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Hyposalivation is a common complaint among the elderly, but no established treatment prevents age-induced hyposalivation. Platelet derivatives such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and plasma rich in growth factor (PRGF), are used widely in different areas of regenerative medicine to enhance the wound healing processes. This study examined whether the local injection of the supernatant of activated PRP (saPRP) into the salivary gland (SG) could help prevent aging-induced SG dysfunction and explored the mechanisms responsible for the protective effects on the SG hypofunction. The platelets were separated from the blood of male SD rats (220 ± 20 g). saPRP was manufactured by removing the fibrin clot after activating platelet with calcium ionophore 10 µM (A23187). The total protein and TGF-ß1 levels were significantly higher in saPRP than in PRP. Human salivary gland epithelial cell(hSGEC) was treated with saPRP or PRP after senescence through irradiation. The significant proliferation of hSGEC was observed in saPRP treated group compared to irradiation only group and irradiation + PRP group. Cellular senescence, apoptosis, and inflammation significantly reduced in saPRP group. The SG function and structural tissue remodeling by the saPRP were investigated with naturally aged mice. The mice were divided into three groups: 3 months old (3 M), 22 months old (22 M), and 22 months old treated with saPRP (22 M + saPRP). Salivary flow rate and lag time were significantly improved in 22 M + saPRP group compared to 22 M group. The histologic examinations showed the significant proliferation of acinar cell in 22 M + saPRP group. The decrease of senescence, apoptosis, and inflammation observed by western blot in 22 M + saPRP group. The saPRP induced the proliferation of hSGECs, leading to a significant decrease in cellular senescence via decrease inflammation and apoptosis, in vitro. Moreover, the acini cells of the salivary gland were regenerated, and the salivary function increased in aged mice. These results showed that saPRP could be a treatment agent against aging-induced SG dysfunction.
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Plasma Rico en Plaquetas , Xerostomía , Masculino , Humanos , Ratones , Ratas , Animales , Anciano , Lactante , Proliferación Celular , Células Cultivadas , Ratas Sprague-Dawley , Plasma Rico en Plaquetas/metabolismo , Envejecimiento , Xerostomía/metabolismo , Inflamación/metabolismoRESUMEN
Fisetin is a flavonoid found in plants and has been reported to be effective in various human diseases. However, the effective mechanisms of ultraviolet-A (UVA)-mediated skin damage are not yet clear. In this study, we investigated the protective mechanisms of fisetin regarding UVA-induced human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs) damages. Fisetin showed a cytoprotective effect against UVA irradiation and suppressed matrix metalloproteinases (MMPs), MMP-1, and MMP-3 expression. In addition, fisetin was rescued, which decreased mRNA levels of pro-inflammatory cytokines, reactive oxygen species production, and the downregulation of MAPK/AP-1 related protein and NADPH oxidase (NOX) mRNA levels. Furthermore, UVA-induced MMP-1 and MMP-3 were effectively inhibited by siRNAs to NOX 1 to 5 in HDFs and HEKs. These results indicate that fisetin suppresses UVA-induced damage through the NOX/ROS/MAPK pathway in HDFs and HEKs.
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Metaloproteinasa 1 de la Matriz , Metaloproteinasa 3 de la Matriz , Humanos , Especies Reactivas de Oxígeno/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/metabolismo , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Células Cultivadas , Piel/metabolismo , Queratinocitos/metabolismo , Fibroblastos/metabolismo , ARN Mensajero/metabolismo , Rayos Ultravioleta/efectos adversosRESUMEN
Protaetia brevitarsis (PB)-derived bioactive substances have been used as food and medicine in many Asian countries because of their antioxidant, antidiabetic, anti-cancer, and hepatoprotective properties. However, the effect of PB extracts (PBE) on osteoclast differentiation is unclear. In this study, we investigated the effect of PBE on RANKL-induced osteoclastogenesis in mouse bone marrow-derived macrophages (BMMs). To investigate the cytotoxicity of PBE, the viability of BMMs was confirmed via MTT assay. Tartrate-resistant acid phosphatase (TRAP) staining and pit assays were performed to confirm the inhibitory effect of PBE on osteoclast differentiation and bone resorption. The expression levels of osteoclast differentiation-related genes and proteins were evaluated using quantitative real-time PCR and Western blotting. PBE attenuated osteoclastogenesis in BMMs in TRAP and pit assays without cytotoxicity. The expression levels of osteoclast marker genes and proteins induced by RANKL were decreased after PBE treatment. PBE suppressed osteoclastogenesis by inhibiting the RANKL-induced activated JNK/NF-κB/PLCγ2 signaling pathway and the expression of NFATc1 and c-Fos. Collectively, these results suggest that PBE could be a potential therapeutic strategy or functional product for osteoclast-related bone disease.
