RESUMEN
Matrix metalloproteinases (MMPs) play a crucial role in the degenerative course of rheumatic disorders. They are responsible for cartilage and other joint-associated tissues breakdown. Amid arthritis treatments, photobiostimulation (PBM), a non-thermal and non-invasive low-power laser application, appears to be an outstanding therapy alternative once it has succeeded in MMPs modulation. Thus, this study aimed to evaluate the PBM effects of low infrared laser (830 nm), testing two different energy densities (3 and 30 Jcm-2) in MMP-2, MMP-9, MMP-13, and MMP-14 as well as the inhibitor TIMP-2 expressions using zymosan-induced arthritis model. C57BL/6 mice were distributed into four groups (n = 8): zymosan-induced arthritis without treatment; zymosan-induced arthritis and dexamethasone-treated; zymosan-induced arthritis and PBM at energy density of 3 Jcm-2 treated; and zymosan-induced arthritis and PBM at energy density of 30 Jcm-2 treated. MMPs and TIMP-2 mRNA relative levels by qRT-PCR and proteins expression by immunohistochemical and Western blotting techniques were performed after PBM treatment in the inflamed joint. Our results demonstrated PBM could modulate both mRNA relative levels and proteins expression of the MMP-2, -9, -13, -14, and TIMP-2 in joint tissues, decreasing MMP-9 protein expression and increasing TIMP-2 protein expression. PBM promotes a better arthritis prognostic, modulating metalloproteinase and its inhibitor, especially MMP-9 and TIMP-2 protein expression that is important inflammatory markers. These findings may also corroborate that PBM may regulate MMPs expression using different pathways.
Asunto(s)
Artritis , Terapia por Luz de Baja Intensidad , Animales , Ratones , Artritis/inducido químicamente , Artritis/genética , Artritis/radioterapia , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Ratones Endogámicos C57BL , ARN Mensajero/genética , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/genética , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , ZimosanRESUMEN
INTRODUCTION: Huangtu decoction (HTD) has been widely used in the treatment of gastrointestinal bleeding, ulcerative colitis (UC) and gastrointestinal tumors in China, but its active compounds and mechanism are still not clear yet. The present research aimed to identify the active compounds and mechanism of HTD for the treatment of UC. METHODS: Firstly, the chemical compounds of HTD were qualitatively identified based on Q Exactive Orbitrap LC-MS/MS, and their potential targets were predicted through SwissTargetPrediction. Secondly, the differential expressed genes (DEGs) in colon tissues of UC patients and normal controls were retrieved from the GEO database. Thirdly, the overlapping targets of DEGs and the predicted targets were obtained and subjected to GO and KEGG analysis. Finally, the key targets in the most significantly enriched pathway were verified by in vivo experiment, and the protein and mRNA expressions of matrix metalloproteinase-1 (MMP1), MMP3, MMP7, MMP9 and MMP12 were determined by immunohistochemistry (IHC), Western blotting (WB) and quantitative real-time-PCR (qRT-PCR). RESULTS: A total of 47 compounds were identified and 29 overlapping targets were obtained from HTD extract. The most significantly enriched pathway of overlapping targets involved was MMP. HTD improved the pathological damage in colon tissues of DSS-induced UC model and significantly decreased the serum levels of IL-1ß and IL-6. The protein and mRNA expressions of MMP1, MMP3 and MMP9 in colon tissues were significantly decreased after HTD treatment. CONCLUSION: HTD treatment can alleviate the colonic inflammation via inhibiting MMPs including MMP1, MMP3 and MMP9.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Inflamación/tratamiento farmacológico , Animales , Estudios de Casos y Controles , Cromatografía Liquida , Colitis Ulcerosa/patología , Bases de Datos Genéticas , Sulfato de Dextran , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/química , Humanos , Inflamación/patología , Masculino , Metaloproteinasas de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Farmacología en Red , Espectrometría de Masas en TándemRESUMEN
