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The endoplasmic reticulum (ER) is a principal organelle for folding, post-translational modifications and transport of secretory, luminal, and membrane proteins. ER stress is a condition induced by the accumulation of unfolded or misfolded proteins owing to a variety of physiological and pathological phenomena. To overcome the deleterious effects of ER stress, unfolded protein response (UPR) is initiated to translocate and remove the misfolded and accumulated proteins. Plenty of evidence shows the correlation between ER stress/UPR and the pathology of inflammatory disease. Periodontal disease is a chronic inflammatory disease characterized by the irreversible destruction of periodontal tissues, which associates with the onset and progress of several systemic diseases. Periodontopathic bacterium and pro-inflammatory mediators play a pivotal role in the progress of periodontal disease. Besides, cigarette smoke has long been associated with periodontal disease. As an inflammatory disorder of the periodontium, periodontal disease is highly related to ER stress. In this review, we provide an overview of the pathophysiological effect of ER stress on periodontal disease through five aspects as follow: ER stress and periodontal tissue remodeling, including both soft tissue and hard tissue; ER stress and the inflammation; ER stress and systematic effect during the periodontal disease; last but not least, ER stress and the autophagic apoptosis in cells.

Simvastatin (SMV) could increase tooth anchorage during orthodontic tooth movement (OTM). However, previous studies on its bone‐specific anabolic and anti‐inflammation properties were based on static in vitro and in vivo conditions. AMPK is a stress‐activated kinase that protects tissue against serious damage from overloading inflammation. Rat periodontal ligament cells (PDLCs) were subjected to a serial of SMV concentrations to investigate the optimization that promoted osteogenic differentiation. The PDLCs in static and/or tensile culturing conditions then received the proper concentration SMV. Related factors expression was measured by the protein array, real‐time PCR and Western blot. The 0.05UM SMV triggered osteogenic differentiation of PDLCs. The inhibition of AMPK activation through a pharmacological approach (Compound C) caused dramatic decrease in osteogenic/angiogenic gene expression and significant increase in inflammatory NF‐κB phosphorylation. In contrast, pharmacological activation of AMPK by AICAR significantly inhibited inflammatory factors expression and activated ERK1/2, P38 MAPK phosphorylation. Moreover, AMPK activation induced by SMV delivery significantly attenuated the osteoclastogenesis and decreased the expression of pro‐inflammatory TNF‐α and NF‐κB in a rodent model of OTM. The current studies suggested that SMV could intrigue intrinsic activation of AMPK in PDLCs that promote attenuate the inflammation which occurred under tensile irritation through AMPK/MAPK/NF‐kB Inhibition.

Periodontitis is characterized by pathological destruction of extracellular matrix (ECM) of periodontal tissues. Matrix metalloproteinases (MMPs) promote the occurrence and development of periodontitis by degrading almost all proteins of ECM. RECK (reversion-inducing-cysteine-rich protein with kazal motifs), a novel membrane-anchored inhibitor of MMPs, could regulate the expression of MMP-2 and MMP-9 at post-transcriptional level. The study was to investigate the expression of RECK in healthy and diseased human gingival tissues and to correlate it with the production of MMP-2 and MMP-9.Gingival biopsies were collected from chronic periodontitis patients and periodontally healthy control individuals. The protein and mRNA of RECK, MMP-2 and MMP-9 was determined by immunohistochemistry and semi-quantitative polymerase chain reaction analysis.The expression of RECK protein was mainly confined to the gingival epithelium in inflamed and non-inflamed gingival tissues. Expression of RECK was significantly lower in tissues from chronic periodontitis patients, while the positive expression levels of MMP-2 and MMP-9 in periodontitis specimens were significantly higher. RECK protein expression was negatively correlated to the expressions of MMP-2 and MMP-9 in periodontitis. Moreover, RECK mRNA was significanly lower in diseased gingiva than in healthy samples(P0.05), while MMP-2 and MMP-9 mRNAs were observed overexpressed in periodontal lesions, with no significant correlation between RECK and MMP-2/MMP-9 mRNA shown in periodontally diseased group.The expression of RECK in human healthy and diseased gingiva may contribute to periodontal physiological and pathological processes; low RECK expression may be associated with the enhanced MMP-2 and MMP-9 production in inflamed gingiva.

