Search

Abstract: Aim: Sulfuretin, a major flavonoid isolated from Rhus verniciflua, is known to have anti-inflammatory effects. However, the mechanisms underlying the anti-inflammatory effect of sulfuretin on rheumatoid arthritis have not been elucidated. In this study we investigated whether sulfuretin treatment modulates the severity of arthritis in an experimental model. Main methods: We evaluated the effects of sulfuretin on tumor necrosis factor-α (TNF-α)-treated human rheumatoid fibroblast-like synoviocytes (FLS) in vitro and on collagen-induced arthritis (CIA) mice in vivo. Key findings: In vitro experiments demonstrated that sulfuretin suppressed the chemokine production, matrix metalloproteinase secretion, and cell proliferation induced by tumor necrosis factor-α in rheumatoid FLS. In addition, sulfuretin inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor and receptor activator of NF-κB ligand in bone marrow macrophages. In mice with CIA, early intervention with sulfuretin prevented joint destruction, as evidenced by a lower cumulative disease incidence and an absence of diverse disease features based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels. In mice with established arthritis, sulfuretin treatment significantly reduced synovial inflammation and joint destruction. The in vitro and in vivo protective effects of sulfuretin were mediated by inhibition of the NF-κB signaling pathway. Significance: These results suggest that using sulfuretin to block the NF-κB pathway in rheumatoid joints reduces both inflammatory responses and joint destruction. Therefore, sulfuretin may have therapeutic value in preventing or delaying the progression of rheumatoid arthritis. [Copyright &y& Elsevier]

Abstract: Brazilin (7, 11b-dihydrobenz[b]indeno[1,2-d]pyran-3,6a,9,10 (6H)-tetrol), the major component of Caesalpinia sappan L., is a natural red pigment used for histological staining. Recent studies have shown that brazilin exhibits distinct biological effects, including anti-hepatotoxicity, antiplatelet activity, and anti-inflammatory activities. In the present study, we evaluated the effects of brazilin on MMP-1 and -3 expressions in human dermal fibroblasts exposed to ultraviolet B (UVB) irradiation. Brazilin showed protective effect on UVB-induced loss of cell viability of fibroblasts. Brazilin also blocked significantly UVB-induced Reactive Oxygen Species generation in fibroblasts. Brazilin inhibited UVB-induced MMP-1/3 expressions and secretions in a dose-dependent manner. Moreover, UVB-induced NF-κB activation was completely blocked by treatment with brazilin. These findings suggest that brazilin inhibits UVB-induced MMP-1/3 expressions and secretions by suppressing of NF-κB activation in human dermal fibroblasts. Thus, brazilin might be used as a potential agent for treatment of UV-induced skin photoaging. [Copyright &y& Elsevier]

Abstract: The pathologic processes of rheumatoid arthritis are mediated by a number of cytokines, chemokines, and matrix metalloproteinases, the expressions of which are controlled by NF-κB. This study was performed to explore the effects of a benzothiazole analog, SPA0537, on the control of the NF-κB activation pathway. We also investigated whether SPA0537 had any anti-inflammatory effects in human rheumatoid fibroblast-like synoviocytes (FLS). SPA0537 inhibited the nuclear translocation and the DNA binding of NF-κB subunits, which correlated with the inhibitory effects on IKK phosphorylation and IκBα degradation in TNF-α-stimulated rheumatoid FLS. These events further suppressed chemokine production, matrix metalloproteinase secretion, and TNF-α-induced cell proliferation. In addition, SPA0537 inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor (MCSF) and receptor activator of the NF-κB ligand (RANKL) in bone marrow macrophages. These findings suggest that SPA0537 exerts anti-inflammatory effects in rheumatoid FLS through the inhibition of the NF-κB pathway. Therefore, it may have therapeutic value for the treatment of rheumatoid arthritis. [Copyright &y& Elsevier]

Abstract: Dihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Previous study demonstrates that DHAvD strongly inhibits activation of nuclear factor-kappa B (NF-κB), which is a major component in cancer cell invasion. The present study investigated whether DHAvD can modulate MMP-9 expression and cell invasion in MCF-7 human breast cancer cells. MMP-9 expression and cell invasion in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) was increased, whereas these inductions were muted by DHAvD. DHAvD also suppressed activation of mitogen-activated protein kinase (MAPK), and MAPK-mediated nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activations in TPA-treated MCF-7 cells. The results indicate that DHAvD-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the MAPK/NF-κB and MAPK/AP-1 pathways in MCF-7 cells. DHAvD may have potential value in breast cancer metastasis. [Copyright &y& Elsevier]

OBJECTIVE: Nuclear factor-kappaB (NF-kappaB) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis (RA). The purpose of this study was to determine whether A20, a universal inhibitor of NF-kappaB, might have antiarthritic effects. METHODS: An adenovirus containing A20 complementary DNA (AdA20) was used to deliver A20 to human rheumatoid fibroblast-like synoviocytes (FLS) in vitro as well as to mice with collagen-induced arthritis (CIA) in vivo via intraarticular injection into the ankle joints bilaterally. RESULTS: In vitro experiments demonstrated that AdA20 suppressed NF-kappaB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor alpha in FLS. Mice with CIA that were treated with AdA20 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels, than did control virus-injected mice. The protective effects of AdA20 were mediated by the inhibition of the NF-kappaB signaling pathway. The severity of arthritis was also significantly decreased in the untreated front paws, indicating a beneficial systemic effect of local suppression of NF-kappaB. Surprisingly, mice treated with AdA20 after the onset of CIA had significantly decreased arthritis severity from the onset of clinical signs to the end of the study. CONCLUSION: These results suggest that using A20 to block the NF-kappaB pathway in rheumatoid joints reduces both the inflammatory response and the tissue destruction. The development of an immunoregulatory strategy based on A20 may therefore have therapeutic potential in the treatment of RA. [ABSTRACT FROM AUTHOR]