Osteoarthritis (OA) is a degenerative disorder that can result in the loss of articular cartilage. No effective treatment against OA is currently available. Thus, interest in natural health products to relieve OA symptoms is increasing. However, their qualities such as efficacy, toxicity, and mechanism are poorly understood. In this study, we determined the efficacy of avenanthramide (Avn)-C extracted from oats as a promising candidate to prevent OA progression and its mechanism of action to prevent the expression of matrix-metalloproteinases (MMPs) in OA pathogenesis. Interleukin-1 beta (IL-1ß), a proinflammatory cytokine as a main causing factor of cartilage destruction, was used to induce OAlike condition of chondrocytes in vitro. Avn-C restrained IL-1ß- mediated expression and activity of MMPs, such as MMP-3, -12, and -13 in mouse articular chondrocytes. Moreover, Avn-C alleviated cartilage destruction in experimental OA mouse model induced by destabilization of the medial meniscus (DMM) surgery. However, Avn-C did not affect the expression of inflammatory mediators (Ptgs2 and Nos) or anabolic factors (Col2a1, Aggrecan, and Sox9), although expression levels of these genes were upregulated or downregulated by IL-1ß, respectively. The inhibition of MMP expression by Avn-C in articular chondrocytes was mediated by p38 kinase and c-Jun N-terminal kinase (JNK) signaling, but not by ERK or NF-κB. Interestingly, Avn-C added with SB203580 and SP600125 as specific inhibitors of p38 kinase and JNK, respectively, enhanced its inhibitory effect on the expression of MMPs in IL-1ß treated chondrocytes. Taken together, these results suggest that Avn-C is an effective candidate to prevent OA progression and a natural health product to relieve OA pathogenesis. [BMB Reports 2021; 54(10): 528-533].
Asunto(s)
Condrocitos/metabolismo , Osteoartritis/tratamiento farmacológico , ortoaminobenzoatos/farmacología , Animales , Avena/metabolismo , Condrocitos/efectos de los fármacos , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Interleucina-1beta/efectos de los fármacos , Interleucina-1beta/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metaloproteinasas de la Matriz/efectos de los fármacos , Metaloproteinasas de la Matriz/genética , Ratones , FN-kappa B/metabolismo , Osteoartritis/patología , Extractos Vegetales/farmacología , Cultivo Primario de Células , Transducción de Señal/efectos de los fármacos , ortoaminobenzoatos/metabolismoRESUMEN
We recently reported that cyclin-dependent kinase inhibitor 1 (p21) deficiency induces osteoarthritis susceptibility. Here, we determined the mechanism underlying the effect of p21 in synovial and cartilage tissues in RA. The knee joints of p21-knockout (p21-/-) (n = 16) and wild type C57BL/6 (p21+/+) mice (n = 16) served as in vivo models of collagen antibody-induced arthritis (CAIA). Arthritis severity was evaluated by immunological and histological analyses. The response of p21 small-interfering RNA (siRNA)-treated human RA FLSs (n = 5 per group) to interleukin (IL)-1ß stimulation was determined in vitro. Arthritis scores were higher in p21-/- mice than in p21+/+ mice. More severe synovitis, earlier loss of Safranin-O staining, and cartilage destruction were observed in p21-/- mice compared to p21+/+ mice. p21-/- mice expressed higher levels of IL-1ß, TNF-α, F4/80, CD86, p-IKKα/ß, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1ß-induced NF-kB signaling. IL-1ß stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKKα/ß and IκBα phosphorylation in human FLSs. p21-deficient CAIA mice are susceptible to RA phenotype alterations, including joint cartilage destruction and severe synovitis. Therefore, p21 may have a regulatory role in inflammatory cytokine production including IL-1ß, IL-6, and TNF-α.