As an essential component of the innate immune system, Toll-like receptors (TLRs) are a family of well-recognized ligand-binding receptors found in various organisms and initiate host immune responses. Activation of TLRs signaling pathways lead to the induction of numerous genes that function in host defense. Baicalin is a natural compound from the dry raw root of Scutellaria baicalensis (S. baicalensis) and it has been found to exhibit several pharmaceutical actions, such as anti-inflammation, anti-tumor and antivirus. These biological activities are mainly related to the regulatory effect of baicalin on the host immune response. In this review, we provide an overview of the regulation of baicalin on TLRs signaling pathways in various pathological conditions, and highlight potential targets for the development of the regulatory effect of natural compound from traditional Chinese medicine on innate immune system.

Periodontal disease is a chronic inflammatory disease leading to destruction of periodontal tissues. As a local inflammation, periodontopathic bacterium, pro-inflammatory mediators, and local immune response play pivotal role in the progress of periodontal disease. Besides, cigarette smoke has long been associated with periodontal disease and tooth loss. Autophagy is an intracellular degradation process highly conserved from yeast to humans. As a lysosomal degradation pathway of self-digestion, it is critical for maintaining cells homeostasis and development. The role of autophagy has been investigated in oral diseases, such as oral cancer, periapical lesions, and oral candidiasis. Recently, increasing studies investigated the role of autophagy in periodontal disease. In this review, we try to illustrate the effect of autophagy on periodontal disease pathogenesis from 5 aspects: autophagy affects the intracellular infection and survival of bacteria; autophagy has an interaction with periodontal inflammation; autophagy is pivotal in periodontal cells biology and periodontal tissues destruction and reconstruction; autophagy can be induced by cigarette smoke; last but not least, autophagy may affect periodontal disease via endoplasmic reticulum stress.

Periodontal diseases are characterized by pathological destruction of extracellular matrix (ECM) of periodontal tissues. Matrix metalloproteinases (MMPs) are a significant part of the degradation of ECM. However, the regulation of MMPs expression level in periodontal diseases is as yet undetermined. RECK (reversion-inducing cysteine-rich protein with Kazal motifs), a novel membrane-anchored inhibitor of MMPs, could regulate the expressions of MMP-2, 9 and MT1-MMP as a cell surface-signaling molecule. Thus, we propose that RECK may play an important role in regulating MMPs in the ECM degradation of periodontal diseases. The RECK/MMPs signaling pathway could provide a new approach for prevention and treatment of RECK in periodontal diseases by blocking MMPs.

Guided tissue regeneration (GTR) is an accepted approach in the correction of periodontal bone loss. Nonetheless, the deficiencies of commonly applied absorbable membrane, such as flexibility and limited osteoconductive and osteoinductive capability, still leave much room for improvement. Thus, the feasibility of applying demineralized dentin tissue to improve the therapeutic effect of GTR in periodontal regeneration was explored.Demineralized dentin was harvested after acid treatment, and its physiochemical properties were assessed in terms of mineralization density, contact angle, three-point test, and cell attachment. Because of its similar characteristics with bone tissue, dentin that had been acid-treated for 6 hours was chosen to repair a periodontal defect using an induced-periodontitis canine model. Histologic measurements were taken to compare its therapeutic effects to an absorbable membrane group and an untreated group.The demineralized dentin displayed continually decreased hardness and density as the acid etching time was prolonged. Enhanced attachment and spreading of bone marrow mesenchymal stem cells were observed on the 6-hour processed dentin. Furthermore, in the demineralized dentin group, more periodontal tissues were newly formed compared with the biomembrane and untreated groups.Acid etching represents an easy and promising approach to obtain demineralized dentin with desirable properties, similar to bone, for clinical application to promote periodontal tissue regeneration.

A single nucleotide polymorphism in the promoter region of -1607 bp of the human MMP-1 gene has been found to be associated with an increased risk of various inflammatory diseases and cancer metastasis. This study aimed to evaluate the association between the MMP-1 promoter gene polymorphism and chronic periodontitis susceptibility and/or severity in a Chinese population. Genomic DNA was obtained from whole blood samples in 60 Chinese subjects with chronic periodontitis and 50 periodontally healthy subjects as controls. MMP-1 promoter fragment was amplified by polymerase chain reaction, and the polymorphism was analyzed by restriction endonuclease cleavage. In the control subjects, the 2G allele was observed a frequency of 49%, while in severely diseased patients, the 2G allele was seen in 73.4%. The individuals with the 2G allele seem to be approximately three times at greater risk for developing the severe chronic periodontitis (chi(2) = 12.148, P = 0.000). The genotype of 2G/2G was found in 58.5% of the severe periodontitis and 24% of the control group (chi(2) = 11.779, P = 0.003). This study suggests that a single nucleotide polymorphism in the MMP-1 promoter region of -1607 bp may be associated with severe chronic periodontitis in a Chinese population.