Abstract: Endothelial hyperpermeability, a hallmark of septicemia, is induced by stress fiber formation, which is primarily regulated by the calcium/calmodulin signaling pathway in endothelial cells. We previously reported that trifluoperazine, a calcium/calmodulin antagonist, blocks Vibrio vulnificus cytolysin (VVC) -induced lethality at in vivo animal model. The object of this study was therefore to examine whether VVC induces stress fiber formation through calcium/calmodulin signaling in endothelial cells. Here, we monitored calcium-influx after treatment of VVC using confocal microscopy in CPAE cells, pulmonary endothelial cell line. Interestingly, we found that VVC-induced dose-dependently increases of [Ca2+]i in CPAE cells. Moreover, VVC-induced stress fiber formation as well as phosphorylation of myosin light chain (MLC) in a dose- and time-dependent manner, which was completely blocked by trifluoperazine. These results suggest that the calcium/calmodulin signaling pathway plays a pivotal role in VVC-induced hyperpermeability. [Copyright &y& Elsevier]

Abstract: The IL-1β-NF-κB axis is a key pathway in the pathogenesis of rheumatoid arthritis (RA) and is central in the production of proinflammatory mediators in the inflamed synovium. Therefore, we examined whether fibroblast-like synoviocytes (FLS) could be spared from IL-1β-induced toxicity by an overexpressing IκB super-repressor. Infection of FLS with Ad-IκBα (S32A, S36A), an adenovirus-containing mutant IκBα, inhibited IL-1β-induced nuclear translocation and DNA binding of NF-κB. In addition, Ad-IκBα (S32A, S36A) prevented IL-1β-induced inflammatory responses; namely, the production of chemokines, such as ENA-78 and RANTES, and activation of MMP-1 and MMP-3. Finally, increased cellular proliferation of FLS after IL-1β treatment was significantly reduced by Ad-IκBα (S32A, S36A). However, Ad-IκBβ (S19A, S23A), the IκBβ mutant, was not effective in preventing IL-1β toxicity. These results suggest that inhibition of IκBα degradation is a potential target for the prevention of joint destruction in patients with RA. [Copyright &y& Elsevier]

Abstract: Peroxisome proliferator-activated receptor γ (PPARγ) ligands inhibit cell proliferation and induce apoptosis in cancer cells. Here we wished to determine whether the PPARγ ligand induces apoptosis and cell cycle arrest of the MDA-MB-231 cell, an estrogen receptor α negative breast cancer cell line. The treatment of MDA-MB-231 cell with PPARγ ligands was shown to induce inhibition of cell growth in a dose-dependent manner as determined by MTT assay. Cell cycle analysis showed a G1 arrest in MDA-MB-231 cells exposed to troglitazone. An apoptotic effect by troglitazone demonstrated that apoptotic cells elevated by 2.5-fold from the control level at 10μM, to 3.1-fold at 50μM and to 3.5-fold at 75μM. Moreover, troglitazone treatment, applied in a dose-dependent manner, caused a marked decrease in pRb, cyclin D1, cyclin D2, cyclin D3, Cdk2, Cdk4 and Cdk6 expression as well as a significant increase in p21 and p27 expression. These results indicate that troglitazone causes growth inhibition, G1 arrest and apoptotic death of MDA-MB-231 cells. [Copyright &y& Elsevier]

Abstract: Guggulsterone is a plant sterol that is used to treat hyperlipidemia, arthritis, and obesity. Although its anti-inflammatory and anti-hyperlipidemic effects have been well documented, the effect of guggulsterone on fibroblast-like synoviocytes (FLS) has not yet been reported. Therefore, in this study, the effect of guggulsterone on interleukin (IL)-1β-induced inflammatory responses in the FLS of rheumatic patients was investigated. Treatment of FLS with IL-1β induced production of chemokines such as RANTES and ENA-78. In addition, Western blot analysis and gelatin zymography revealed that IL-1β activated matrix metalloproteinase (MMP)-1 and -3 in FLS. However, pre-incubation with guggulsterone completely inhibited the ability of IL-1β to induce the production of chemokines and to activate MMPs. Although the NF-κB binding activity and nuclear p50 and p65 subunit levels, as well as IκBα degradation in the cytoplasm was greater in cells stimulated with IL-1β than in unstimulated cells, treatment with guggulsterone abolished all of these increases. Collectively, these results suggest that guggulsterone would be useful as an inhibitor of joint destruction in patients with rheumatoid arthritis. [Copyright &y& Elsevier]

Abstract: NAD is available in the extracellular environment and elicits immune modulation such as T cell apoptosis by being used as the substrate of cell surface ADP-ribosyl transferase. However, it is unclear whether extracellular NAD affects function of macrophages expressing cell surface ADP-ribosyl transferase. Here we show that extracellular NAD enhances Fcγ receptor (FcγR)-mediated phagocytosis in J774A.1 macrophages via the conversion into cyclic ADP-ribose (cADPR), a potent calcium mobilizer, by CD38, an ADP-ribosyl cyclase. Extracellular NAD increased the phagocytosis of IgG-coated sheep red blood cells (IgG-SRBC) in J774A.1 macrophages, which was completely abolished by pretreatment of 8-bromo-cADPR, an antagonist of cADPR, or CD38 knockdown. Extracellular NAD increased basal intracellular Ca2+ concentration, which also was abolished by pretreatment of 8-bromo-cADPR or CD38 knockdown. Moreover, the chelation of intracellular calcium abolished NAD-induced enhancement of phagocytosis of IgG-SRBC. Our results suggest that extracellular NAD act as a regulator for FcγR-mediated phagocytosis in macrophages. [Copyright &y& Elsevier]

