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The mechanisms underlying chronic inflammatory diseases remain unclear. Therefore, researchers have explored the mechanisms underlying colitis using diverse materials. Recently, there has been an increasing interest in fermented products and bioconversion materials, their potential efficacy is being actively studied. Gochujang, a traditional Korean fermented product, is crafted by blending fermented Meju powder, gochu (Korean chili) powder, glutinous rice, and salt. In our study, we explored the effectiveness of Gochujang (500 mg/kg; Cheongju and Hongcheon, Korea) in dextran sulfate sodium (DSS)-induced colitis mice model. Gochujang was orally administered for 2 weeks, followed by the induction of colitis using 3% DSS in the previous week. During our investigation, Gochujang variants (TCG22-25, Cheongju and TCG22-48, Hongcheon) did not exhibit significant inhibition of weight reduction (p = 0.061) but notably (p = 0.001) suppressed the reduction in large intestine length in DSS-induced colitis mice. In the serum from colitis mice, TCG22-48 demonstrated reduced levels of the inflammatory cytokines interleukin (IL)-6 (p = 0.001) and tumor necrosis factor (TNF)-α (p = 0.001). Additionally, it inhibited the phosphorylation of Erk (p = 0.028), p38, and NF-κB (p = 0.001) the inflammatory mechanism. In our study, TCG22-25 demonstrated a reduction in the IL-6 level (p = 0.001) in serum and inhibited the phosphorylation of p38 and NF-κB (p = 0.001). Histological analysis revealed a significant (p = 0.001) reduction in the pathological score of the large intestine from TCG22-25 and TCG22-48. In conclusion, the intake of Gochujang demonstrates potent anti-inflammatory effects, mitigating colitis by preventing the large intestine length reduction of animals with colitis, lowering serum levels of TNF-α and IL-6 cytokines, and inhibiting histological disruption and inflammatory mechanism phosphorylation.
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Osteoarthritis is a chronic inflammatory disease, and, due to the lack of fundamental treatment, the main objective is to alleviate pain and prevent cartilage damage. Kalopanax pictus Nakai and Achyranthes japonica Nakai are herbal plants known for their excellent anti-inflammatory properties. The objective of this study is to confirm the potential of a mixture extract of Kalopanax pictus Nakai and Achyranthes japonica Nakai as a functional raw material for improving osteoarthritis through anti-inflammatory effects in macrophages and MIA-induced arthritis experimental animals. In macrophages inflamed by lipopolysaccharide (LPS), treatment of Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture inhibits NF-κB and mitogen-activated protein kinase (MAPK) activities, thereby inhibiting inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), inflammatory factors PGE2, MMP-2, and MMP-9, and nitric oxide (NO) was reduced. In addition, in an animal model of arthritis induced by MIA (monosodium iodoacetate), administration of Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture reduced blood levels of inflammatory cytokines TNF-α and IL-6, inflammatory factors prostaglandin E2(PGE2), matrix metalloproteinase-2(MMP-2), and NO. Through these anti-inflammatory effects, MIA-induced pain reduction (recovery of clinical index, increase in weight bearing, and increase in area and width of the foot), recovery of meniscus damage, loss of cartilage tissue or inflammatory cells in tissue infiltration reduction, and recovery of the proteglycan layer were confirmed. Therefore, it is considered that Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture has the potential as a functional raw material that promotes joint health.