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Resorción Ósea , FN-kappa B , Animales , Ratones , FN-kappa B/metabolismo , Osteogénesis , Fosfolipasa C gamma/metabolismo , Osteoclastos , Sistema de Señalización de MAP Quinasas , Resorción Ósea/metabolismo , Ligando RANK/metabolismo , Diferenciación CelularRESUMEN
Dry mouth is frequently observed in the elderly, and enhanced lipid accumulation plays a critical role in cellular senescence in the salivary gland (SG). We investigated the mechanisms that mediate lipogenesis-associated SG senescence. Adult (28.6 ± 6.6 y.o. and 43.3 ± 1.5 y.o.) and aged (82.0 ± 4.3 y.o. and 88.0 ± 4.3 y.o.) human parotid and submandibular glands were compared with respect to histologic findings, 8-OHdG (8-hydroxy 2 deoxyguanosine) expression patterns, TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) and SA-ß-gal (senescence-associated ß-galactosidase) assay results. Also, microarray analysis was performed on RNA extracted from adult and aged SG to identify DEGs (differentially expressed genes). The effects of silencing ADIPOQ (Adiponectin) were evaluated by quantifying cell proliferation, immunohistochemical staining for cellular senescence and inflammation-associated proteins, SA-ß-gal assays, RT-PCR, and western blot. Histological findings demonstrated the presence of more lipocytes, chronic inflammation, fibrosis, and lymphocytic infiltration in old SG. In addition, old tissues demonstrated higher expressions of SA-ß-gal, more apoptotic cells in TUNEL assays, and higher oxidative stress by 8-OHdG immunostaining. Microarray analysis showed lipogenesis was significantly upregulated in old tissues. Silencing of ADIPOQ (a lipogenesis-related gene) reduced inflammation and SA-ß-gal levels and increased cell proliferation and the expressions of amylase and aquaporin 5 in human SG epithelial cells. The study shows ADIPOQ is a potential target molecule for the modulation of lipogenesis associated with SG senescence.
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Adiponectina , Glándulas Salivales , Anciano , Humanos , Adiponectina/genética , Senescencia Celular/genética , beta-Galactosidasa/metabolismo , Inflamación , LípidosRESUMEN
OBJECTIVE: This article compares and evaluates the marginal and internal fitness and three-dimensional (3D) accuracy of class II inlays fabricated using Tescera (TS) resin, milling of hybrid and zirconia blocks, and 3D printing with NextDent C&B. MATERIALS AND METHODS: Fifty-two mesio-occlusal inlays were fabricated using conventional method with TS, milling of Lava Ultimate (LU), milling of Zolid Fx multilayer (ZR), and 3D printing (n = 13 each). The marginal and internal fitness were evaluated at six points in the mesio-distal section of a replica under a digital microscope (160× magnification), and the accuracy was evaluated using 3D software. Analyses were conducted using t-test, one-way analysis of variance (ANOVA) and two-way ANOVA, while Duncan's multiple range test was used for post hoc analyses (α = 0.05). RESULTS: The marginal and internal fitness of the 3D and ZR were significantly superior to that of the TS and LU. For LU, ZR, and 3D, a significant discrepancy between the marginal gap and internal gap was observed (p < 0.05). On evaluating accuracy, trueness was significantly higher in ZR than in TS and LU; precision was significantly higher in 3D and ZR than in TS and LU (p < 0.05). CONCLUSION: The marginal and internal fitness and the accuracy of TS, ZR, and 3D were within the clinically acceptable range. The marginal and internal fitness and accuracy of 3D were better than those of TS and LU, which are commonly used in dentistry. There is immense potential for using 3D-printed inlays in routine clinical practice.
