Association between multimorbidity and periodontal disease in Korean adults: A nationwide cross-sectional cohort study.

OBJECTIVES: This study aimed to investigate the association between multimorbidity, which refers to the presence of two or more chronic diseases, and periodontal disease in Korean adults using national survey data. METHODS: A total of 12,440 Korean adults aged ≥19 years were selected from the seventh Korea National Health and Nutrition Examination Survey (KNHANES). We investigated periodontal disease status based on various variables, including the gender, age, educational level, income level, smoking and alcohol drinking status, frequency of daily toothbrushing, and unmet dental treatment needs. Furthermore, periodontal status according to diagnosed chronic diseases, including hypertension, dyslipidaemia, stroke, myocardial infarction, angina pectoris, and diabetes, was investigated, and the association between multimorbidity and periodontal disease was analysed through multiple logistic regression using SAS 9.4. RESULTS: According to the general characteristics of the study participants, the prevalence of periodontal disease was higher in males, smokers, older age, and lower educational and income levels (p < 0.001). Moreover, as the frequency of daily toothbrushing increased, the distribution of periodontal disease decreased (p < 0.001). The prevalence of periodontal disease was higher in those with chronic diseases than in those without chronic diseases and was statistically significantly higher as the number of diagnosed chronic diseases increased (p < 0.001). Additionally, an increase in the number of chronic diseases was observed to increase the prevalence and risk of periodontal disease. CONCLUSION: These results suggest that multimorbidity significantly affects the prevalence of periodontal disease.

Anti-Periodontitis Effects of Dendropanax morbiferus H.Lév Leaf Extract on Ligature-Induced Periodontitis in Rats.

Periodontitis is caused by pathogens in the oral cavity. It is a chronic infectious disease that causes symptoms including gingival bleeding and tooth loss resulting from the destruction of periodontal tissues coupled with inflammation. Dendropanax morbiferus H.Lév (DM) is a natural product that exhibits various biological activities with few side effects. In this study, the potential of DM leaf hot-water extracts (DMWE) as a treatment for periodontitis was determined and its anti-oxidant and anti-inflammatory effects were evaluated. Compounds in DMWE were identified by high-performance liquid chromatography (HPLC) and nitric oxide (NO) and prostaglandin E2 (PGE2) production was measured in RAW 264.7 cells. We measured the gingival index and gingival sulcus depth, and micro-CT was performed in vivo using a ligature-induced periodontitis rat model, which is similar to human periodontitis. The DMWE-treated group exhibited a decrease in cytokine concentration and relieved the gingival index and gingival sulcus depth compared with the periodontitis-induced control group. In addition, micro-CT and histological analysis revealed that DMWE exhibited anti-inflammatory effects and improved alveolar bone loss in periodontitis-induced rats. These findings suggest that DMWE has excellent anti-oxidant and anti-inflammatory effects that protect and prevent periodontal tissue damage and tooth loss caused by the inflammatory response.

Transforming growth factor-ß-regulated fractalkine as a marker of erosive bone invasion in oral squamous cell carcinoma.

Patients with oral squamous cell carcinoma (OSCC) bone invasion are surgically treated with bone resection, which results in severe physical and psychological damage. Here, we investigated the potential of fractalkine (CX3CL1), which is regulated by transforming growth factor (TGF-ß), as a novel biomarker for correct prediction and early detection of OSCC-associated bone invasion. TGF-ß knockdown and treatment with a TGF-ß-neutralizing antibody decreased the level of fractalkine in the culture media of HSC-2 and YD10B OSCC cells. Treatment with a fractalkine-neutralizing antibody reduced TGF-ß-stimulated invasion by HSC-2 and YD10B cells. Fractalkine treatment increased the viability, invasion, and uPA secretion of both OSCC cell lines. Furthermore, OSCC cell bone invasion was assessed following subcutaneous inoculation of wild-type or TGF-ß knockdown OSCC cells in mouse calvaria. TGF-ß knockdown prevented erosive bone invasion, reduced the number of osteoclasts at the tumor-bone interface, and downregulated fractalkine expression in mouse tumor tissues. Our results indicate that the production of fractalkine is stimulated by TGF-ß and mediates TGF-ß-induced cell invasion in several OSCC cell lines showing an erosive pattern of bone invasion. Fractalkine may be a useful predictive marker and therapeutic target for OSCC-induced bone destruction.

