transient overexpression with hepcidin was used to reverse the downregulation of Pdx-1 and insulin synthesis induced by gluco-toxicity. Results Exposure of MIN6 cells to high glucose significantly decreased GSIS and inhibited insulin synthesis as well as Pdx-1 transcriptional activity and expression at both the mRNA and protein levels. High glucose also decreased hepcidin expression and secretion. Hepcidin overexpression in MIN6 cells partially reversed the gluco-toxicity-induced downregulation of Pdx-1 and insulin expression and improved GSIS. The restoration of insulin synthesis by transfection of a hepcidin overexpression plasmid confirmed the role of hepcidin in mediating the gluco-toxic inhibition of insulin synthesis. Conclusions Our observations suggest that hepcidin is associated with gluco-toxicity-reduced pancreatic β-cell insulin synthesis in type 2 diabetes by inhibiting Pdx-1 expression.

scholarly journals Mixed lineage kinase domain-like pseudokinase mediated necroptosis aggravates periodontitis progression

2021 ◽  
Author(s):  
Yanan Yang ◽  
Lingxia Wang ◽  
Haibing Zhang ◽  
Lijun Luo
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Porphyromonas Gingivalis ◽  
Alveolar Bone ◽  
Alveolar Bone Loss ◽  
Mrna Levels ◽  
Genetic Ablation ◽  
Osteoclast Activation

Abstract Necroptosis is a form of cell death that is reportedly involved in the pathogenesis of periodontitis. However, the role of Mlkl-involved necroptosis remains unclear. Herein, we aim to explore the role of MLKL-mediated necroptosis in periodontitis in vitro and in vivo. Expression of RIPK3, MLKL, and phosphorylated MLKL is observed in gingival tissues obtained from healthy subjects or patients with periodontitis. Viability of Porphyromonas gingivalis lipopolysaccharide (LPS-Pg)-treated cells was detected. In wild type or Mlkl deficiency mice with ligature-induced periodontitis, alveolar bone loss and osteoclast activation were assessed. mRNA levels of inflammatory cytokines in bone marrow-derived macrophages were tested by qRT-PCR. Increased expression of RIPK3, MLKL, and phosphorylated MLKL is observed in gingival tissues obtained from patients with periodontitis. Porphyromonas gingivalis lipopolysaccharide (LPS-Pg)-treated cells developed necroptosis after caspase inhibition and negatively regulated the NF-κB signaling pathway. In mice with ligature-induced periodontitis, Mlkl deficiency reduced alveolar bone loss and weakened osteoclast activation. Furthermore, genetic ablation of Mlkl in LPS-Pg-treated bone marrow-derived macrophages increased the mRNA levels of tumor necrosis factor-α, interleukin (Il)-1β, Il-6, cyclooxygenase 2, matrix metalloproteinase 9, and receptor activator of nuclear factor kappa-B ligand. Our data indicated that MLKL-mediated necroptosis aggravates the development of periodontitis in a Mlkl-deficient mouse. And this will provide a new sight for the understanding of etiology and therapies of periodontitis.

scholarly journals The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice

2021 ◽  
Vol 23 (1) ◽  
pp. 55
Author(s):  
Zamzam Awida ◽  
Almog Bachar ◽  
Hussam Saed ◽  
Anton Gorodov ◽  
Nathalie Ben-Califa ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Loss ◽  
Bone Mineral ◽  
Molecular Mechanisms ◽  
Mineral Density ◽  
Female Mice ◽  
Epo Receptor

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin−CD11b−Ly6Chi CD115+, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.

The regulatory role of Rho GTPases and their substrates in osteoclastogenesis

2020 ◽  
Vol 21 ◽  
Author(s):  
Lin Gao ◽  
Lingbo Kong ◽  
Yuanting Zhao
Keyword(s):  
Bone Loss ◽  
Therapeutic Target ◽  
Rho Gtpases ◽  
Molecular Mechanisms ◽  
Special Role ◽  
Cellular Functions ◽  
Potential Therapeutic Target ◽  
Cytoskeletal Organization ◽  
Osteoclastic Differentiation

: Pathological bone loss diseases (osteolysis, Paget’s diseases) are commonly caused by the over differentiation and activity of osteoclasts. The Rho GTPases family members Rac1/2 (Rac1 and Rac2) have been reported for their special role in exerting multiple cellular functions during osteoclastic differentiation, which including the most prominent function on dynamic actin cytoskeleton rearranging. Besides that, the increasing studies demonstrated the regulating effects of Rac1/2 on osteoclastic cytoskeletal organization is through the GEFs member Dock5. Although the amount of relevant studies on this topic still limited, there are several excellent studies have been reported for extensively explored the molecular mechanisms involved in Rac1/2 and Dock5 during the osteoclastogenesis regulation, as well as their role as the therapeutic target in bone loss disesases. Herein in this review, we aim to focus on recent advances studies for extensively understanding the role of Rho GTPases Rac1/2 and Dock5 in osteoclastogenesis, as well as their role as a potential therapeutic target in regulating osteoclastogenesis.