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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 ß-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-Iß. 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.
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Fibroblastos , Metaloproteinasa 1 de la Matriz , Periodontitis , Serina Endopeptidasas , Citocinas/metabolismo , Regulación hacia Abajo , Fibroblastos/metabolismo , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lipopolisacáridos/toxicidad , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , FN-kappa B/metabolismo , Periodontitis/genética , Periodontitis/metabolismo , Porphyromonas gingivalis , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Receptores Proteinasa-Activados/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Transducción de Señal , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Introduction: Salivary gland (SG) damage is commonly caused by aging, irradiation, and some medications, and currently, no damage modifying agent is available. However, cell therapy based on mesenchymal stem cells (MSCs) has been proposed as a therapeutic modality for irradiated SGs. Therefore, we administered cell-derived vesicles (CDVs) of adipose-derived mesenchymal stem cells (ADMSCs) to irradiated SG cells to investigate their radioprotective effects in vitro. Methods: The artificial CDVs were obtained from ADMSC by tangential flow filtration (TFF) purification and ultracentrifugation. Cultured human SG epithelial cells were exposed to 2, 5 or 15 Gy of 4 MV X-rays produced by a linear accelerator. The effects of ADMSC-CDVs on SG epithelial cells damaged by irradiation were tested by proliferation activity, transepithelial electrical resistance (TEER), and amylase activity. Results: Exposure to penetrating radiation inhibited the proliferation of SG epithelial cells, but the radiation intensity required to reduce the proliferation of human submandibular gland epithelial cells (hSMGECs) was greater than required for other SG cells. ADMSC-CDVs restored the proliferative ability of SG epithelial cells reduced by irradiation, and the proliferation capacities of irradiated human parotid gland epithelial cells (hPGECs) and human sublingual gland epithelial cells (hSLGECs) were increased by administering ADMSC-CDVs to non-irradiated SG epithelial cells. Furthermore, amylase activity in irradiated hPGECs, hSMGECs, and hSLGECs was lower than in non-irradiated controls. However, amylase ability was restored in all by ADMSC-CDV treatment. Also, TEER was diminished by irradiation in hPGECs, hSMGECs, and hSLGECs and restored by ADMSC-CDV administration. Conclusion: Overall, our findings demonstrate that ADMSC-CDVs have potent radioprotective effects on irradiated SG cells.
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Vocal cord paralysis caused by recurrent laryngeal nerve (RLN) injury during thyroidectomy results in hoarseness, aspiration, and dyspnea. We evaluated the usefulness of nerve guidance conduits (NGCs) constructed from an asymmetric polycaprolactone (PCL)/Pluronic F127 porous membrane and filled with platelet-rich plasma (PRP) for functional RLN regeneration. We evaluated the proliferation and migration of Schwann cells (SCs) after PRP treatment in vitro. For the in vivo study, rabbits were divided into a non-loaded NGC group and a PRP-loaded NGC group. The left RLNs were resected and interposed with the NGCs. Functional and histological examinations of the vocal cords were performed. SC proliferation and migration increased in a PRP dose-dependent manner, with the PRP increasing the levels of neurotrophic factors, myelin-associated glycoprotein, and ERK. In vivo, the PRP group showed significantly better vocal cord mobility and less vocalis muscle atrophy than the non-loaded NGC group. Histologically, the ingrowth of nerve endings occurred more rapidly in the PRP group, and acetylcholinesterase, neurofilament, and S-100 expression in neural endings were significantly higher in the PRP group. Furthermore, transmission electron microscopy showed that myelinated axons were more tightly packed in the PRP group. This study shows that PRP-loaded NGCs provide a favorable environment for neural regeneration and suggests that this technique has therapeutic potential for promoting RLN recovery.