Costunolide Induces Apoptosis via the Reactive Oxygen Species and Protein Kinase B Pathway in Oral Cancer Cells.

Oral cancer (OC) has been attracted research attention in recent years as result of its high morbidity and mortality. Costunolide (CTD) possesses potential anticancer and bioactive abilities that have been confirmed in several types of cancers. However, its effects on oral cancer remain unclear. This study investigated the potential anticancer ability and underlying mechanisms of CTD in OC in vivo and in vitro. Cell viability and anchorage-independent colony formation assays were performed to examine the antigrowth effects of CTD on OC cells; assessments for migration and invasion of OC cells were conducted by transwell; Cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. The results revealed that CTD suppressed the proliferation, migration and invasion of oral cancer cells effectively and induced cell cycle arrest and apoptosis; regarding the mechanism, CTD bound to AKT directly by binding assay and repressed AKT activities through kinase assay, which thereby downregulating the downstream of AKT. Furthermore, CTD remarkably promotes the generation of reactive oxygen species by flow cytometry assay, leading to cell apoptosis. Notably, CTD strongly suppresses cell-derived xenograft OC tumor growth in an in vivo mouse model. In conclusion, our results suggested that costunolide might prevent progression of OC and promise to be a novel AKT inhibitor.

Chemerin Treatment Inhibits the Growth and Bone Invasion of Breast Cancer Cells.

Chemerin is secreted as prochemerin from various cell types and then cleaved into the bioactive isoform by specific proteases. In various cancer types, chemerin exhibits pro- or antitumor effects. In the present study, chemerin treatment significantly inhibited the viability and invasion of breast cancer cells in the absence or presence of transforming growth factor (TGF)-ß and insulin-like growth factor (IGF)-1. The expression levels of E-cadherin and vimentin were reduced in chemerin-treated breast cancer cells. However, chemerin treatment recovered the reduced E-cadherin expression level in breast cancer cells treated with TGF-ß or IGF-1. Chemerin treatment inhibited nuclear ß-catenin levels in breast cancer cells stimulated with or without TGF-ß or IGF-1. In addition, chemerin treatment blocked the increase in the receptor activator of nuclear factor kappa-Β ligand (RANKL)/osteoprotegerin (OPG) ratio in osteoblastic cells exposed to metastatic breast cancer cell-derived conditioned medium. Chemerin treatment inhibited RANKL-induced osteoclast formation and bone resorption by reducing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K. Intraperitoneal administration of chemerin inhibited tumor growth in MCF-7 breast cancer cell-injected mice and reduced the development of osteolytic lesions resulting from intratibial inoculation of MDA-MB-231 cells. Taken together, chemerin inhibits the growth and invasion of breast cancer cells and prevents bone loss resulting from breast cancer cells by inhibiting finally osteoclast formation and activity.

Loss of RUNX3 expression promotes cancer-associated bone destruction by regulating CCL5, CCL19 and CXCL11 in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) frequently metastasizes to bone, which is associated with significant morbidity and a dismal prognosis. RUNX3 functions as a tumour suppressor in lung cancer and loss of expression occurs more frequently in invasive lung adenocarcinoma than in pre-invasive lesions. Here, we show that RUNX3 and RUNX3-regulated chemokines are linked to NSCLC-mediated bone resorption. Notably, the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio, an index of osteoclastogenic stimulation, was significantly increased in human osteoblastic cells treated with conditioned media derived from RUNX3-knockdown NSCLC cells. We aimed to identify RUNX3-regulated factors that modify the osteoblastic RANKL/OPG ratio and found that RUNX3 knockdown led to CCL5 up-regulation and down-regulation of CCL19 and CXCL11 in NSCLC cells. Tumour size was noticeably increased and more severe osteolytic lesions were induced in the calvaria and tibiae of mice that received RUNX3-knockdown cells. In response to RUNX3 knockdown, serum and tissue levels of CCL5 increased, whereas CCL19 and CXCL11 decreased. Furthermore, CCL5 increased the proliferation, migration, and invasion of lung cancer cells in a dose-dependent manner; however, CCL19 and CXCL11 did not show any significant effects. The RANKL/OPG ratio in osteoblastic cells was increased by CCL5 but reduced by CCL19 and CXCL11. CCL5 promoted osteoclast differentiation, but CCL19 and CXCL11 reduced osteoclastogenesis in RANKL-treated bone marrow macrophages. These findings suggest that RUNX3 and related chemokines are useful markers for the prediction and/or treatment of NSCLC-induced bone destruction.