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Prenatal and perinatal infections and inflammation appear to associated with the development of retinopathy of prematurity (ROP). In this study, we evaluated whether inflammatory mediators in amniotic fluid (AF) retrieved during cesarean delivery influence the development of ROP in very low birth weight (VLBW) infants. This retrospective study included 16 and 32 VLBW infants who did and did not develop any stage of ROP, respectively. Each infant with ROP was matched with 2 infants without ROP based on days of ventilation care, gestational age, and birth weight. AF was obtained during cesarean delivery, and the levels of intra-amniotic inflammatory mediators such as interleukin (IL)-1ß, IL-2, IL-6, IL-8, IL-10, matrix metalloproteinase (MMP)-2, MMP-8, MMP-9, and tumor necrosis factor (TNF)-α were measured using a Human Magnetic Luminex assay (R&D Systems, Minneapolis, MN). The differences in the levels of inflammatory mediators according to the presence or absence of ROP were compared. In patients who developed ROP, the level of MMP-2 in the AF was significantly increased (P = .011), whereas the levels of IL-10 and TNF-α were significantly decreased (P = .028 and .046, respectively) compared with those in infants who did not develop ROP. The levels of the other mediators were not significantly different between the 2 groups. Multivariate regression analysis showed that MMP-2 was a risk factor for the development of ROP (odds ratio, 2.445; 95% confidence interval, 1.170-5.106; P = .017). The concentration of MMP-2 in AF is an independent factor in the development of ROP. Further studies are needed to determine whether the levels of inflammatory mediators in AF affect the ROP severity.
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Retinopatia da Prematuridade , Líquido Amniótico , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Mediadores da Inflamação , Interleucina-10 , Metaloproteinase 2 da Matriz , Gravidez , Retinopatia da Prematuridade/epidemiologia , Retinopatia da Prematuridade/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Congenital granular cell lesion (CGCL) is a rare benign oral cavity tumor in infants. Neonatal teeth are also rare dental anomalies that appear during the first month of life. This report describes a case of eruption of neonatal teeth after surgical excision of CGCL. Surprisingly, residual neonatal teeth erupted after extraction of the neonatal teeth. If neonatal teeth are mobile, they should be carefully extracted with curettage of the underlying tissues of the dental papilla; failure to curette the socket might result in eruption of odontogenic remnants. If neonatal teeth were exfoliated, parents should be informed of the need for regular checkups with a dentist due to possibility of development of residual neonatal teeth.
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Dentes Natais , Assistência Odontológica , Humanos , Dentes Natais/cirurgia , Odontogênese , Erupção DentáriaRESUMO
Purpose: The purpose of this umbrella review was to summarize and evaluate the available evidence concerning risk factors for early childhood caries (ECC). Methods: Literature searches were performed until July 2020 in Medline, Web of Science, and EMBASE databases. Systematic reviews were selected, and their methodological qualities were assessed using the AMSTAR 2 tool (16 items). Results: A total of 977 articles for possible inclusion were identified, and 15 studies were finally selected for qualitative analysis. In these 15 studies, the risk of bias varied from critically low to high. The included studies reported risk factors for ECC such as dietary factors, mutans streptococci, low maternal education, maternal age, low family income and parental education level, low social class, enamel defects, obesity, the presence of dentinal caries, presence of Candida albicans, moderate to late preterm birth, and prenatal maternal cigarette smoking. Conclusions: The potential risk factors for early childhood caries are enamel defects, high levels of mutans streptococci, the presence of dentinal caries, increased consumption of soda, daily intake of sugary snacks, and obesity. In the future, longitudinal studies are needed to explore the potential relationship between these risk factors and ECC.
