Current application and future perspectives of antimicrobial degradable bone substitutes for chronic osteomyelitis.

Chronic osteomyelitis remains a persistent challenge for the surgeons due to its refractory nature. Generally, treatment involves extensive debridement of necrotic bone, filling of dead space, adequate antimicrobial therapy, bone reconstruction, and rehabilitation. However, the optimal choice of bone substitute to manage the bone defect remains debatable. This paper reviewed the clinical evidence for antimicrobial biodegradable bone substitutes in the treatment of osteomyelitis in recent years. Indeed, this combination was proved to eradicate infection and facilitate bone reconstruction, which might reduce the cost and hospital stay. Handling was associated with increased risk of unwanted side effect to affect bone healing. The study provides some valuable insights into the clinical evaluation of treatment outcomes in the aspects of infection eradication, bone reconstruction, and complications caused by materials. However, achieving complete infection eradication and subsequently perfect bone reconstruction remains challenging in compromised conditions, hence advanced innovative bone substitutes are imperative. In this review, we mainly focus on the desired functional effects of advanced bone substitutes on infection eradication and bone reconstruction from the future perspective. Handling property was optimized to simplify surgery process. It is expected that this review will provide an important opportunity to enhance the understanding of the design and application of innovative biomaterials to synergistically eradicate infection and restore integrity and function of bone.

Association between gingival bleeding and hematuria as biomarkers of periodontitis and renal disease: a review.

Gingival bleeding is a common complaint and symptom in patients with periodontitis. In clinics, gingival bleeding is regarded as an important sign of gingival inflammation, which is also of great significance in predicting the activity of periodontitis. Existing research has indicated that periodontitis has an impact on distant sites, such as the kidney. Hematuria is the principal feature of glomerular disease, which can reflect the degree and condition of glomerular inflammation. Previous studies have revealed an association between periodontal diseases with renal diseases, so a study is necessary to discuss their representative signs of them. For the moment, there are no reports that are concerned about the correlation between gingival bleeding with hematuria. The main point of this text is to review the potential association between gingival bleeding with hematuria, reveal their underlying mechanisms, and provide instructions for the therapy of periodontitis and glomerular diseases.

The role of secreted osteoclastogenic factor of activated T cells in bone remodeling.

The process of bone remodeling is connected with the regulated balance between bone cell populations (including bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte). And the mechanism of bone remodeling activity is related to the major pathway, receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) signaling axis. Recently, researchers have found a novel cytokine secreted by activated T cells, which is related to osteoclastogenesis in the absence of osteoblasts or RANKL, leading to bone destruction. They name it the secreted osteoclastogenic factor of activated T cells (SOFAT). SOFAT has been proven to play an essential role in bone remodeling, like mediating the bone resorption in rheumatoid arthritis (RA) and periodontitis. In this review, we outline the latest research concerning SOFAT and discuss the characteristics, location, and regulation of SOFAT. We also summarize the clinical progress of SOFAT and assume the future therapeutic target in some diseases related to bone remodeling.

The role of endoplasmic reticulum stress in the pathophysiology of periodontal disease.

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.

CDK5RAP3, an essential regulator of checkpoint, interacts with RPL26 and maintains the stability of cell growth.

PURPOSE AND MATERIALS: CDK5RAP3 (CDK5 regulatory subunit associated protein 3) was originally identified as a binding protein of CDK5. It is a crucial gene controlling biological functions, such as cell proliferation, apoptosis, invasion, and metastasis. Although previous studies have also shown that CDK5RAP3 is involved in a variety of signalling pathways, however, the mechanism of CDK5RAP3 remains largely undefined. This study utilized MEFs from conditional knockout mice to inhibit CDK5RAP3 and knockdown CDK5RAP3 in MCF7 to explore the role of CDK5RAP3 in cell growth, mitosis, and cell death. RESULTS: CDK5RAP3 was found to be widely distributed throughout the centrosome, spindle, and endoplasmic reticulum, indicating that it is involved in regulating a variety of cellular activities. CDK5RAP3 deficiency resulted in instability of cell growth. CDK5RAP3 deficiency partly blocks the cell cycle in G2 /M by downregulating CDK1 (Cyclin-dependent kinase 1) and CCNB1 (Cyclin B1) expression levels. The cell proliferation rate was decreased, thereby slowing down the cell growth rate. Furthermore, the results showed that CDK5RAP3 interacts with RPL26 (ribosome protein L26) to regulate the mTOR pathway. CDK5RAP3 and RPL26 deficiency inhibited mTOR/p-mTOR protein and induce autophagy, resulting in an upregulation of the percentage of apoptosis, and the upregulated percentage of apoptosis also slowed cell growth. CONCLUSIONS: Our experiments show that CDK5RAP3 interacts with RPL26 and maintains the stability of cell growth. It shows that CDK5RAP3 plays an important role in cell growth and can be used as the target of gene medicine.