Abstract: Estrogen stimulates cell proliferation in breast cancer. The biological effects of estrogen are mediated through two intracellular receptors, estrogen receptor-α (ERα) and estrogen receptor-β (ERβ). However, the role of ERs in the proliferative action of estrogen is not well established. Recently, it has been known that ER activates phosphatidylinositol-3-OH kinase (PI3K) through binding with the p85 regulatory subunit of PI3K. Therefore, possible mechanisms may include ER-mediated phosphoinositide metabolism with subsequent formation of phosphatidylinositol-3,4,5-trisphosphate (PIP3), which is generated from phosphatidylinositol 4,5-bisphosphate via PI3K activation. The present study demonstrates that 17β-estradiol (E2) up-regulates PI3K in an ERα-dependent manner, but not ERβ, and stimulates cell growth in breast cancer cells. In order to study this phenomenon, we have treated ERα-positive MCF-7 cells and ERα-negative MDA-MB-231 cells with 10nM E2. Treatment of MCF-7 cells with E2 resulted in a marked increase in PI3K (p85) expression, which paralleled an increase in phospho-Akt (Ser-473) and PIP3 level. These observations also correlated with an increased activity to E2-induced cell proliferation. However, these effects of E2 on breast cancer cells were not observed in the MDA-MB-231 cell line, indicating that the E2-mediated up-regulation of PI3K/Akt pathway is ERα-dependent. These results suggest that estrogen activates PI3K/Akt signaling through ERα-dependent mechanism in MCF-7 cells. [Copyright &y& Elsevier]

Abstract: Dimethylsulfoxide (DMSO) has been known to differentiate HL60 cells into neutrophil like cells. Here, we provide an evidence for the involvement of tumor suppressor PTEN, an antagonist of phosphatidylinositol 3-kinase (PI3K) in the DMSO-induced differentiation of HL60 cells. DMSO upregulated PTEN with unaffecting the expression of PI3K. The upregulation of PTEN by DMSO lead to the decrease of Akt phosphorylation, a downstream of PI3K. The DMSO-induced upregulation of PTEN might be mediated by NF-κB activation, which was evidenced by the blockage of DMSO-induced PTEN upregulation with an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC). [Copyright &y& Elsevier]

Purpose: Although adrenal computed tomography (CT) percentage washout is a potentially powerful imaging technique for differentiating adrenal adenomas from non-adenomas, its application to non-adenomas can be problematic. Recently, modified criteria for diagnosing pheochromocytomas using adrenal CT were developed based on data from 199 patients with surgically proven pheochromocytomas and adenomas. However, these criteria have not been thoroughly validated. The purpose of this study was to validate the performance of the modified criteria for diagnosing non-adenomas including pheochromocytomas. Methods: The conventional and modified criteria were applied to 266 patients from two cohorts who had surgically proven lipid-poor adenomas (155/266, 58.3%) and non-adenomas (111/266, 41.7%) and underwent adrenal CT. Two radiologists calculated the attenuation on each dynamic phase and percentage washout of adrenal masses. The final assessments based on the conventional and modified criteria were categorized into adenomas or non-adenomas. The diagnostic performance of each criterion for diagnosing non-adenomas was evaluated using the area under the receiver operating characteristic curve (AUC). False negatives and positives were also compared. Results: The AUC for the diagnosis of non-adenomas was 0.806 for conventional criteria and 0.858 for modified criteria (p = 0.047). The false-negative rate of conventional criteria for the diagnosis of non-adenomas was 29.7%. Use of modified criteria could have reduced the false-negative rate by to 7.2%. The false-positive rate increased from 9% to 21.3% when using the modified criteria. Conclusion: The utilization of modified criteria has the potential to identify additional non-adenomas that would otherwise be misdiagnosed as adenomas using conventional criteria alone. [ABSTRACT FROM AUTHOR]

Sirtuin 6 (SIRT6) regulation is involved in carcinogenesis. However, its role in breast cancer (BC) metastasis remains unclear. We investigated the effects of SIRT6 on protein kinase C activator- and cytokine-mediated cancer cell invasion and migration in MCF-7 and MDA-MB-231 cells and the association between SIRT6 and matrix metalloproteinase-9 (MMP-9) expression. To assess MMP-9 and SIRT6 expression in patients, protein levels in BC tissues were analyzed. MCF-7 and MDA-MB-231 cell viability was analyzed using MTT assays. SIRT6 was silenced in both cell lines and protein secretion, expression, and mRNA levels were analyzed. Transcription factor DNA activity was investigated using luciferase assays. Matrigel invasion assays were used to assess the effects of SIRT6 in both cell lines. SIRT6 and MMP-9 expression in cancer tissues was significantly higher than in paired normal breast tissues. 12-O-tetradecanoylphorbol-13-acetate (TPA) or tumor necrosis factor-α (TNF-α) increased MMP-9 expression and cell invasion and migration, but SIRT6 knockdown abolished these effects. SIRT6 overexpression additively increased TPA- and TNF-α-induced MMP-9 expression. SIRT6 knockdown suppressed the mitogen-activated protein kinase (MAPK) signaling pathway and thus TPA- and TNF-α-induced MMP-9 expression. SIRT6 silencing suppressed TPA- and TNF-α-induced nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) expressions in both cell lines, and treatment with MAPK, NF-κB, and AP-1 inhibitors reduced MMP-9 expression. The anti-invasive effects of SIRT6 in BC cells might be mediated by suppression of MAPK phosphorylation and reduction in NF-κB and AP-1 DNA activities, leading to MMP-9 downregulation, suggesting that SIRT6 modulation has the potential to target BC metastasis. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate tumor feeders, image quality, and performance of cone-beam computed tomography (CBCT) renal arteriography for renal tumor embolization.Methods: Fifty-four patients with renal tumors were included in this study. The performance of CBCT renal arteriography was classified into three groups: group A, all tumor feeders could be confirmed solely based on the CBCT maximum intensity projection (MIP); group B, all feeders were detected in CBCT MIP, but there were some possible feeders which needed to be confirmed with selective digital subtraction angiography (DSA); and group C, tumor feeders were not detected in CBCT MIP, hence, the feeder was detected based on selective DSA. Tumor size, location, and enhancement on pre-procedure CT and tumor identification, overall image quality, breathing motion and opacification of the renal collecting system on CBCT MIP were also evaluated.Results: There were 32 (59.2%) patients in group A, 15 (27.8%) patients in group B, and 7 (13.0%) patients in group C. Significant determining factors for performance of CBCT renal arteriography were age, tumor identification, overall image quality, and breathing motion (all p < 0.05). In six out of seven cases in group C, overall image quality deteriorated due to breathing motion (significant blurring of renal artery branches with difficulty in identifying the interlobar artery level).Conclusion: In most cases, CBCT renal arteriography was sufficient to detect tumor feeders for renal tumor embolization. However, additional selective DSA is required when the overall image quality deteriorates owing to the patient's motion. [ABSTRACT FROM AUTHOR]