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Cárie Dentária , Nascimento Prematuro , Pré-Escolar , Suscetibilidade à Cárie Dentária , Feminino , Humanos , Recém-Nascido , Gravidez , Fatores de Risco , Streptococcus mutansRESUMO
The discovery of effective therapeutic agents against neurodegenerative diseases (NDDs) remains challenging. Neurotoxicity, inflammations, and oxidative stress are associating factors of NDDs. Sodium butyrate (NaB) is a short-chain fatty acid found in diet and produced in the gut that reportedly protects cancer, inflammation, obesity and so on. Previously, SH-SY5Y cells were studied as in vitro models of cerebral diseases. We have investigated the neuroprotective effects of NaB in SH-SY5Y cells stimulated with TNF-α. The expression of inflammatory mediators, including iNOS, COX-2, and mitogen-activated protein kinases (MAPK) and the apoptotic regulators, including P-53, Bcl-2 associated X (BAX) Protein, and caspase-3 were analyzed by western blot analysis. The anti-apoptotic gene Bcl-2 and the pro-apoptotic gene BAX translocation were also investigated. Our results showed that NaB attenuated cell death and inhibited the NO production and decreased the expression of iNOS and COX-2 in TNF-α-stimulated SH-SY5Y cells. NaB notably ameliorated apoptotic regulatory proteins p-53, Caspase-3 and caspase-1 level, and reversed phosphorylation of extracellular signal-regulated kinases and p-38 proteins. NaB ameliorated Glucocorticoid receptor and NLRP3 inflammasome expressions. NaB also suppressed the BAX nuclear translocation and modulated Nrf-2, HO-1 and MnSOD expression in neuroblastoma cells. In addition, NaB substantially reversed the reactive oxygen species in H2O2 induced SH-SY5Y cells. Altogether, our results suggest that sodium butyrate has potential therapeutic effects against NDDs.
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Ácido Butírico/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/enzimologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa , Glutationa Peroxidase GPX1RESUMO
Recent parallel studies clearly indicated that Merkel cells and the mechanosensitive piezo2 ion channel play critical roles in the light-touch somatosensation. Moreover, piezo2 was suggested to be a light-touch sensing ion channel without a role in pain sensing in mammals. However, biophysical characteristics of piezo2, such as single channel conductance and sensitivities to various mechanical stimuli, are unclear, hampering a precise understanding of its role in touch sensation. Here, we describe the biophysical properties of piezo2 in human Merkel cell carcinoma (MCC)-13 cells; piezo2 is a low-threshold, positive pressure-specific, curvature-sensitive, mechanically activated cation channel with a single channel conductance of ~28.6 pS. Application of step indentations under the whole-cell mode of the patch-clamp technique, and positive pressures ≥5 mmHg under the cell-attached mode, activated piezo2 currents in MCC-13 and human embryonic kidney 293 T cells where piezo2 was overexpressed. By contrast, application of a negative pressure failed to activate piezo2 in these cells, whereas both positive and negative pressure activated piezo1 in a similar manner. Our results are the first to demonstrate single channel recordings of piezo2. We anticipate that our findings will be a starting point for a more sophisticated understanding of piezo2 roles in light-touch sensation.
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Canais Iônicos/metabolismo , Pressão , Tato , Linhagem Celular Tumoral , Células HEK293 , Humanos , Mecanotransdução CelularRESUMO
Estrogen has diverse effects on cardiovascular function, including regulation of the contractile response to vasoactive substances such as serotonin. The serotonin system recently emerged as an important player in the regulation of vascular tone in humans. However, hyperreactivity to serotonin appears to be a critical factor for the pathophysiology of hypertension. In this study, we examined the modulatory mechanisms of estrogen in serotonin-induced vasoconstriction by using a combinatory approach of isometric tension measurements, molecular biology, and patch-clamp techniques. 17ß-Estradiol (E2) elicited a significant and concentration-dependent relaxation of serotonin-induced contraction in deendothelialized aortic strips isolated from male rats. E2 triggered a relaxation of serotonin-induced contraction even in the presence of tamoxifen, an estrogen receptor antagonist, suggesting that E2-induced changes are not mediated by estrogen receptor. Patch-clamp studies in rat arterial myocytes showed that E2 prevented Kv channel inhibition induced by serotonin. Serotonin increased Src activation in arterial smooth muscle required for contraction, which was significantly inhibited by E2. The estrogen receptor-independent inhibition of Src by E2 was confirmed in HEK293T cells that do not express estrogen receptor. Taken together, these results suggest that estrogen exerts vasodilatory effects on serotonin-precontracted arteries via Src, implying a critical role for estrogen in the prevention of vascular hyperreactivity to serotonin.