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BACKGROUND: Early identification of patients with high-risk papillary thyroid microcarcinoma (PTMC) that is likely to progress has become a critical challenge. We aimed to identify somatic mutations associated with lateral neck lymph node (LN) metastasis (N1b) in patients with PTMC. METHODS: Whole-exome sequencing (WES) of 14 PTMCs with no LN metastasis (N0) and 13 N1b PTMCs was performed using primary tumors and matched normal thyroid tissues. RESULTS: The mutational burden was comparable in N0 and N1b tumors, as the median number of mutations was 23 (range, 12 to 46) in N0 and 24 (range, 12 to 50) in N1b PTMC (P=0.918). The most frequent mutations were detected in PGS1, SLC4A8, DAAM2, and HELZ in N1b PTMCs alone, and the K158Q mutation in PGS1 (four patients, Fisher's exact test P=0.041) was significantly enriched in N1b PTMCs. Based on pathway analysis, somatic mutations belonging to the receptor tyrosine kinase-RAS and NOTCH pathways were most frequently affected in N1b PTMCs. We identified four mutations that are predicted to be pathogenic in four genes based on Clinvar and Combined Annotation-Dependent Depletion score: BRAF, USH2A, CFTR, and PHIP. A missense mutation in CFTR and a nonsense mutation in PHIP were detected in N1b PTMCs only, although in one case each. BRAF mutation was detected in both N0 and N1b PTMCs. CONCLUSION: This first comprehensive WES analysis of the mutational landscape of N0 and N1b PTMCs identified pathogenic genes that affect biological functions associated with the aggressive phenotype of PTMC.
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Ganglios Linfáticos , Biomarcadores , Carcinoma Papilar , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Neoplasias de la Tiroides , Secuenciación del ExomaRESUMEN
Matriptases, members of the type II transmembrane serine protease family, are cell surface proteolytic enzymes that mediate tumor invasion and metastasis. Matriptase is highly expressed in breast cancer and is associated with poor patient outcome. However, the cellular mechanism by which matriptase mediates breast cancer invasion remains unknown. The present study aimed to determine the role of matriptase in the protein kinase C (PKC)mediated metastasis of MCF7 human breast cancer cells. Matriptase small interfering RNAmediated knockdown significantly attenuated the 12Otetradecanoylphorbol13acetate (TPA)induced invasiveness and migration of MCF7 cells, and inhibited the activation of phospholipase C γ2 (PLCγ2)/PKC/MAPK signaling pathways. Matriptaseknockdown also suppressed the expression of MMP9 and inhibited the activation of NFκB/activator protein1 in MCF7 cells. Additionally, GB83 [an inhibitor of proteaseactivated receptor2 (PAR2)] inhibited PKCmediated MMP9 expression and metastatic ability in MCF7 cells. Furthermore, downregulation of matriptase suppressed TPAinduced MMP9 expression and invasiveness via PAR2/PLCγ2/PKC/MAPK activation. These findings shed light on the mechanism underlying the role of matriptase in MCF7 cell invasion and migration ability, and suggest that matriptase modulation could be a promising therapeutic strategy for preventing breast cancer metastasis.
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Neoplasias de la Mama/enzimología , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica/prevención & control , Fosfolipasa C gamma/metabolismo , Proteína Quinasa C/metabolismo , Receptor PAR-2/metabolismo , Serina Endopeptidasas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Movimiento Celular , Regulación hacia Abajo , Humanos , Células MCF-7RESUMEN
Periodontitis is a Gram-negative bacterial infectious disease. Numerous inflammatory cytokines, including interleukin-1ß (IL-1ß), regulate periodontitis pathophysiology and cause periodontal tissue destruction. In human gingival fibroblasts (HGFs), IL-1ß 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-1ß-stimulated HGFs. EFE inhibited the expression of MMP-1, MMP-3, and proinflammatory cytokines (TNF-α, IL-6, and IL-8) in IL-1ß-stimulated HGFs through the inhibition of IL-1ß-induced MAPK/STAT-3 activation. Also, these results suggest that the EFE may be a useful for the bioactive material for oral care.