Matriptases are cell surface proteolytic enzymes belonging to the type II transmembrane serine protease family that mediate inflammatory skin disorders and cancer progression. Matriptases may affect the development of periodontitis via protease-activated receptor-2 activity. However, the cellular mechanism by which matriptases are involved in periodontitis is unknown. In this study, we examined the antiperiodontitis effects of matriptase on Porphyromonas gingivalis-derived lipopolysaccharide (PG-LPS)-stimulated human gingival fibroblasts (HGFs). Matriptase small interfering RNA-transfected HGFs were treated with PG-LPS. The mRNA and protein levels of proinflammatory cytokines and matrix metalloproteinase 1 (MMP-1) were evaluated using the quantitative real-time polymerase chain reaction (qRT-PCR) and an enzyme-linked immunosorbent assay (ELISA), respectively. Western blot analyses were performed to measure the levels of Toll-like receptor 4 (TLR4)/interleukin-1 (IL-1) receptor-associated kinase (IRAK)/transforming growth factor β-activated kinase 1 (TAK1), p65, and p50 in PG-LPS-stimulated HGFs. Matriptase downregulation inhibited LPS-induced proinflammatory cytokine expression, including the expression of IL-6, IL-8, tumor necrosis factor-α (TNF-α), and IL-Iβ. Moreover, matriptase downregulation inhibited PG-LPS-stimulated MMP-1 expression. Additionally, we confirmed that the mechanism underlying the effects of matriptase downregulation involves the suppression of PG-LPS-induced IRAK1/TAK1 and NF-κB. These results suggest that downregulation of matriptase PG-LPS-induced MMP-1 and proinflammatory cytokine expression via TLR4-mediated IRAK1/TAK1 and NF-κB signaling pathways in HGFs. [ABSTRACT FROM AUTHOR]

Abstract: Dihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Although its anti-inflammatory, antiatherosclerotic, and antioxidant effects have been reported, the effect of DHAvD on type 1 diabetes is unknown. Therefore, in this study, the effect of DHAvD on cytokine- or streptozotocin-induced β-cell damage was investigated. Treatment of RINm5F insulinoma cells or isolated islets with IL-1β and IFN-γ induced β-cell damage through a NF-κB-dependent signaling pathway. DHAvD-pretreated RINm5F cells or islets showed resistance to cytokine toxicity, namely suppressed nitric oxide (NO) production, reduced the inducible form of NO synthase expression, and decreased β-cell destruction and the normal insulin secretion capacity. Furthermore, pretreatment with DHAvD blocked the development of type 1 diabetes in streptozotocin-treated mice. Prior injection with DHAvD maintained a normal range of plasma glucose and insulin, and retained immunoreactivity for insulin in the pancreas. These results suggest that DHAvD may be used to preserve functional β-cell mass. [Copyright &y& Elsevier]

Abstract: Peroxisome proliferator-activated receptor γ (PPARγ) ligands have been identified as a potential source of therapy for human cancers. However, PPARγ ligands have a limitation for breast cancer therapy, since estrogen receptor α (ERα) negatively interferes with PPARγ signaling in breast cancer cells. Here we show that ERα inhihits PPARγ transactivity and ERα-mediated inhibition of PPARγ transactivity is blocked by tamoxifen, an estrogen receptor blocker. The activation of ERα with 17-β-estradiol blocked PPRE transactivity induced by troglitazone, a PPARγ ligand, indicating the resistance of ERα-positive breast cancer cells to troglitazone. Indeed, troglitazone inhibited the growth of ERα-negative MDA-MB-231 cells more than that of ERα-positive MCF-7 cells. Combination of troglitazone with tamoxifen led to a marked increase in growth inhibition of ERα-positive MCF-7 cells compared to either agent alone. Our data indicates that troglitazone enhances the growth inhibitory activity of tamoxifen in ERα-positive MCF-7 cells. [Copyright &y& Elsevier]

Background: Intractable bladder hemorrhage from pelvic malignancy can be potentially life-threatening and its management can be a challenging clinical problem. Purpose: To evaluate safety, efficacy, and clinical outcome of superselective vesical artery embolization for the control of intractable bladder hemorrhage from pelvic malignancy. Material and Methods: Between January 2010 and September 2018, 20 patients underwent superselective vesical artery embolization for intractable hematuria secondary to pelvic malignancy arising from or invading the bladder. Treatment details and clinical outcomes were obtained. Results: There were 12 men and 8 women (mean age = 77 years). Bilateral embolization was performed in 10 patients and unilateral approach in 10 patients. Two patients died within four days after embolization due to underlying heart failure and systemic metastasis, respectively. The remaining 18 patients had a follow-up of >30 days. Bleeding was controlled after the first embolization in 17/18 patients and after a repeat embolization in the remaining one patient. The mean follow-up period of 18 patients was 10.6 months (range = 1–77 months). Late recurrent hemorrhage (≥ 30 days after embolization) was reported in 6 (33.3%) patients. Five of these six patients underwent repeat embolization. There were no major complications related to embolization. Conclusion: Palliative superselective vesical artery embolization is a feasible, effective, and safe procedure to control intractable hematuria in patients with pelvic malignancy. [ABSTRACT FROM AUTHOR]