Local delivery of simvastatin maintains tooth anchorage during mechanical tooth moving via anti-inflammation property and AMPK/MAPK/NF-kB inhibition.

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.

Immunological regulatory effect of flavonoid baicalin on innate immune toll-like receptors.

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.

The role of autophagy in the pathogenesis of periodontal disease.

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.

Indispensable role of the Ubiquitin-fold modifier 1-specific E3 ligase in maintaining intestinal homeostasis and controlling gut inflammation.

Intestinal exocrine secretory cells, including Paneth and goblet cells, have a pivotal role in intestinal barrier function and mucosal immunity. Dysfunction of these cells may lead to the pathogenesis of human diseases such as inflammatory bowel disease (IBD). Therefore, identification and elucidation of key molecular mechanisms that regulate the development and function of these exocrine cells would be crucial for understanding of disease pathogenesis and discovery of new therapeutic targets. The Ufm1 conjugation system is a novel ubiquitin-like modification system that consists of Ufm1 (Ubiquitin modifier 1), Uba5 (Ufm1-activating enzyme, E1), Ufc1 (Ufm1-conjugating enzyme, E2) and poorly characterized Ufm1 E3 ligase(s). Recent mouse genetic studies have demonstrated its indispensable role in embryonic development and hematopoiesis. Yet its role in other tissues and organs remains poorly defined. In this study, we found that both Ufl1 and Ufbp1, two key components of the Ufm1 E3 ligase, were highly expressed in the intestinal exocrine cells. Ablation of either Ufl1 and Ufbp1 led to significant loss of both Paneth and goblet cells, which in turn resulted in dysbiotic microbiota and increased susceptibility to experimentally induced colitis. At the cellular and molecular levels, Ufbp1 deficiency caused elevation of endoplasmic reticulum stress and activation of the Unfolded Protein Response (UPR) and cell death program. Administration of small molecular chaperone partially prevented loss of Paneth cells caused by acute Ufbp1 deletion. Taken together, our results have provided unambiguous evidence for the crucial role of the Ufm1 E3 ligase in maintenance of intestinal homeostasis and protection from inflammatory diseases.

Expression of matrix metalloproteinases-2, -9 and reversion-inducing cysteine-rich protein with Kazal motifs in gingiva in periodontal health and disease.

BACKGROUND AND OBJECTIVE: 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. MATERIAL AND METHODS: 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. RESULTS: 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(P<0.05), 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. CONCLUSION: 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.

Potential Role of Reversion-Inducing Cysteine-Rich Protein with Kazal Motifs (RECK) in Regulation of Matrix Metalloproteinases (MMPs) Expression in Periodontal Diseases.

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.

Demineralized Dentin as a Semi-Rigid Barrier for Guiding Periodontal Tissue Regeneration.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Inhibitory effects of baicalin on IL-1beta- induced MMP-1/TIMP-1 and its stimulated effect on collagen-I production in human periodontal ligament cells.

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<0.05) stimulated the production of MMP-1 by PDLC at both the transcriptional and the translational level. Different concentration PMA enhanced TIMP-1 mRNA expression, but IL-1beta did not affect the TIMP-1 mRNA expression. Moreover, in the presence of 100 ng/ml baicalin, both the MMP-1 and TIMP-1 mRNA expression were down regulated. The present study suggests that baicalin inhibits IL-1beta induction of MMP-1 by altering the mRNA and protein levels. In addition, baicalin may increase Collagen I mRNA and total protein levels in PDLC.

Toll-like receptors 2 and 4 gene polymorphisms in a Chinese population with periodontitis.

OBJECTIVES: 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. METHOD AND MATERIALS: 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. RESULTS: 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. CONCLUSION: 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.

Inhibitory effect of flavonoid baicalin on degranulation of human polymorphonuclear leukocytes induced by interleukin-8: potential role in periodontal diseases.

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.