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BACKGROUND: We examined the regenerative efficacy of the activated platelet-rich plasma (PRP) concentrate administered by local injection in an animal model mimicking partial glossectomy for tongue cancer. METHODS: Four-week-old mice were randomized to four groups; (1) a treatment-naïve control group, (2) a PRP group, (3) a hemiglossectomy group, and (4) a hemiglossectomy + PRP group. The activated PRP concentrate was injected into the deep layer of resected surfaces of mouse tongues immediately after excision, and tongue widths and lengths were measured on postoperative days (POD) 5 and 12. Gross tongue morphologies and microscopic findings were investigated. Inflammation and fibrous tissue areas were also measured, and immunohistochemical analysis was performed for c-kit, neurofilament, and S-100. RESULTS: The activated PRP concentrate reduced wound scar contracture, promoted wound healing, and reduced inflammation and wound fibrosis. On POD 12, histologic findings in the hemiglossectomy + PRP group were similar to those in the normal control group, and the intensity of stem cell factor receptor c-kit expression was also significantly greater in the PRP group than in the hemiglossectomy group on POD 12. Immunohistochemical staining revealed S100 and neurofilament expressions in the hemiglossectomy + PRP group were significantly more intense than in the hemiglossectomy group. CONCLUSION: Intralesional activated PRP concentrate injection has potential use for tongue regeneration, wound healing, and neural regeneration with minimal scarring after partial glossectomy.
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Glosectomía , Plasma Rico en Plaquetas , Regeneración , Lengua , Animales , Modelos Animales de Enfermedad , Inflamación , Ratones , Lengua/cirugía , Cicatrización de HeridasRESUMEN
Lymphoma is widely recognized in veterinary medicine. However, studies focused on secondary lymphoma after chemotherapy do not exist in veterinary medicine. An 11-year-old, spayed female Shih-Tzu dog was diagnosed with mammary gland carcinoma. Twenty-five months after carboplatin treatment, the dog developed generalized lymphadenopathy (GL), diagnosed as high-grade T-cell lymphoma by immunohistochemistry. Another spayed female Shih-Tzu dog who was 15-year-old had biopsy-induced gastrointestinal stromal tumour. Three months after being treated with Toceranib, the dog developed GL that was diagnosed by PCR for antigen receptor rearrangement as T-cell lymphoma. An eight-year-old, castrated male Mongrel dog was diagnosed with mast cell tumour. The dog was treated with vinblastine, but 14 months later, GL was revealed. Fine-needle aspiration indicated lymphoma. The owner declined to investigate the cell lineage. All three dogs developed GL after chemotherapy. We suggest that secondary lymphoma can develop in dogs after chemotherapy for a primary cancer, and thus long-term follow-up is necessary.
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Enfermedades de los Perros/diagnóstico , Linfoma de Células T/veterinaria , Animales , Enfermedades de los Perros/patología , Perros , Femenino , Linfoma de Células T/diagnóstico , Linfoma de Células T/patología , MasculinoRESUMEN
Bruton's agammaglobulinemia tyrosine kinase (BTK) is an important cytoplasmic tyrosine kinase involved in Blymphocyte development, differentiation, and signaling. Activated protein kinase C (PKC), in turn, induces the activation of mitogenactivated protein kinase (MAPK) signaling, which promotes cell proliferation, viability, apoptosis, and metastasis. This effect is associated with nuclear factorκB (NFκB) activation, suggesting an antimetastatic effect of BTK inhibitors on MCF7 cells that leads to the downregulation of matrix metalloproteinase (MMP)9 expression. However, the effect of BTK on breast cancer metastasis is unknown. In this study, the antimetastatic activity of BTK inhibitors was examined in MCF7 cells focusing on MMP9 expression in 12Otetradecanoylphorbol13acetate (TPA)stimulated MCF7 cells. The expression and activity of MMP9 in MCF7 cells were investigated using quantitative polymerase chain reaction analysis, western blotting, and zymography. Cell invasion and migration were investigated using the Matrigel invasion and cell migration assays. BTK inhibitors [ibrutinib (10 µM), CNX774 (10 µM)] significantly attenuated TPAinduced cell invasion and migration in MCF7 cells and inhibited the activation of the phospholipase Cγ2/PKCß signaling pathways. In addition, small interfering RNA specific for BTK suppressed MMP9 expression and cell metastasis. Collectively, results of the present study indicated that BTK suppressed TPAinduced MMP9 expression and cell invasion/migration by activating the MAPK or IκB kinase/NFκB/activator protein1 pathway. The results clarify the mechanism of action of BTK in cancer cell metastasis by regulating MMP9 expression in MCF7 cells.