Periodontitis is a Gram-negative bacterial infectious disease. Numerous inflammatory cytokines, including interleukin-1β (IL-1β), regulate periodontitis pathophysiology and cause periodontal tissue destruction. In human gingival fibroblasts (HGFs), IL-1β stimulates the production of matrix metalloproteinases (MMPs) and proinflammatory cytokines via various mechanisms. Several transcription factors, such as signal transducer and activator of transcription 3 (STAT-3), activator protein 1 (AP-1), and nuclear factor-κB (NF-κB), regulate gene expression. Mitogen-activated protein kinases (MAPKs) regulate these transcription factors. However, the MAPK/STAT-3 activation signal in HGFs is unknown. We investigated the potential inhibitory effects of the extract of Evodiae fructus (EFE), the dried, ripe fruit of Evodia rutaecarpa, on MMP and proinflammatory cytokine expression in IL-1β-stimulated HGFs. EFE inhibited the expression of MMP-1, MMP-3, and proinflammatory cytokines (TNF-α, IL-6, and IL-8) in IL-1β-stimulated HGFs through the inhibition of IL-1β-induced MAPK/STAT-3 activation. Also, these results suggest that the EFE may be a useful for the bioactive material for oral care. [ABSTRACT FROM AUTHOR]

We previously showed that Amomum xanthoides extract prevented alloxan-induced diabetes through the suppression of NF-κB activation. In this study, the preventive effects of A. xanthoides extract on cytokine-induced β-cell destruction were examined. Cytokines produced by immune cells infiltrating pancreatic islets are important mediators of β-cell destruction in insulin-dependent diabetes mellitus. A. xanthoides extract completely protected interleukin-1β (IL-1β) and interferon-γ (IFN-γ)-mediated cytotoxicity in rat insulinoma cell line (RINm5F). Incubation with A. xanthoides extract resulted in a significant reduction in IL-1β and IFN-γ-induced nitric oxide (NO) production, a finding that correlated well with reduced levels of the inducible form of NO synthase (iNOS) mRNA and protein. The molecular mechanism by which A. xanthoides extract inhibited iNOS gene expression appeared to involve the inhibition of NF-κB activation. Our results revealed the possible therapeutic value of A. xanthoides extract for the prevention of diabetes mellitus progression. [Copyright &y& Elsevier]

Portulaca oleracea L. is a traditional oriental medicine known for its pharmacological effects. The present study aimed to investigate the immunostimulatory effects of PPCE on cyclophosphamide-stimulated rat model and in isolated spleen cells. The result showed that PPCE exerted an immunostimulatory effect in vivo and in vitro. Specifically, PPCE significantly enhanced splenocyte proliferation and upregulated inflammatory cytokines (IL-2, IL-12, TNF-α, and IFN-γ) and NK cell activity in vitro. The immunostimulatory effect was further investigated through various immunological assays. Oral administration of PPCE increased the swimming time and number of immune cells in rats. Histological analysis revealed that PPCE administration exerted splenic recovery. Thus, P. oleracea L. based complex extracts may be used as an immunostimulatory agent in medicine or functional foods. [ABSTRACT FROM AUTHOR]

Complex oil of Zanthoxylum schinifolium and Perilla frutescens seed (ZPCO) is used as a traditional medicine due to its pharmacological activities. The aim of this study was to investigate the immunostimulatory effect of ZPCO in isolated splenocytes as well as in an immunosuppressed rat model, which was generated via oral administration of cyclophosphamide. Notably, our results showed that ZPCO exerted an immunity-enhancing effect both in vitro and in vivo. Specifically, ZPCO treatment enhanced the viability and inflammatory cytokine production of splenocytes and NK cell activity in vitro. Moreover, this product improved host defense under immunosuppressive conditions by increasing the number of immune cells and promoting the expression of cytokines involved in immune responses. Our results suggest that complex oil including Z. schinifolium should be explored as a novel immunostimulatory agent that could potentially be used for therapeutic purposes or as an ingredient in functional foods. [ABSTRACT FROM AUTHOR]

Casein kinase 2 (CK2) is a serine/threonine protein kinase that has been considered to represent an important factor in mammary tumorigenesis. Increased expression of matrix metalloproteinase‑9 (MMP‑9) via nuclear factor‑κB (NF‑κB) activation has been demonstrated to promote breast cancer cell invasion. In the present study, the involvement of CK2 in protein kinase C (PKC) induced cell invasion in MCF‑7 breast cancer cells was investigated as well as the underlying molecular mechanisms. The mRNA and protein levels of MMP‑9 in MCF‑7 cells were investigated using reverse transcription‑quantitative polymerase chain reaction, western blot analyses and a zymography assay. Cell invasiveness was investigated using a Matrigel invasion assay, and it was revealed that small interfering RNA specific for CK2 suppressed PKC induced cell invasion by regulating MMP‑9 expression via activation of the p38 kinase/c‑Jun N‑terminal kinase/NF‑κB pathway. In addition, it was demonstrated that CK2 inhibitors [apigenin (20 μM), emodin (20 μM) or 2‑dimethylamino‑4,5,6,7‑tetrabromo‑1H‑benzimidazole (2 μM)] suppressed PKC induced cell invasion and MMP‑9 expression. The results of the present study suggested that CK2 is an important factor involved in the induction of MCF‑7 breast cancer cell invasion by PKC. Therefore, CK2 may represent novel candidates for therapy intended to inhibit invasion in breast cancer. [ABSTRACT FROM AUTHOR]