Our previous research has proved that baicalin can inhibit the expression of Matrix metalloproteinases (MMPs) in periodontal ligament cells (PDLC) by cell immunocytochemistry. Therefore, the purpose of this study was to address the effects of baicalin on the total protein amount and Collagen I mRNA expression in PDLC, and the regulatory effects on Matrix metalloproteinase-1/ tissue inhibitors of metalloproteinase-1( MMP-1/ TIMP-1 ) expression. PDLC were incubated with 0-1000 ng/ml baicalin for 1, 3 and 5 days. Coomassie Brilliant Blue staining was used to detect the synthesis of the total protein, and the collagen I mRNA expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). PDLC were treated with phorbol 12-myristate 13-acetate (PMA) or interleukin-1beta (IL-1beta) with or without 100 ng/ml baicalin and then mRNA levels for MMP-1 and TIMP-1 were detected. Enzyme linked immunosorbent assay (ELISA) was used to assess the MMP-1 protein. The range of 1-1000 ng/ml baicalin can enhance the amount of the total protein of PDL cells and the response had a dose-dependent manner in the range of 1-100 ng/ml baicalin. And 0-1000 ng/ml baicalin also significantly increased the Collagen I mRNA expression of PDLC. 1-100 pmol/ml PMA and 0.01-1 ng/ml IL-1beta significantly (p

Polymorphisms for toll-like receptor (TLR) 2 gene (Arg677Trp, Arg753Gln) and TLR4 gene (Asp299Gly, Thr399Ile) that are associated with impaired lipopolysaccharide (LPS) signal transduction have recently been described. The present study aimed to investigate the relationship between TLRs 2 and 4 gene polymorphisms and periodontitis in a Chinese population.Forty patients with generalized aggressive periodontitis, 50 patients with chronic periodontitis, and 100 periodontally healthy controls were recruited. All these subjects were of Han Chinese ethnicity. Genomic DNA was extracted from whole-blood samples. TLRs 2 and 4 genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with respective restriction endonucleases. The alleles were detected by polyacrylamide gel electrophoresis and visualized with ethidium bromide.Heterozygosity for the TLR2 Arg677Trp polymorphism was found in all subjects. The TLR2 Arg753Gln mutant allele was not found in periodontitis patients, while a heterozygous frequency of 6% (6 of 100) was detected in the controls. The TLR4 Asp299Gly and Thr399Ile mutant alleles were not found in any of the subjects.TLR2 Arg753Gln polymorphism may not be associated with aggressive or chronic periodontitis in the Chinese population. The prevalence of TLR2 Arp677Trp polymorphism seemed to be rather high, while that of TLR4 Asp299Gly and Thr399Ile polymorphisms seemed to be rather low in the Chinese population, which did not permit any conclusion regarding its effects on periodontitis.

Baicalin is a flavonoid compound purified from the medicinal plant Scutellaria baicalensis Georgi and has been reported to possess anti-inflammatory activity through its ability to complex with chemokines and thus reduces the capacity of chemokines to bind and activate their receptors. In the present study, we investigated whether baicalin could block polymorphonuclear leukocytes (PMNs) degranulation induced by interleukin (IL)-8, a CXC chemokine. Human PMNs were isolated from the peripheral blood of periodontal healthy donors and incubated with various concentrations of IL-8 (preincubated with or without baicalin). The morphology of PMNs was examined by transmission electron microscopy and extracellular concentration of granule component matrix metalloproteinase-8 (MMP-8) was detected by enzyme-linked immunosorbent assay (ELISA). Results showed that IL-8 could significantly induce MMP-8 release from PMNs when compared to control, and its inductive activity was concentration-dependent. But when preincubated with various concentrations of baicalin, the amount of MMP-8 release from PMNs decreased significantly. The present study concludes that baicalin could block MMP-8 release from PMNs induced by IL-8, which suggests that it may play an important role in the prevention and treatment of periodontal disease.