Platycodin D Blocks Breast Cancer-Induced Bone Destruction by Inhibiting Osteoclastogenesis and the Growth of Breast Cancer Cells.

BACKGROUND: Metastatic breast cancer cells are frequently associated with osteoclast-mediated bone resorption, resulting in severe bone destruction and increased mortality in patients. Platycodin D (PD) isolated from Platycodon grandiflorum is a triterpenoid saponin with anti-cancer and anti-angiogenic potential. METHODS: The in vivo activity was determined in mice with the intratibial injection of human metastatic breast cancer cells. Osteoclast formation and activity were detected using tartrate-resistant acid phosphatase staining and calcium phosphate-coated plates. The expression of osteoclastogenesis-inducing molecules was detected by RT-PCR and western blotting in RANKL-treated bone marrow macrophages (BMMs). Cell viability and DNA synthesis were measured with MTT and BrdU incorporation assays. The induction of apoptosis was estimated using TUNEL staining and a caspase-3 activity assay. RESULTS: The oral administration of PD inhibited MDA-MB-231 cell-induced osteolysis in an intratibial mouse model. PD treatment blocked RANKL-induced osteoclast formation by inhibiting the expression and nuclear translocation of NFATc1 and c-Fos in BMMs and consequently reduced osteoclast-mediated bone resorption. Furthermore, PD treatment induced apoptosis in osteoclasts and inhibited the growth of MDA-MB-231 cells. CONCLUSION: PD may block breast cancer-induced bone loss by suppressing the formation, activity, and survival of osteoclasts, as well as the growth of metastatic breast cancer cells.

The role of APCDD1 in epithelial rearrangement in tooth morphogenesis.

Adenomatosis polyposis coli downregulated 1 (APCDD1), a negative regulator of Wnt signaling, was examined to understand detailed mechanisms underlying Wnt signaling tooth development. In situ hybridization showed that Apcdd1 was expressed in the condensed mesenchyme at the bud stage, and in the inner enamel epithelium (IEE), including enamel knot (EK) at the cap stage. In vitro organ cultivation by using Apcdd1 antisense oligodeoxynucleotides was performed at E13.5 for 2 days to define the developmental functions of APCDD1 during tooth development. Analysis of histogenesis and cellular events such as cell adhesion, proliferation, apoptosis and epithelial rearrangement after Apcdd1 knockdown showed altered morphogenesis of the tooth germ with decreased cell proliferation and altered localization of cell adhesion molecules. Actin filament staining and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) labeling of IEE cells showed that Apcdd1 knockdown enhanced epithelial rearrangement in the IEE and EK. To understand the precise signaling regulations of Apcdd1, we evaluated the altered expression patterns of signaling molecules, related with Wnt and enamel knot signalings using RT-qPCR. Tooth germs at cap stage were transplanted into the kidney capsules and were allowed to develop into calcified teeth for 3 weeks. Apcdd1 knockdown increased the number of ectopic cusps on the mesial side of the tooth. Our results suggested that APCDD1 modulates the gene expression of Wnt- and EK-related signaling molecules at the cap stage of tooth development, and is involved in tooth cusp patterning by modulating the epithelial rearrangement in the IEE.

Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment.