Chamaecyparis obtusa (C. obtusa) is known to have antimicrobial effects and has been used as a medicinal plant and in forest bathing. This study aimed to evaluate the anticariogenic activity of essential oil of C. obtusa on Streptococcus mutans, which is one of the most important bacterial causes of dental caries and dental biofilm formation. Essential oil from C. obtusa was extracted, and its effect on bacterial growth, acid production, and biofilm formation was evaluated. C. obtusa essential oil exhibited concentration-dependent inhibition of bacterial growth over 0.025 mg/mL, with 99% inhibition at a concentration of 0.2 mg/mL. The bacterial biofilm formation and acid production were also significantly inhibited at the concentration greater than 0.025 mg/mL. The result of LIVE/DEAD® BacLight™ Bacterial Viability Kit showed a concentration-dependent bactericidal effect on S. mutans and almost all bacteria were dead over 0.8 mg/mL. Real-time PCR analysis showed that gene expression of some virulence factors such as brpA, gbpB, gtfC, and gtfD was also inhibited. In GC and GC-MS analysis, the major components were found to be α-terpinene (40.60%), bornyl acetate (12.45%), α-pinene (11.38%), β-pinene (7.22%), β-phellandrene (3.45%), and α-terpinolene (3.40%). These results show that C. obtusa essential oil has anticariogenic effect on S. mutans. [ABSTRACT FROM AUTHOR]

Invasion and metastasis are among the main causes of death in patients with malignant tumors. Fisetin (3,3′,4′,7-tetrahydroxyflavone), a natural flavonoid found in the smoke tree (Cotinus coggygria), is known to have antimetastatic effects on prostate and lung cancers; however, the effect of fisetin on breast cancer metastasis is unknown. The aim of this study was to determine the anti-invasive activity of fisetin in human breast cancer cells. Matrix metalloproteinase (MMP)-9 is a major component facilitating the invasion of many cancer tumor cell types, and thus the inhibitory effect of fisetin on MMP-9 expression in 12- O -tetradecanoylphorbol-13-acetate (TPA)-stimulated human breast cancer cells was investigated in this study. Fisetin significantly attenuated TPA-induced cell invasion in MCF-7 human breast cancer cells, and was found to inhibit the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways. This effect was furthermore associated with reduced NF-κB activation, suggesting that the anti-invasive effect of fisetin on MCF-7 cells may result from inhibited TPA activation of NF-κB and reduced TPA activation of PKCα/ROS/ERK1/2 and p38 MAPK signals, ultimately leading to the downregulation of MMP-9 expression. Our findings indicate the role of fisetin in MCF-7 cell invasion, and clarify the underlying molecular mechanisms of this role, suggesting fisetin as a potential chemopreventive agent for breast cancer metastasis. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the antibacterial activity of essential oil extracted from Chrysanthemum boreale (C. boreale) on Streptococcus mutans (S. mutans). To investigate anticariogenic properties, and bacterial growth, acid production, biofilm formation, bacterial adherence of S. mutans were evaluated. Then gene expression of several virulence factors was also evaluated. C. boreale essential oil exhibited significant inhibition of bacterial growth, adherence capacity, and acid production of S. mutans at concentrations 0.1–0.5 mg/mL and 0.25–0.5 mg/mL, respectively. The safranin staining and scanning electron microscopy results showed that the biofilm formation was also inhibited. The result of live/dead staining showed the bactericidal effect. Furthermore, real-time PCR analysis showed that the gene expression of some virulence factors such as gtfB, gtfC, gtfD, gbpB, spaP, brpA, relA, and vicR of S. mutans was significantly decreased in a dose dependent manner. In GC and GC-MS analysis, seventy-two compounds were identified in the oil, representing 85.42% of the total oil. The major components were camphor (20.89%), β-caryophyllene (5.71%), α-thujone (5.46%), piperitone (5.27%), epi-sesquiphellandrene (5.16%), α-pinene (4.97%), 1,8-cineole (4.52%), β-pinene (4.45%), and camphene (4.19%). These results suggest that C. boreale essential oil may inhibit growth, adhesion, acid tolerance, and biofilm formation of S. mutans through the partial inhibition of several of these virulence factors. [ABSTRACT FROM AUTHOR]

Objective: SIRT1 modulates the acetylation of the p65 subunit of nuclear factor-κB (NF-κB) and plays a pivotal role in the inflammatory response. This study sought to assess the role of SIRT1 in rheumatoid arthritis (RA) using a myeloid cell-specific SIRT1 knockout (mSIRT1 KO) mouse. Methods: mSIRT1 KO mice were generated using the loxP/Cre recombinase system. K/BxN serum transfer arthritis was induced in mSIRT1 KO mice and age-matched littermate loxP control mice. Arthritis severity was assessed by clinical and pathological scoring. The levels of inflammatory cytokines in the serum and joints were measured by ELISA. Migration, M1 polarization, cytokine production, osteoclastogenesis, and p65 acetylation were assessed in bone marrow-derived monocytes/macrophages (BMMs). Results: mSIRT1 KO mice showed more severe inflammatory arthritis and aggravated pathological findings than control mice. These effects were paralleled by increases in IL-1, TNF-α, TRAP-positive osteoclasts, and F4/80+ macrophages in the ankles of mSIRT1 KO mice. In addition, BMMs from mSIRT1 KO mice displayed hyperacetylated p65 and increased NF-κB binding activity when compared to control mice, which resulted in increased M1 polarization, migration, pro-inflammatory cytokine production, and osteoclastogenesis. Conclusion: Our study provides in vivo evidence that myeloid cell-specific deletion of SIRT1 exacerbates inflammatory arthritis via the hyperactivation of NF-κB signaling, which suggests that SIRT1 activation may be beneficial in the treatment of inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Objective. Emodin (3-methyl-1,6,8-trihydroxyanthraquinone) is one of the active components present in the root and rhizome of Rheum palmatum. It has been shown to contain biological activity (antitumour, antibacterial, diuretic and vasorelaxant effects). However, the mechanisms underlying the anti-arthritic effect of emodin have not been elucidated. Here we investigated whether emodin treatment would modulate the severity of the disease in an experimental arthritis model.Methods. We evaluated the effects of emodin on CIA mice in vivo.Results. The pathological processes of RA are mediated by a number of cytokines and MMPs. Expression of these proinflammatory mediators is controlled by nuclear factor-κB (NF-κB). This study was performed to explore the effect of emodin on control of the NF-κB activation pathway and to investigate whether emodin has anti-inflammatory effects in CIA mice in vivo. Emodin inhibited the nuclear translocation and DNA binding of NF-κB subunits, which were correlated with its inhibitory effect on cytoplasmic IκBα degradation in CIA mice. These events further suppressed chemokine production and MMP expression. In addition, emodin inhibited the osteoclast differentiation induced by M-CSF and receptor activation of NF-κB ligand in bone marrow macrophages.Conclusion. These findings suggest that emodin exerts anti-inflammatory effects in CIA mice through inhibition of the NF-κB pathway and therefore may have therapeutic value for the treatment of RA. [ABSTRACT FROM AUTHOR]

