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[This corrects the article e22 in vol. 21, PMID: 34277112.].
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Osteoarthritis (OA) is a chronic degenerative joint disease that causes chronic pain, swelling, stiffness, disability, and significantly reduces the quality of life. Typically, OA is treated using painkillers and non-steroidal anti-inflammatory drugs (NSAIDs). While current pharmacologic treatments are common, their potential side effects have prompted exploration into functional dietary supplements. Recently, eggshell membrane (ESM) has emerged as a potential functional ingredient for joint and connective tissue disorders due to its clinical efficacy in relieving joint pain and stiffness. Despite promising clinical evidence, the effects of ESM on OA progression and its mechanism of action remain poorly understood. This study evaluated the efficacy of Ovomet®, a powdered natural ESM, against joint pain and disease progression in a monosodium iodoacetate (MIA)-induced rodent model of OA in mice and rats. The results demonstrate that ESM significantly alleviates joint pain and attenuates articular cartilage destruction in both mice and rats that received oral supplementation for 5 days prior to OA induction and for 28 days thereafter. Interestingly, ESM significantly inhibited mRNA expression levels of pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), as well as inflammatory mediators, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase in the knee joint cartilage at the early stage of OA, within 7 days after OA induction. However, this effect was not observed in the late stage at 28 days after OA induction. ESM further attenuates the induction of protein expression for cartilage-degrading enzymes like matrix metalloproteinase (MMPs) 3 and 13, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), in the late-stage. In addition, MIA-induced reduction of the protein expression levels of cartilage components, cartilage oligomeric matrix protein (COMP), aggrecan (ACAN) and collagen type II α-1 chain (COL2α1), and cartilage extracellular matrix (ECM) synthesis promoting transcriptional factor SRY-Box 9 (SOX-9) were increased via ESM treatment in the cartilage tissue. Our findings suggest that Ovomet®, a natural ESM powder, is a promising dietary functional ingredient that can alleviate pain, inflammatory response, and cartilage degradation associated with the progression of OA.
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Cartílago Articular , Cáscara de Huevo , Osteoartritis , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Cartílago Articular/patología , Osteoartritis/tratamiento farmacológico , Osteoartritis/inducido químicamente , Masculino , Ratones , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Ratas , Inflamación/tratamiento farmacológico , Suplementos Dietéticos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Artralgia/tratamiento farmacológico , Artralgia/inducido químicamente , Factores de Tiempo , Ácido Yodoacético , Antiinflamatorios/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Chitinase-3-like 1 (CHI3L1) causes skin inflammation in the progression of atopic dermatitis. We investigated if anti-CHI3L1 antibody could prevent the development of atopic dermatitis and its mechanisms of action. EXPERIMENTAL APPROACH: The effect of CHI3L1 antibody on phthalic anhydride-induced atopic dermatitis animal model and in vitro reconstructed human skin (RHS) model were investigated. Expression and release of atopic dermatitis-related cytokines were determined using an enzyme-linked immunosorbent assay, and RT-qPCR, STAT3 and CXCL8 signalling were measured by western blotting. KEY RESULTS: Anti-CHI3L1 antibody suppressed phthalic anhydride-induced epidermal thickening, clinical score, IgE level and infiltration of inflammatory cells, and reduced phthalic anhydride-induced inflammatory cytokines concentration. In addition, CHI3L1 antibody treatment inhibited the expression of STAT3 activity in phthalic anhydride-treated skin. It was also confirmed that CHI3L1 antibody treatment alleviated atopic dermatitis-related inflammation in the RHS model. The inhibitory effects of CHI3L1 antibody was similar or more effective compared with that of the IL-4 antibody. We further found that CHI3L1 is associated with CXCL8 by protein-association network analysis. siRNA of CHI3L1 blocked the mRNA levels of CHI3L1, IL-1ß, IL-4, CXCL8, TSLP, and the expression of CHI3L1 and p-STAT, and the level of CXCL8, whereas recombinant level of CXCL8 was elevated. Moreover, siRNA of STAT3 reduced the mRNA level of these cytokines. CHI3L1 and p-STAT3 expression correlated with the reduced CXCL8 level in the RHS in vitro model. CONCLUSION AND IMPLICATIONS: Our data demonstrated that CHI3L1 antibody could be a promising effective therapeutic drug for atopic dermatitis.