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Aorta/patologia , Estrogênios/metabolismo , Artérias Mesentéricas/patologia , Vasoconstrição/fisiologia , Animais , Regulação para Baixo , Células HEK293 , Humanos , Masculino , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/metabolismo , Serotonina/metabolismo , Quinases da Família src/metabolismoRESUMO
Primary impaction of primary teeth might be due to genetic predisposition or physical disturbance including odontoma, supernumerary tooth, and crowded tooth. Among them, calcific deposit or odontoma is commonly associated with primary dentition. Early diagnosis and treatment is the key to prevent complications. However, results of treatment may vary depending on the condition of unerupted tooth. Here we report two clinical cases of unerupted primary mandibular second molars with physical barriers such as compound odontoma and calcific deposit focusing on diagnostic means and the importance of early treatment of these lesions.
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Descompressão Cirúrgica , Doenças Dentárias/cirurgia , Pré-Escolar , Feminino , Humanos , Masculino , Doenças Dentárias/etiologiaRESUMO
The proarrhythmic effects of new drugs have been assessed by measuring rapidly activating delayed-rectifier K+ current (IKr) antagonist potency. However, recent data suggest that even drugs thought to be highly specific IKr blockers can be arrhythmogenic via a separate, time-dependent pathway such as late Na+ current augmentation. Here, we report a mechanism for a quinolone antibiotic, sparfloxacin-induced action potential duration (APD) prolongation that involves increase in late L-type Ca2+ current (ICaL) caused by a decrease in Ca2+-dependent inactivation (CDI). Acute exposure to sparfloxacin, an IKr blocker with prolongation of QT interval and torsades de pointes (TdP) produced a significant APD prolongation in rat ventricular myocytes, which lack IKr due to E4031 pretreatment. Sparfloxacin reduced peak ICaL but increased late ICaL by slowing its inactivation. In contrast, ketoconazole, an IKr blocker without prolongation of QT interval and TdP produced reduction of both peak and late ICaL, suggesting the role of increased late ICaL in arrhythmogenic effect. Further analysis showed that sparfloxacin reduced CDI. Consistently, replacement of extracellular Ca2+ with Ba2+ abolished the sparfloxacin effects on ICaL. In addition, sparfloxacin modulated ICaL in a use-dependent manner. Cardiomyocytes from adult mouse, which is lack of native IKr, demonstrated similar increase in late ICaL and afterdepolarizations. The present findings show that sparfloxacin can prolong APD by augmenting late ICaL. Thus, drugs that cause delayed ICaL inactivation and IKr blockage may have more adverse effects than those that selectively block IKr. This mechanism may explain the reason for discrepancies between clinically reported proarrhythmic effects and IKr antagonist potencies.
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Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Fluoroquinolonas/farmacologia , Miócitos Cardíacos/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Canais de Potássio Éter-A-Go-Go/metabolismo , Ventrículos do Coração/patologia , Camundongos , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Ratos Sprague-Dawley , Torsades de Pointes/induzido quimicamenteRESUMO
Hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor. Since opposing vasoactive effects have been reported for H2O2 depending on the vascular bed and experimental conditions, this study was performed to assess whether H2O2 acts as a vasodilator in the rat mesenteric artery and, if so, to determine the underlying mechanisms. H2O2 elicited concentration-dependent relaxation in mesenteric arteries precontracted with norepinephrine. The vasodilatory effect of H2O2 was reversed by treatment with dithiothreitol. H2O2-elicited vasodilation was significantly reduced by blocking 4-aminopyridine (4-AP)-sensitive Kv channels, but it was resistant to blockers of big-conductance Ca(2+)-activated K(+) channels and inward rectifier K(+) channels. A patch-clamp study in mesenteric arterial smooth muscle cells (MASMCs) showed that H2O2 increased Kv currents in a concentration-dependent manner. H2O2 speeded up Kv channel activation and shifted steady state activation to hyperpolarizing potentials. Similar channel activation was seen with oxidized glutathione (GSSG). The H2O2-mediated channel activation was prevented by glutathione reductase. Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester showed incorporation of glutathione (GSH) in the Kv channel proteins in the presence of H2O2. Interestingly, conditions of increased oxidative stress within MASMCs impaired the capacity of H2O2 to stimulate Kv channels. Not only was the H2O2 stimulatory effect much weaker, but the inhibitory effect of H2O2 was unmasked. These data suggest that H2O2 activates 4-AP-sensitive Kv channels, possibly through S-glutathionylation, which elicits smooth muscle relaxation in rat mesenteric arteries. Furthermore, our results support the idea that the basal redox status of MASMCs determines the response of Kv currents to H2O2.