Curcumin (diferuloylmethane) is a polyphenol derived from turmeric ( Curcuma longa), which is commonly used as a spice. Recent studies have shown that curcumin has a wide range of pharmacological activities, including anticarcinogenic, antioxidant, anti-inflammatory and antiangiogenic activities. However, the antiphotoageing effects of curcumin have yet to be characterized. In this study, we investigated the inhibitory effects of curcumin on matrix metalloproteinase ( MMP)-1 and MMP-3 expression in human dermal fibroblast cells. Western blot analysis revealed that curcumin inhibited ultraviolet ( UV) B-induced MMP-1 and MMP-3 expression. Furthermore, curcumin significantly blocked UVB-induced reactive oxygen species generation in fibroblasts. Curcumin treatment significantly blocked the UVB-induced activation of nuclear factor ( NF)-κB and activator protein ( AP)-1. Additionally, curcumin strongly repressed the UVB-induced phosphorylation of p38 and c-Jun N-terminal kinase. Curcumin prevented UVB-induced MMP expression through mitogen-activated protein kinase/ NF-κB inhibition and AP-1 activation. In conclusion, curcumin may be useful for preventing and treating skin photoageing. [ABSTRACT FROM AUTHOR]

Abstract: The ADP-ribose (ADPR) pyrophosphatase (ADPRase) NUDT5, a member of a superfamily of Nudix hydrolases, hydrolyzes ADP-ribose (ADPR) to AMP and ribose 5′-phosphate. Nitric oxide (NO) enhances nonenzymatic ADP-ribosylation of proteins such as β-actin and glyceraldehydes 3-phosphate dehydrogenase in the presence of free ADPR, suggesting a possibility that NUDT5 could also be ADP-ribosylated by its substrate, ADPR. Here, we show that NO stimulates nonenzymatic ADP-ribosylation of NUDT5 using ADP-ribose and consequently activates its ADPRase activity. We found that ADPRase activity in J774 macrophage cells is increased by the treatment with SNP, an exogenous NO generator or TNF-α/IFN-γ, endogenous NO inducers. Anti-NUDT5 antibody pulled down most of the ADPRase activity increased by NO, indicating that the ADPRase regulated by NO is NUDT5. Using recombinant human NUDT5, we also demonstrated that the increase of ADPRase activity is mediated via ADP-ribosylation at cysteine residue(s) in the presence of reductant. This result suggests that NO activates NUDT5 through ADP-ribosylation at cysteine residues of the enzyme in macrophages. [Copyright &y& Elsevier]

Abstract: Scopoletin (6-methoxy-7-hydroxycoumarin) is a phenolic coumarin and a member of the phytoalexins. In this study we investigated whether scopoletin caused apoptosis in HL-60 promyelocytic cells and, if so, by what mechanisms. We found that scopoletin induced apoptosis as confirmed by a characteristic ladder pattern of discontinuous DNA fragments in a dose-dependent manner. The signal cascade activated by scopoletin included the heterodimeric redox-sensitive transcription factor NF-κB, which exhibited an upregulation of nuclear factor-kappa B (NF-κB) translocation to the nucleus by increase of IκBα degradation. In addition, scopoletin activated caspase-3 as was evidenced by both the proteolytic cleavage of the proenzyme and increased protease activity. Activation of caspase-3 resulted in the cleavage of 116 kDa poly(ADP-ribose) polymerase (PARP) to 85 kDa cleavage product in time-and dose-dependent fashions. Prior treatment of the cells with pyrrolidine dithiocarbamate, a potent inhibitor of NF-κB activation, or Ac-DEVD-CHO, a specific caspase-3 inhibitor, prevented scopoletin-induced caspase-3 activation, PARP cleavage, and finally DNA fragmentation. Taken together, these results suggest that scopoletin induces NF-κB activation, which, in turn, causes activation of caspase-3, degradation of PARP, and eventually leads to apoptotic cell death in HL-60 cells. [Copyright &y& Elsevier]

Cytokines produced by immune cells infiltrating pancreatic islets are important mediators of β-cell destruction in insulin-dependent diabetes mellitus. In this study, the effects of Fructus Benincasae Recens (FBR) extract on cytokine-induced β-cell dysfunction were examined. Fructus Benincasae Recens extract completely protected interleukin-1β (IL-1β) and interferon-γ (IFN-γ)-mediated cytotoxicity in rat insulinoma cell line (RINm5F). Incubation with FBR extract resulted in a significant reduction of IL-1β and IFN-γ-induced nitric oxide (NO) production, a finding that correlated well with reduced levels of the inducible form of NO synthase (iNOS) mRNA and protein. The molecular mechanism by which FBR extract inhibited iNOS gene expression appeared to involve the inhibition of NF-κB activation. Our results revealed the possible therapeutic value of FBR extract for the prevention of diabetes mellitus progression. [ABSTRACT FROM AUTHOR]