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Proteína 1 Similar a Quitinasa-3 , Dermatitis Atópica , Interleucina-8 , Factor de Transcripción STAT3 , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Humanos , Animales , Interleucina-8/metabolismo , Proteína 1 Similar a Quitinasa-3/antagonistas & inhibidores , Proteína 1 Similar a Quitinasa-3/metabolismo , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Masculino , Ratones Endogámicos BALB C , Anhídridos Ftálicos/farmacología , Anticuerpos/farmacología , Ratones , Femenino , Inflamación/tratamiento farmacológico , Inflamación/metabolismoRESUMEN
Recently, increasing evidence suggests that neuroinflammation may be a critical factor in the development of Parkinson's disease (PD) in addition to the ratio of acetylcholine/dopamine because dopaminergic neurons are particularly vulnerable to inflammatory attack. In this study, we investigated whether botulinum neurotoxin A (BoNT-A) was effective for the treatment of PD through its anti-neuroinflammatory effects and the modulation of acetylcholine and dopamine release. We found that BoNT-A ameliorated MPTP and 6-OHDA-induced PD progression, reduced acetylcholine release, levels of IL-1ß, IL-6 and TNF-α as well as GFAP expression, but enhanced dopamine release and tyrosine hydroxylase expression. These results indicated that BoNT-A had beneficial effects on MPTP or 6-OHDA-induced PD-like behavior impairments via its anti-neuroinflammation properties, recovering dopamine, and reducing acetylcholine release.
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Chitinase-3-like-1 (CHI3L1) is known to induce inflammation in the progression of allergic diseases. Previous our studies revealed that 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111; K284), the CHI3L1 inhibiting compound, has the anti-inflammatory effect on neuroinflammation. In this study, we investigated that K284 treatment could inhibit the development of atopic dermatitis (AD). To identify the effect of K284, we used phthalic anhydride (5% PA)-induced AD animal model and in vitro reconstructed human skin model. We analyzed the expression of AD-related cytokine mediators and NF-κB signaling by Western blotting, ELISA and quantitative real-time PCR. Histological analysis showed that K284 treatment suppressed PA-induced epidermal thickening and infiltration of mast cells. K284 treatment also reduced PA-induced release of inflammatory cytokines. In addition, K284 treatment inhibited the expression of NF-κB activity in PA-treated skin tissues and TNF-α and IFN-γ-treated HaCaT cells. Protein-association network analysis indicated that CHI3L1 is associated with lactoferrin (LTF). LTF was elevated in PA-treated skin tissues and TNF-α and IFN-γ-induced HaCaT cells. However, this expression was reduced by K284 treatment. Knockdown of LTF decreased the expression of inflammatory cytokines in TNF-α and IFN-γ-induced HaCaT cells. Moreover, anti-LTF antibody treatment alleviated AD development in PA-induced AD model. Our data demonstrate that CHI3L1 targeting K284 reduces AD-like skin inflammation and K284 could be a promising therapeutic agent for AD by inhibition of LTF expression.
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Previously, we found that astaxanthin (AST) elicited an anti-inflammatory response in an experimental atopic dermatitis (AD) model. However, the use of AST was limited because of low bioavailability and solubility. We hypothesized that liposome formulation of AST could improve this. In this study, we compared the anti-inflammatory and anti-dermatotic effects of liposomal AST (L-AST) and free AST. We evaluated the effect of L-AST on a phthalic anhydride (PA)-induced animal model of AD by analyzing morphological and histopathological changes. We measured the mRNA levels of AD-related cytokines in skin tissue and immunoglobulin E concentrations in the serum. Oxidative stress and transcriptional activities of signal transducer and activator of transcription 3 (STAT3) and nuclear factor (NF)-κB were analyzed via western blotting and enzyme-linked immunosorbent assay. PA-induced dermatitis severity, epidermal thickening, and infiltration of mast cells in skin tissues were ameliorated by L-AST treatment. L-AST suppressed AD-related inflammatory mediators and the inflammation markers, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 in PA-induced skin conditions. Oxidative stress and expression of antioxidant proteins, glutathione peroxidase-1 (GPx-1) and heme oxygenase-1 (HO-1), were recovered by L-AST treatment in skin tissues from PA-induced mice. L-AST treatment reduced transcriptional activity of STAT3 and NF-κB in PA-induced skin tissues. Our results indicate that L-AST could be more effective than free AST for AD therapy.