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Agammaglobulinemia Tirosina Quinasa/metabolismo , Neoplasias de la Mama/patología , Metaloproteinasa 9 de la Matriz/genética , Adenina/análogos & derivados , Adenina/farmacología , Adenina/uso terapéutico , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Células MCF-7 , Metaloproteinasa 9 de la Matriz/metabolismo , FN-kappa B/metabolismo , Invasividad Neoplásica/patología , Invasividad Neoplásica/prevención & control , Fosfolipasa C gamma/metabolismo , Piperidinas/farmacología , Piperidinas/uso terapéutico , Acetato de Tetradecanoilforbol/toxicidad , Factor de Transcripción AP-1/metabolismoRESUMEN
OBJECTIVE: 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). STUDY DESIGN: Bone marrow-derived macrophages (BMMs) isolated from the C57BL/6â¯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. RESULTS: 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. CONCLUSION: 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.
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Resorción Ósea , Diferenciación Celular/efectos de los fármacos , Chrysanthemum/química , Osteoclastos/efectos de los fármacos , Extractos Vegetales/farmacología , Ligando RANK/metabolismo , Animales , Células de la Médula Ósea , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/metabolismo , Osteoclastos/citología , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
OBJECTIVE: Little is known about the role of estrogen in thyroid cancer development. We aimed to evaluate the association between hysterectomy or bilateral salpingo-oophorectomy (BSO) and the risk of subsequent thyroid cancer. DESIGN: A nationwide cohort study. METHODS: Data from the Korea National Health Insurance Service between 2002 and 2017 were used. A total of 78 961 and 592 330 women were included in the surgery group and no surgery group, respectively. The surgery group was categorized into two groups according to the extent of surgery: hysterectomy with ovarian conservation (hysterectomy-only) and BSO with or without hysterectomy (BSO). RESULTS: During 8 086 396.4 person-years of follow-up, 12 959 women developed thyroid cancer. Women in the hysterectomy-only (adjusted hazard ratio = 1.7, P < 0.001) and BSO (adjusted hazard ratio = 1.4, P < 0.001) groups had increased risk of thyroid cancer compared to those in the no surgery group. In premenopausal women, hysterectomy-only (adjusted hazard ratio = 1.7, P < 0.001) or BSO (adjusted hazard ratio = 1.4, P < 0.001) increased the risk of subsequent thyroid cancer, irrespective of hormone therapy, whereas, there was no significant association between hysterectomy-only (P = 0.204) or BSO (P = 0.857) and thyroid cancer development in postmenopausal women who had undergone hormone therapy. CONCLUSIONS: Our findings do not support the hypotheses that sudden or early gradual decline in estrogen levels is a protective factor in the development of thyroid cancer, or that exogenous estrogen is a risk factor for thyroid cancer.
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Histerectomía/efectos adversos , Ovariectomía/efectos adversos , Neoplasias de la Tiroides/epidemiología , Adulto , Factores de Edad , Estudios de Cohortes , Terapia de Reemplazo de Estrógeno , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Premenopausia , República de Corea/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: Only few studies have shown the efficacy and safety of glucose-control strategies using the quadruple drug combination. Therefore, the aim of the present study was to investigate the usefulness of the quadruple combination therapy with oral hypoglycemic agents (OHAs) in patients with uncontrolled type 2 diabetes mellitus (T2DM). METHODS: From March 2014 to December 2018, data of patients with T2DM, who were treated with quadruple hypoglycemic medications for over 12 months in 11 hospitals in South Korea, were reviewed retrospectively. We compared glycosylated hemoglobin (HbA1c) levels before and 12 months after quadruple treatment with OHAs. The safety, maintenance rate, and therapeutic patterns after failure of the quadruple therapy were also evaluated. RESULTS: In total, 357 patients were enrolled for quadruple OHA therapy, and the baseline HbA1c level was 9.0%±1.3% (74.9±14.1 mmol/mol). After 12 months, 270 patients (75.6%) adhered to the quadruple therapy and HbA1c was significantly reduced from 8.9%±1.2% to 7.8%±1.3% (mean change, -1.1%±1.2%; P<0.001). The number of patients with HbA1c <7% increased significantly from 5 to 68 (P<0.005). In addition, lipid profiles and liver enzyme levels were also improved whereas no changes in body weight. There was no significant safety issue in patients treated with quadruple OHA therapy. CONCLUSION: This study shows the therapeutic efficacy of the quadruple OHA regimen T2DM and demonstrates that it can be an option for the management of T2DM patients who cannot use insulin or reject injectable therapy.