• CME suppresses RANKL-induced osteoclast differentiation and bone resorption. • CME inhibits RANKL-induced c-Fos and NFATc1 expression. • CME inhibits RANKL-induced PLCγ2 and CREB activation. The flower of chrysanthemum, used worldwide as a medicinal and edible product, has shown various bioactivities, such as anti-inflammatory, antioxidant, anti-tumorigenic, and hepatoprotective activities, as well as cardiovascular protection. However, the effect of Chrysanthemum morifolium Ramat. on the regulation of osteoclast differentiation has not yet been reported. In this study, we aimed to investigate the inhibitory effect of Chrysanthemum morifolium Ramat. water extract (CME) on RANKL-induced osteoclast differentiation in mouse bone marrow-derived macrophages (BMMs). Bone marrow-derived macrophages (BMMs) isolated from the C57BL/6 J mice. The viability of BMMs was detected with MTT assays. Inhibitory effects of CME on osteoclast differentiation and bone resorption was measured by TRAP staining and Pit assay. Osteoclast differentiation-associated gene expression were assessed by Real-time quantitative polymerase chain reaction. Intracellular signaling molecules was assessed by western blot. CME significantly inhibited osteoclast differentiation in BMMs without cytotoxicity, besides inhibiting MAPK/c-fos and PLCγ2/CREB activation. The inhibitory effects of CME on differentiation-related signaling molecules resulted in significant repression of NFATc1 expression, which is a key transcription factor in osteoclast differentiation, fusion, and activation. Our results confirmed the inhibition of RANKL-induced PLCγ2/CREB/c-fos/NFATc1 activation by CME during osteoclast differentiation. The findings collectively suggested CME as a traditional therapeutic agent for osteoporosis, RA, and periodontitis. [ABSTRACT FROM AUTHOR]

Ultraviolet B ( UVB) radiation induces photoageing by upregulating the expression of matrix metalloproteinases ( MMPs) in human skin cells. Dihydroavenanthramide D ( DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component in oats. Although anti-inflammatory, anti-atherosclerotic and antioxidant effects have been reported, the antiphotoageing effects of DHAv D are yet to be understood. In this study, we investigated the inhibitory effects of DHAv D on UVB-induced production of reactive oxygen species ( ROS) and expression of MMPs, and its molecular mechanism in UVB-irradiated human dermal fibroblasts. Western blot and real-time PCR analyses revealed that DHAv D inhibited UVB-induced MMP-1 and MMP-3 expression. It also significantly blocked UVB-induced ROS generation in fibroblasts. Additionally, DHAv D attenuated UVB-induced phosphorylation of MAPKs, activation of NF-κB and AP-1. DHAv D regulates UVB-irradiated MMP expression by inhibiting ROS-mediated MAPK/ NF-κB and AP-1 activation. DHAv D may be a useful candidate for preventing UV light-induced skin photoageing. [ABSTRACT FROM AUTHOR]

• Reversine inhibits IL-1β-induced MMP-3, IL-6, and IL-8 expression. • Reversine suppresses IL-1β-induced ROS generation. • Reversine inhibits IL-1β-stimulated JNK MAP Kinase and AP-1 activation. Periodontitis is an inflammatory disease of the supporting tissue around teeth commonly caused by gram-negative bacterial infections. Interleukin (IL)-1β, a cytokine involved in host immune and inflammatory responses, is known to induce the activation of various intracellular signaling pathways. One of these signaling mechanisms involves the regulation of gene expression by activation of transcription factors (AP-1 and NF-κB). These transcription factors are controlled by mitogen-activated protein kinases (MAPKs), which increase cytokine and matrix metalloproteinase (MMP) expression. We examined the preventive effects of reversine, a 2,6-disubstituted purine derivative, on cytokine and MMP-3 expression in human gingival fibroblasts (HGFs) stimulated with IL-lβ. Western blot analyses were performed to verify the activities of MAPK, p65, p50, and c-Jun and the expression of MMPs in IL-1β-stimulated HGFs. Cytokine and MMP-3 expression in IL-1β-stimulated HGFs was measured by real-time quantitative polymerase chain reaction. Reversine decreased the IL-1β-induced expression of proinflammatory cytokines (IL-6 and IL-8) and MMP-3 in HGFs. Furthermore, the mechanism underlying the effects of reversine involved the suppression of IL-1β-stimulated MAPK activation and AP-1 activation. Reversine inhibits IL-1β-induced MMP and cytokine expression via inhibition of MAPK/AP-1 activation and ROS generation. Therefore, we suggest that reversine may be an effective therapeutic candidate for preventing periodontitis. [ABSTRACT FROM AUTHOR]

Invasion and metastasis are among the main causes of death in patients with malignant tumors. Fisetin (3,3′,4′,7-tetrahydroxyflavone), a natural flavonoid found in the smoke tree (Cotinus coggygria), is known to have antimetastatic effects on prostate and lung cancers; however, the effect of fisetin on breast cancer metastasis is unknown. The aim of this study was to determine the anti-invasive activity of fisetin in human breast cancer cells. Matrix metalloproteinase (MMP)-9 is a major component facilitating the invasion of many cancer tumor cell types, and thus the inhibitory effect of fisetin on MMP-9 expression in 12- O -tetradecanoylphorbol-13-acetate (TPA)-stimulated human breast cancer cells was investigated in this study. Fisetin significantly attenuated TPA-induced cell invasion in MCF-7 human breast cancer cells, and was found to inhibit the activation of the PKCa/ROS/ERK1/2 and p38 MAPK signaling pathways. This effect was furthermore associated with reduced NF-κB activation, suggesting that the anti-invasive effect of fisetin on MCF-7 cells may result from inhibited TPA activation of NF-κB and reduced TPA activation of PKCα/ROS/ERK1/2 and p38 MAPK signals, ultimately leading to the downregulation of MMP-9 expression. Our findings indicate the role of fisetin in MCF-7 cell invasion, and clarify the underlying molecular mechanisms of this role, suggesting fisetin as a potential chemopreventive agent for breast cancer metastasis. [ABSTRACT FROM AUTHOR]