scholarly journals mPGES-1-Derived PGE2 Contributes to Indoxyl Sulfate-Induced Mesangial Cell Proliferation

2017 ◽  
Vol 43 (1) ◽  
pp. 271-281
Author(s):  
Shuzhen Li ◽  
Zhenzhen Sun ◽  
Guixia Ding ◽  
Wei Gong ◽  
Jing Yu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mesangial Cell ◽  
Cell Number ◽  
Pathological Process ◽  
Indoxyl Sulfate ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Mesangial Cell Proliferation ◽  
Cox 2

Background/Aims: We previously reported that indoxyl sulfate (IS) could cause mesangial cell (MC) proliferation via a cyclooxygenase (COX)-2-dependent mechanism. However, the specific prostaglandin contributing to COX-2 effect on IS-induced MC proliferation remained unknown. Thus, the present study was undertaken to examine the role of microsomal prostaglandin E synthase-1 (mPGES-1)-derived Prostaglandin E2 (PGE2) in IS-induced MC proliferation. Methods: IS was administered to the MCs with or without mPGES-1 siRNA pretreatment to induce the MC proliferation which was determined by cell cycle analysis, DNA synthesis, and the expressions of cyclins. In another experimental setting, PGE2 was applied to the MCs to examine its direct effect on MC proliferation, as well as the regulation of prostaglandin E receptors (EPs) by qRT-PCR. Results: With the administration of IS, mPGES-1(not mPGES-2 and cytosolic PGES) was significantly upregulated at both protein and mRNA levels in line with a promoted MC proliferation. Interestingly, silencing mPGES-1 reduced cell number in S and G2 phases and blocked the upregulation of cyclin A2 and cyclin D1 in parallel with blunted PGE2 release after IS treatment, indicating that mPGES-1-derived PGE2 could contribute to MC proliferation. Furthermore, we confirmed that exogenous PGE2 could directly trigger the proliferative response in MCs. Lastly, we observed a selective upregulation of EP2 after PGE2 treatment and enhanced phosphorylation of NF-κB following IS administration in MCs, suggesting the potential involvements of EP2 and NF-κB in this pathological process. Conclusion: mPGES-1-derived PGE2 contributed to IS-induced mesangial cell proliferation.

scholarly journals A regulatory role of LPCAT1 in the synthesis of inflammatory lipids, PAF and LPC, in the retina of diabetic mice

2009 ◽  
Vol 297 (6) ◽  
pp. E1276-E1282 ◽  
Author(s):  
Long Cheng ◽  
Xiao Han ◽  
Yuguang Shi
Keyword(s):  
Diabetic Retinopathy ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Regulatory Role ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Acyltransferase Activity ◽  
Onset Of Diabetes ◽  
Anti Inflammatory

Platelet-activating factor (PAF) and lysophosphatidylcholine (LPC) are potent inflammatory lipids. Elevated levels of PAF and LPC are associated with the onset of diabetic retinopathy and neurodegeneration. However, the molecular mechanisms underlying such defects remain elusive. LPCAT1 is a newly reported lysophospholipid acyltransferase implicated in the anti-inflammatory response by its role in conversion of LPC to PC. Intriguingly, the LPCAT1 enzyme also catalyzes the synthesis of PAF from lyso-PAF with use of acetyl-CoA as a substrate. The present studies investigated regulatory roles of LPCAT1 in the synthesis of inflammatory lipids during the onset of diabetes. Our work shows that LPCAT1 plays an important role in the inactivation of PAF by catalyzing the synthesis of alkyl-PC, an inactivated form of PAF with use of acyl-CoA and lyso-PAF as substrates. In support of a role of LPCAT1 in anti-inflammatory responses in diabetic retinopathy, LPCAT1 is most abundantly expressed in the retina. Moreover, LPCAT1 mRNA levels and acyltransferase activity toward lyso-PAF and LPC were significantly downregulated in retina and brain tissues in response to the onset of diabetes in Ins2 Akita and db/db mice, mouse models of type 1 and type 2 diabetes, respectively. Conversely, treatment of db/db mice with rosiglitazone, an antidiabetes compound, significantly upregulated LPCAT1 mRNA levels concurrently with increased acyltransferase activity in the retina and brain. Collectively, these findings identified a novel regulatory role of LPCAT1 in catalyzing the inactivation of inflammatory lipids in the retina of diabetic mice.

scholarly journals CTGF Attenuates Tendon-Derived Stem/Progenitor Cell Aging

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Yun-feng Rui ◽  
Min-hao Chen ◽  
Ying-juan Li ◽  
Long-fei Xiao ◽  
Peng Geng ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Tendon Healing ◽  
Vital Role ◽  
Tissue Growth ◽  
Molecular Therapy ◽  
Cell Aging ◽  
Cell Cycle Distribution ◽  
Mrna Levels ◽  
Age Related