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Antiinflamatorios/administración & dosificación , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Anhídridos Ftálicos/efectos adversos , Animales , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos/métodos , Liposomas , Masculino , Ratones , Ratones Pelados , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Piel/inmunología , Piel/patología , Resultado del Tratamiento , Xantófilas/administración & dosificaciónRESUMEN
To investigate whether Helicobacter pylori (HP) infection affects the clinical response to levodopa and whether its eradication could improve motor fluctuation in patients with Parkinson's disease (PD). Using the [(13)C] urea breath test, we monitored HP infection in 65 patients with PD and motor fluctuations of the "wearing-off" or delayed "on" types, with or without dyskinesia. We compared the clinical features and response to L-dopa between HP noninfected (n = 30) and HP infected patients (n = 35) by reviewing home diaries kept for 72 hours. Among HP infected patients, we compared the differences in L-dopa "onset" time, "on-time" duration, and scores on the motor examination section of the Unified PD Rating Scale (UPDRS-III) during the medication "on" phase before and after HP eradication. There were no differences in the age, disease duration, Hoehn and Yahr stage, UPDRS-III score, L-dopa daily dose, and frequency of dyskinesia between HP noninfected and HP infected groups. However, L-dopa "onset" time was longer and "on-time" duration was shorter in HP infected patients than in HP noninfected patients (78.4 +/- 28.2 vs. 56.7 +/- 25.1 and 210.0 +/- 75.7 vs. 257.7 +/- 68.9 min, respectively, P < 0.05). HP eradication improved the delay L-dopa "onset" time and short "on-time" duration (to 58.1 +/- 25.6 and to 234.4 +/- 66.5 min, respectively, P < 0.05). These data demonstrated that HP infection could interfere with the absorption of L-dopa and provoke motor fluctuations. HP eradication can improve the motor fluctuations of HP infected patients with PD.
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Infecciones por Helicobacter/patología , Infecciones por Helicobacter/fisiopatología , Helicobacter pylori , Actividad Motora/fisiología , Enfermedad de Parkinson/fisiopatología , Anciano , Antiparkinsonianos/uso terapéutico , Femenino , Helicobacter pylori/efectos de los fármacos , Humanos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Índice de Severidad de la EnfermedadRESUMEN
Transcranial sonography (TCS) is potentially useful for the diagnosis of Parkinson's disease (PD). However, studies on TCS have so far been restricted to European populations. To investigate the efficacy of TCS in Korean PD patients and its correlation with the clinical features, we carried out midbrain TCS in 43 PD patients and 35 normal controls and evaluated the area of the substantia nigra (SN) hyperechogenicity and its ratio to the area of the whole midbrain. In 16 subjects (21%), TCS was unsuccessful due to insufficient acoustic temporal bone windows. The mean area of bilateral SN hyperechogenicity and its ratio to the midbrain area were greater in the PD patients than that in the controls (P < 0.01). In the PD patients, the area of SN hyperechogenicity and its ratio to the individual midbrain area were moderately correlated with the PD duration (r = 0.526 and 0.536, P = 0.01, respectively) but not with the age, UPDRS motor scores or H-Y stage. There was no difference in the SN hyperechogenicity between the tremor-dominant, akinetic-rigid, and mixed-type PD patients. In conclusion, midbrain TCS is an effective diagnostic tool for detecting PD in the Korean population. However, it does not reflect the severity or phenotypes of parkinsonism.