Many breast cancer patients experience bone metastases and suffer skeletal complications. The present study provides evidence on the protective and therapeutic potential of betulinic acid on cancer-associated bone diseases. Betulinic acid is a naturally occurring triterpenoid with the beneficial activity to limit the progression and severity of cancer, diabetes, cardiovascular diseases, atherosclerosis, and obesity. We first investigated its effect on breast cancer cells, osteoblastic cells, and osteoclasts in the vicious cycle of osteolytic bone metastasis. Betulinic acid reduced cell viability and the production of parathyroid hormone-related protein (PTHrP), a major osteolytic factor, in MDA-MB-231 human metastatic breast cancer cells stimulated with or without tumor growth factor-ß. Betulinic acid blocked an increase in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin ratio by downregulating RANKL protein expression in PTHrP-treated human osteoblastic cells. In addition, betulinic acid inhibited RANKL-induced osteoclastogenesis in murine bone marrow macrophages and decreased the production of resorbed area in plates with a bone biomimetic synthetic surface by suppressing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Furthermore, oral administration of betulinic acid inhibited bone loss in mice intra-tibially inoculated with breast cancer cells and in ovariectomized mice causing estrogen deprivation, as supported by the restored bone morphometric parameters and serum bone turnover markers. Taken together, these findings suggest that betulinic acid may have the potential to prevent bone loss in patients with bone metastases and cancer treatment-induced estrogen deficiency.

Anticancer effects of gossypetin from Hibiscus sabdariffa in oral squamous cell carcinoma.

OBJECTIVE: Gossypetin, isolated from Hibiscus sabdariffa L, has been shown to have various pharmacological effects including anti-inflammatory and antibacterial activity against various diseases. However, since the effect of gossypetin in oral cancer remains to be reported, we aimed to investigate the anticancer activity and mechanisms of gossypetin in oral squamous cell carcinoma (OSCC). METHODOLOGY: The proliferation of OSCC cells was evaluated by cell viability and soft agar colony assays. The effects of gossypetin on the migration and invasion of OSCC cells was investigated by wound healing and transwell invasion assays, respectively. Apoptosis and cell cycle arrest were measured by flow cytometry. Moreover, the anticancer mechanism of gossypetin in OSCC cells was analyzed by western blotting. RESULTS: Gossypetin inhibited the proliferation, migration, and invasion of OSCC cells and induced apoptosis by upregulating the Bax/Bcl-2 ratio and cell cycle arrest at the G2/M phase. Furthermore, gossypetin regulated the activation of extracellular signal-regulated kinase and nuclear factor-kappa B. CONCLUSION: Results showed that gossypetin inhibits the proliferation, migration, and invasion of OSCC cells and triggers apoptosis and cell cycle arrest in OSCC. Therefore, gossypetin has the potential for use as a chemopreventive agent in oral cancer.

Evaluation of antimicrobial activity of chlorhexidine-containing oral gels against aspiration pneumonia-inducing bacteria: An In Vitro study.

Aim: Hospitalised patients have a high risk of developing aspiration pneumonia because of poor oral care and oral microbial flora changes. Chlorhexidine (CHX) solution has been used to reduce inflammation and prevent infections in oral cavity, but it is difficult to use in inpatients. Gel-type antimicrobial agents rather than the liquid form may be effective for the oral management of hospitalised patients. Therefore, we evaluated the in vitro antimicrobial effects of CHX-containing oral gels on aspiration pneumonia-inducing bacteria compared to the CHX solution. Materials and Methods: The experimental products of two oral gel types containing 1% and 0.1% CHX, respectively, were selected. Hexamedine, a 0.12% CHX solution, was used as a positive control. The antimicrobial activity of CHX agents against six pneumonia-causing bacteria and Streptococcus mutans, one of the most common oral bacteria, was comparatively analysed using the agar disk diffusion method. Results: In the disk diffusion assay, the 1% CHX gels showed the highest inhibitory effect on all bacteria. All CHX agents including gels and solution had the highest antibacterial activity against Staphylococcus aureus compared with other bacteria. Conclusions: We confirmed the significant antimicrobial effects of the 1% CHX oral gels on aspiration pneumonia-inducing bacteria. These results suggest that CHX gels may be an effective oral care method for preventing infection in inpatients who have difficulty using the solution.

Platycodin D Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis by Blocking the Activation of Mitogen-Activated Protein Kinases and the Production of Interleukin-8.