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Diabetes Mellitus Tipo 2 , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: This study aimed to evaluate the benefit of brachial-ankle pulse wave velocity (baPWV) as a noninvasive marker of arterial stiffness for the prediction of all-cause and cause-specific mortality in patients with type 2 diabetes. METHODS: This multicenter prospective observational study analyzed 2308 patients with type 2 diabetes between 2008 and 2018. The patients were categorized according to the quartiles of baPWV. Cause of mortality was determined using death certificates and patient clinical records. We estimated proportional mortality rates from all causes, cardiovascular, cancer, and other causes among adults with diabetic status according to their baPWV. Cox regression models were used to estimate hazard ratios (HRs). RESULTS: There were 199 deaths (8.6%) in the study population during a median follow-up duration of 8.6 years. When baPWV was assessed as quartiles, a significantly higher risk of all-cause mortality (HR = 5.39, P < 0.001), cardiovascular-mortality (HR = 14.89, P < 0.001), cancer-mortality (HR = 5.42, P < 0.001), and other-cause mortality (HR = 4.12, P < 0.001) was found in quartile 4 (Q4, ≥ 1830 cm/s) than in quartiles 1-3 (Q1-3). Adding baPWV to baseline model containing conventional risk factors such as age, sex, diabetes duration, body mass index, glycated hemoglobin, systolic blood pressure, glomerular filtration rate, smoking, and insulin improved the risk prediction for all-cause (net reclassification index (NRI) = 49%, P < 0.001) and cause-specific (cardiovascular NRI = 28%, P = 0.030; cancer NRI = 55%, P < 0.001; other-cause NRI 51%, P < 0.001) mortality. CONCLUSION: This long-term, large-scale, multicenter prospective observational cohort study provide evidence that increased arterial stiffness, as measured by baPWV, predicts the risk of all-cause and cause-specific mortality in type 2 diabetes, supporting the prognostic utility of baPWV. Trial registration Clinical Research Information Service (CRIS), KCT 0005010. Retrospectively Registered May 12, 2020. https://cris.nih.go.kr/cris/search/search_result_st01.jsp?seq=16677.
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Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus Tipo 2/fisiopatología , Mortalidad , Neoplasias/mortalidad , Rigidez Vascular/fisiología , Anciano , Causas de Muerte , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Análisis de la Onda del Pulso , Factores de RiesgoRESUMEN
BACKGROUND: Most patients with thyroid cancer suffer from salivary gland (SG) dysfunctions after radioiodine (RI) therapy. We investigated the effects of keratinocyte growth factor (KGF)-1 on RI-induced SG dysfunction in an animal model. METHODS: Six C57BL/6 mice were assigned to each of the following groups: treatment naïve control group, RI group, and RI+KGF-1 group. Body and SG weights, salivary flow rates, salivary lag times and changes in 99mTc pertechnetate uptake and excretion were measured, and histologic changes were noted. Amylase activities and epidermal growth factor (EGF) concentrations in saliva were also measured. In addition, TUNEL assays were performed and apoptosis-related protein expressions were assessed. RESULTS: RI-induced reductions in salivary flow rates and increases in salivary lag times observed in the RI group were not observed in RI+KGF-1 group. Mice in RI group had higher HIF1a levels than controls, but HIF1a levels in RI+KGF-1 group were similar to those in control group. Furthermore, mice in RI+KGF-1 group had more mucin stained acini and decreased periductal fibrosis than mice in RI group, and tissue remodeling of many salivary epithelial cells (AQP5) and endothelial cells (CD31) were observed in RI+KGF-1 group. Amylase activity and expression in saliva were greater in RI+KGF-1 group than in RI group, and fewer apoptotic cells were observed in RI+KGF-1 group. Furthermore, BCLxl (anti-apoptotic) expression was higher, and Bax (pro-apoptotic) expression was lower in RI+KGF-1 group than in RI group. CONCLUSIONS: Local delivery of KGF-1 might prevent RI-induced SG damage by reducing apoptosis.