Aged tendon-derived stem/progenitor cells (TSPCs) lead to age-related tendon disorders and impair tendon healing. However, the underlying molecular mechanisms of TSPC aging remain largely unknown. Here, we investigated the role of connective tissue growth factor (CTGF) in TSPC aging. CTGF protein and mRNA levels were markedly decreased in the aged TSPCs. Moreover, recombinant CTGF attenuates TSPC aging and restores the age-associated reduction of self-renewal and differentiation of TSPCs. In addition, cell cycle distribution of aged TSPCs was arrested in the G1/S phase while recombinant CTGF treatment promoted G1/S transition. Recombinant CTGF also rescued decreased levels of cyclin D1 and CDK4 and reduced p27kip1 expression in aged TSPCs. Our results demonstrated that CTGF plays a vital role in TSPC aging and might be a potential target for molecular therapy of age-related tendon disorders.

scholarly journals Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers

2010 ◽  
Vol 299 (5) ◽  
pp. G1139-G1146 ◽  
Author(s):  
Takako Ae ◽  
Takashi Ohno ◽  
Youichiro Hattori ◽  
Tatsunori Suzuki ◽  
Kanako Hosono ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Growth Factor ◽  
Ulcer Healing ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Gastric Ulcers ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Healing Processes

The importance of prostaglandin E2 in various pathophysiological events emphasizes the necessity of understanding the role of PGE synthases (PGESs) in vivo. However, there has been no report on the functional relevance of microsomal PGES-1 (mPGES-1) to the physiological healing processes of gastric ulcers, or to angiogenesis, which is indispensable to the healing processes. In this report, we tested whether mPGES-1 plays a role in the healing of gastric ulcers and in the enhancement of angiogenesis using mPGES-1 knockout mice (mPGES-1 KO mice) and their wild-type (WT) counterparts. Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcers were measured thereafter. mPGES-1 together with cyclooxygenase-2 were induced in the granulation tissues compared with normal stomach tissues. The healing of acetic acid-induced ulcers was significantly delayed in mPGES-1 KO mice compared with WT. This was accompanied with reduced angiogenesis in ulcer granulation tissues, as estimated by CD31 mRNA levels determined by real-time PCR and the microvessel density in granulation tissues. The mRNA levels of proangiogenic growth factors, such as transforming growth factor-β, basic fibroblast growth factor, and connective tissue growth factor in ulcer granulation tissues determined were reduced in mPGES-1 KO mice compared with WT. The present results suggest that mPGES-1 enhances the ulcer-healing processes and the angiogenesis indispensable to ulcer healing, and that a selective mPGES-1 inhibitor should be used with care in patients with gastric ulcers.

scholarly journals IL-6 Induced by Periodontal Inflammation Causes Neuroinflammation and Disrupts the Blood–Brain Barrier

2020 ◽  
Vol 10 (10) ◽  
pp. 679
Author(s):  
Daisuke Furutama ◽  
Shinji Matsuda ◽  
Yosuke Yamawaki ◽  
Saki Hatano ◽  
Ai Okanobu ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Gingival Tissue ◽  
Mrna Levels ◽  
Expression Levels ◽  
Protein Levels ◽  
Periodontal Inflammation ◽  
Blood Brain

Background: Periodontal disease (PD) is a risk factor for systemic diseases, including neurodegenerative diseases. The role of the local and systemic inflammation induced by PD in neuroinflammation currently remains unclear. The present study investigated the involvement of periodontal inflammation in neuroinflammation and blood–brain barrier (BBB) disruption. Methods: To induce PD in mice (c57/BL6), a ligature was placed around the second maxillary molar. Periodontal, systemic, and neuroinflammation were assessed based on the inflammatory cytokine mRNA or protein levels using qPCR and ELISA. The BBB permeability was evaluated by the mRNA levels and protein levels of tight junction-related proteins in the hippocampus using qPCR and immunofluorescence. Dextran tracing in the hippocampus was also conducted to examine the role of periodontal inflammation in BBB disruption. Results: The TNF-α, IL-1β, and IL-6 levels markedly increased in gingival tissue 1 week after ligation. The IL-6 serum levels were also increased by ligature-induced PD. In the hippocampus, the IL-1β mRNA expression levels were significantly increased by ligature-induced PD through serum IL-6. The ligature-induced PD decreased the claudin 5 expression levels in the hippocampus, and the neutralization of IL-6 restored its levels. The extravascular 3-kDa dextran levels were increased by ligature-induced PD. Conclusions: These results suggest that the periodontal inflammation-induced expression of IL-6 is related to neuroinflammation and BBB disruption in the hippocampus, ultimately leading to cognitive impairment. Periodontal therapy may protect against neurodegenerative diseases.

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