Platycodin D is a major constituent in the root of Platycodon grandiflorum and has diverse pharmacologic activities, including anti-inflammatory, anti-allergic, and antitumor activities. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) are potent angiogenic factors and contribute to tumor angiogenesis by directly and indirectly promoting angiogenic processes, including the proliferation, adhesion, migration, and tube formation of endothelial cells. Here, we found that platycodin D at noncytotoxic concentrations inhibited VEGF-induced proliferation, adhesion to the extracellular matrix proteins fibronectin and vitronectin, chemotactic motility, and tube formation of human umbilical vein endothelial cells (HUVECs). Platycodin D reduced the phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) and the secretion of IL-8 in VEGF-stimulated HUVECs. Moreover, platycodin D inhibited tube formation and the phosphorylation of ERK and p38 in IL-8-stimulated HUVECs. The in vitro anti-angiogenic activity of platycodin D was confirmed by in vivo experimental models. Platycodin D inhibited the formation of new blood vessels into mouse Matrigel plugs with VEGF or IL-8. In mice injected with MDA-MB-231 human breast cancer cells, orally administered platycodin D inhibited tumor growth, the number of CD34 [Formula: see text]vessels, and the expression of VEGF and IL-8. Taken together, platycodin D directly and indirectly prevents VEGF-induced and IL-8-induced angiogenesis by blocking the activation of mitogen-activated protein kinases (MAPKs). Platycodin D may be beneficial for the prevention or treatment of tumor angiogenesis and angiogenesis-related human diseases.

Anticancer effects of 6-shogaol via the AKT signaling pathway in oral squamous cell carcinoma.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is one of the common type of cancer that leads to death; and is becoming a global concern. Due to the lack of efficient chemotherapeutic agents for patients with oral cancer, the prognosis remains poor. 6-shogaol, a bioactive compound of ginger, has a broad spectrum of bioactivities and has been widely used to relieve many diseases. However, its effects on human oral cancer have not yet been fully evaluated. In our study, we investigated the anticancer effects of 6-shogaol on the proliferation, migration, invasion, apoptosis, and underlying mechanisms within human OSCC cell lines. METHODOLOGY: We investigated the effect of 6-shogaol on the growth of OSCC cells by cell viability and soft agar colony formation assay. Migration and invasion assays were conducted to confirm the effect 6-shogaol on OSCC cell metastasis. Apoptosis was detected by flow cytometry and the underlying mechanism on the antigrowth effect of 6-shogaol in OSCC cells was assessed using western blotting. RESULTS: In our results, 6-shogaol not only suppressed proliferation and anchorage-independent cell growth in OSCC cells, but also induced apoptosis by regulating the apoptosis-associated factors such as p53, Bax, Bcl-2, and cleaved caspase-3. Migration and invasion of OSCC cells were inhibited following the regulation of E-cadherin and N-cadherin by 6-shogaol. Additionally, 6-shogaol treatment significantly inhibited the PI3K/AKT signaling pathway. CONCLUSION: Therefore, our results may provide critical evidence that 6-shogaol can be a potential new therapeutic candidate for oral cancer.

The Potential Impact of Salivary IL-1 on the Diagnosis of Periodontal Disease: A Pilot Study.

The aim of this study was to identify inflammatory cytokines as salivary biomarkers for periodontal disease. The subjects were 33 Korean adults aged 23 to 71 years. Using a multiplexed bead immunoassay called Luminex, the levels of inflammatory cytokines related to periodontal disease were evaluated. Oral examination for periodontal disease and gingival bleeding was conducted. With these two independent variables, differences in inflammatory cytokines were analyzed by an independent t-test and age-adjusted ANCOVA. Among the subjects, 21 had periodontal disease and 12 were healthy subjects. The gingival bleeding status was classified into low and high levels. Among 13 inflammatory cytokines in saliva, IL-1α, IL-1ß, IL-4, IL-8, CCL2/MCP-1, CCL3/MIP-1α, and TNF-α were found to be significant biomarkers within the standard curve. The quantity of IL-1ß was increased in subjects with high levels of gingival bleeding. IL-1α levels were increased in subjects with periodontal disease. After adjusting for age, the significant biomarkers for gingival bleeding and periodontal disease were IL-1ß and IL-1α, respectively. Using the receiver operating characteristic (ROC) curve, IL-1ß was confirmed as a significant biomarker. The sensitivity and specificity of IL-1ß for predicting periodontitis were 88.24% and 62.5%, respectively. Therefore, IL-1 was found to be a significant biomarker for periodontal disease, and it could be used in the diagnosis of periodontal disease using saliva.