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Glutationa/metabolismo , Peróxido de Hidrogênio/farmacologia , Músculo Liso Vascular/metabolismo , Canais de Potássio/metabolismo , Vasodilatação , 4-Aminopiridina/farmacologia , Potenciais de Ação , Animais , Células Cultivadas , Glutationa Redutase/metabolismo , Masculino , Artérias Mesentéricas/citologia , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Some azole antifungal agents induce long QT syndrome and arrhythmias. Although composite functions of ion channels in cardiomyocytes contribute to the shaping of action potentials, information on the effects of azole antifungal agents on ion currents, except human-ether-a-go-go-related gene (HERG) K+ currents, is largely lacking. Using the whole cell patch-clamp technique, we investigated the effects of four azole agents (miconazole, ketoconazole, fluconazole, and itraconazole) on inward rectifying K+ currents (IKir), voltage-gated L-type Ca2+ currents (ICaL), and delayed rectifier K+ currents (IKdr) in rat neonate ventricular myocytes. Strikingly, miconazole and ketoconazole strongly inhibited IKir, IKdr, and ICaL at clinically relevant concentrations. The IC50 values of miconazole for IKdr, IKir, and ICaL inhibition were 2.5, 10.4, and 3.0 µM, respectively. The IC50 values of ketoconazole for IKdr, IKir and ICaL inhibition were 3.2, 20.8, and 3.5 µM, respectively. Fluconazole and itraconazole had relatively little effect on ion currents. These findings indicate that miconazole and ketoconazole are multiple ion channel inhibitors in cardiomyocytes. We suggest that it is necessary to consider this inhibition of ion channels by azole agents when assessing cardiovascular side effects.
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Antifúngicos/efeitos adversos , Azóis/efeitos adversos , Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Canais de Potássio/metabolismo , Potássio/metabolismo , Potenciais de Ação , Animais , Animais Recém-Nascidos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Canais de Potássio Éter-A-Go-Go/metabolismo , Ventrículos do Coração/citologia , Ventrículos do Coração/metabolismo , Concentração Inibidora 50 , Cetoconazol/efeitos adversos , Miconazol/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/efeitos adversos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Potassium channel activity has been shown to facilitate cell proliferation in cancer cells. In the present study, the role of Kv4.1 channels in immortal and tumorigenic human mammary epithelial cells was investigated. Kv4.1 protein expression was positively correlated with tumorigenicity. Moreover, transfection with siRNAs targeting Kv4.1 mRNA suppressed proliferation of tumorigenic mammary epithelial cells. Experiments using mRNA isolated from human breast cancer tissues revealed that the level of Kv4.1 mRNA expression varied depending on the stage of the tumor. Kv4.1 protein expression increased during stages T2 and T3 compared to normal tissue. These results demonstrated that Kv4.1 plays a role in proliferation of tumorigenic human mammary epithelial cells. In addition, elevated Kv4.1 expression may be useful as a diagnostic marker for staging mammary tumors and selective blockers of Kv4.1 may serve to suppress tumor cell proliferation.