Xanthorrhizol Suppresses Vascular Endothelial Growth Factor-Induced Angiogenesis by Modulating Akt/eNOS Signaling and the NF-[Formula: see text]B-Dependent Expression of Cell Adhesion Molecules.

Angiogenesis plays a crucial role in tumor growth and metastasis. Vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation and migration are critical steps in tumor angiogenesis. Here, we investigated the anti-angiogenic activity of xanthorrhizol, a sesquiterpenoid isolated from the Indonesian medicinal plant Curcuma xanthorrhiza. Xanthorrhizol at noncytotoxic concentrations inhibited the proliferation, migration, and formation of capillary-like tubes in VEGF-treated human umbilical vein endothelial cells (HUVECs). Xanthorrhizol inhibited the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) and the expression of vascular cell adhesion molecule (VCAM)-1 and E-selectin in VEGF-treated HUVECs. The expression and transcriptional activity of NF-[Formula: see text]B were downregulated by xanthorrhizol in VEGF-treated HUVECs. Furthermore, xanthorrhizol significantly inhibited VEGF-induced angiogenesis in the chorioallantoic membrane of fertilized eggs and Matrigel plugs subcutaneously injected into mice. Xanthorrhizol inhibited tumor volume and tumor-derived angiogenesis in mice inoculated with breast cancer cells. The in vitro and in vivo anti-angiogenic activities of xanthorrhizol were as potent as those of curcumin, a well-known anticancer agent derived from C. longa. Taken together, xanthorrhizol inhibits VEGF-induced angiogenesis of endothelial cells by blocking the activation of the PI3K/Akt/eNOS axis and subsequent upregulation of adhesion molecules induced by the transcriptional activation of NF-[Formula: see text]B. Xanthorrhizol is a promising anti-angiogenic agent and can serve as a beneficial agent to enhance anticancer treatments.

Anti-inflammatory effects of licorice and roasted licorice extracts on TPA-induced acute inflammation and collagen-induced arthritis in mice.

The anti-inflammatory activity of licorice (LE) and roasted licorice (rLE) extracts determined in the murine phorbol ester-induced acute inflammation model and collagen-induced arthritis (CIA) model of human rheumatoid arthritis. rLE possessed greater activity than LE in inhibiting phorbol ester-induced ear edema. Oral administration of LE or rLE reduced clinical arthritis score, paw swelling, and histopathological changes in a murine CIA. LE and rLE decreased the levels of proinflammatory cytokines in serum and matrix metalloproteinase-3 expression in the joints. Cell proliferation and cytokine secretion in response to type II collagen or lipopolysaccharide stimulation were suppressed in spleen cells from LE or rLE-treated CIA mice. Furthermore, LE and rLE treatment prevented oxidative damages in liver and kidney tissues of CIA mice. Taken together, LE and rLE have benefits in protecting against both acute inflammation and chronic inflammatory conditions including rheumatoid arthritis. rLE may inhibit the acute inflammation more potently than LE.

Honokiol inhibits the progression of collagen-induced arthritis by reducing levels of pro-inflammatory cytokines and matrix metalloproteinases and blocking oxidative tissue damage.

Plant-derived compounds with potent anti-inflammatory activity have attracted a great deal of attention as a source for novel anti-arthritic agents with minimal side effects. We attempted to determine the anti-arthritic effects of orally administered honokiol isolated from Magnolia species. The oral administration of honokiol inhibited the progression and severity of type II collagen (CII)-induced arthritis (CIA) by reducing clinical arthritis scores and paw swelling. The histological analysis demonstrated preserved joint space; and the immunohistochemical data showed that the levels of interleukin (IL)-17, matrix metalloproteinase (MMP)-3, MMP-9, MMP-13, and receptor activator for nuclear factor-κB ligand, as well as nitrotyrosine formation, were substantially suppressed in the honokiol-treated CIA mice. The elevated serum levels of tumor necrosis factor-α and IL-1ß in the CIA mice were also restored to control levels via honokiol treatment. In the CIA mice, honokiol inhibited CII- or lipopolysaccharide-stimulated cytokine secretion in spleen cells, as well as CII-stimulated spleen cell proliferation. Furthermore, honokiol treatment reduced CIA-induced oxidative damage in the liver and kidney tissues of CIA mice. Collectively, the oral administration of honokiol inhibited CIA development by reducing the production of pro-inflammatory cytokines, MMP expressions, and oxidative stress. Thus, honokiol is an attractive candidate for an anti-arthritic agent.

Red ginseng saponin extract attenuates murine collagen-induced arthritis by reducing pro-inflammatory responses and matrix metalloproteinase-3 expression.

Ginseng, the root of Panax ginseng C. A. MEYER, has been used as a food product and medicinal ingredient. In this study, we assessed the anti-arthritic effects of red ginseng saponin extract (RGSE), including ginsenosides Rg3, Rk1 and Rg5 as major components, on a murine type II collagen (CII)-induced arthritis (CIA), which is a valid animal model of human arthritis. Oral administration of RGSE at 10 mg/kg reduced the clinical arthritis score and paw swelling in the CIA mice, and inhibited joint space narrowing and histological arthritis, illustrating the severity of synovial hyperplasia, inflammatory cell infiltration, pannus formation, and erosion of cartilage. RGSE inhibited the expression of matrix metalloproteinase-3 and nitrotyrosine formation, and recovered the expression of superoxide dismutase in the joints of the CIA mice. Orally administered RGSE also reduced the levels of serum tumor necrosis factor-alpha and interleukin-1beta in the CIA mice. CII- or lipopolysaccharide-stimulated cytokine production, in addition to CII-specific proliferation, was reduced in the spleen cells of the RGSE-treated CIA mice, as compared with those from vehicle-treated CIA mice. Furthermore, RGSE administration protected against CIA-induced oxidative tissue damage by restoring the increased malondialdehyde levels and the decreased glutathione levels and catalase activities almost to control levels. Therefore, RGSE may be a beneficial supplement which can improve human arthritis.

Erratum: Anti-growth Effects of Imatinib and GNF5 via Regulation of Skp2 in Human Hepatocellular Carcinoma Cells.

[This corrects the article on p. 170 in vol. 23, PMID: 30671399.].

CCL28-induced RARß expression inhibits oral squamous cell carcinoma bone invasion.

Oral squamous cell carcinoma (OSCC) frequently invades the maxillary or mandibular bone, and this bone invasion is closely associated with poor prognosis and survival. Here, we show that CCL28 functions as a negative regulator of OSCC bone invasion. CCL28 inhibited invasion and epithelial-mesenchymal transition (EMT), and its inhibition of EMT was characterized by induced E-cadherin expression and reduced nuclear localization of ß-catenin in OSCC cells with detectable RUNX3 expression levels. CCL28 signaling via CCR10 increased retinoic acid receptor-ß (RARß) expression by reducing the interaction between RARα and HDAC1. In addition, CCL28 reduced RANKL production in OSCC and osteoblastic cells and blocked RANKL-induced osteoclastogenesis in osteoclast precursors. Intraperitoneally administered CCL28 inhibited tumor growth and osteolysis in mouse calvaria and tibia inoculated with OSCC cells. RARß expression was also increased in tumor tissues. In patients with OSCC, low CCL28, CCR10, and RARß expression levels were highly correlated with bone invasion. Patients with OSCC who had higher expression of CCL28, CCR10, or RARß had significantly better overall survival. These findings suggest that CCL28, CCR10, and RARß are useful markers for the prediction and treatment of OSCC bone invasion. Furthermore, CCL28 upregulation in OSCC cells or CCL28 treatment can be a therapeutic strategy for OSCC bone invasion.