Asunto(s)
Artritis Experimental/genética , Artritis Reumatoide/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inflamación/genética , Interleucina-1beta/genética , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/patología , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/patología , Antígeno B7-2/genética , Proteínas de Unión al Calcio/genética , Cartílago/metabolismo , Cartílago/patología , Regulación de la Expresión Génica/efectos de los fármacos , Predisposición Genética a la Enfermedad , Humanos , Inflamación/inducido químicamente , Inflamación/patología , Interleucina-1beta/efectos adversos , Interleucina-1beta/farmacología , Interleucina-6/genética , Articulación de la Rodilla , Metaloproteinasas de la Matriz/genética , Ratones , Ratones Noqueados , Receptores Acoplados a Proteínas G/genética , Líquido Sinovial/metabolismo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Compound Ruteng (CRT) is a prescribed formulation based on the theory of Tibetan medicine for the treatment of yellow-water-disease. It is consisted with 7 medicinal material include Boswellia carterii Birdw (named "Ruxiang" in Chinese); Tinospora sinensis (Lour.) Merr. (named "Kuan-Jin-Teng" in Chinese), Cassia obtusifolia L (named "Jue-Ming-Zi" in Chinese); Abelmoschus manihot (L.) Medic (named "Huang-Kui-Zi" in Chinese); Terminalia chebula Retz. (named "He-Zi" in Chinese); Lamiophlomis rotata (Benth.) Kudo (named "Du-Yi-Wei" in Chinese) and Pyrethrum tatsienense (Bur. et Franch.) Ling (named "Da-Jian-Ju" in Chinese). They are widely distributed in Tibet area of China and have been used to treat rheumatism, jaundice, and skin diseases for centuries. AIM OF THE STUDY: The present study was conducted to investigate the anti-arthritis effect of CRT and to disclose the systems pharmacology-based dissection of mechanisms. MATERIALS AND METHODS: The chemical constituents in CRT were identified using HPLC method, and CRT candidate targets against RA were screened by network pharmacology-based analysis and further experimentally validated based on collagen-induced arthritis (CIA) rat model. Furthermore, therapeutic mechanisms and pathways of CRT were investigated. RESULTS: 391 potential targets (protein) were predicted against 92 active ingredients of 7 medicinal materials in CRT. Enrichment analysis and molecular docking studies also enforced the practiced results. X-ray based physiological imaging showed the attenuated effect of CRT on paw swelling, synovial joints and cartilage with improved inflammation in CIA rats. Moreover, the expression of biomarkers associated with RA such as MMP1, MMP3 and MMP13 and TNF-a, COX2 and iNOS are down-regulated in ankle joints, serum, or liver. CONCLUSION: In conclusion, CRT compound could attenuate RA symptoms and active ingredients of this compound could be considered for drug designing to treat RA.
Asunto(s)
Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Animales , Antirreumáticos/química , Artritis Experimental/sangre , Artritis Experimental/diagnóstico por imagen , Artritis Experimental/patología , Colágeno/toxicidad , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/química , Articulaciones/diagnóstico por imagen , Articulaciones/efectos de los fármacos , Articulaciones/patología , Masculino , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Medicina Tradicional Tibetana , Simulación del Acoplamiento Molecular , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Mapas de Interacción de Proteínas , Ratas Wistar , Triterpenos/químicaRESUMEN
Metastasis represents a major obstacle in cancer treatment and the leading cause of cancer-related deaths. Therefore, the identification of compounds targeting the multi-step and complex process of metastasis could improve outcomes in the management of cancer patients. Carotenoids are naturally occurring pigments with a plethora of biological activities. Carotenoids exert a potent anti-cancer capacity in various cancer models in vitro and in vivo, mediated by the modulation of signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of the epithelial-mesenchymal transition and regulatory molecules, such as matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), urokinase plasminogen activator (uPA) and its receptor (uPAR), hypoxia-inducible factor-1α (HIF-1α), and others. Moreover, carotenoids modulate the expression of genes associated with cancer progression and inflammatory processes as key mediators of the complex process involved in metastasis. Nevertheless, due to the predominantly preclinical nature of the known anti-tumor effects of carotenoids, and unclear results from certain carotenoids in specific cancer types and/or specific parts of the population, a precise analysis of the anti-cancer effects of carotenoids is essential. The identification of carotenoids as effective compounds targeting the complex process of cancer progression could improve the outcomes of advanced cancer patients.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Carotenoides/uso terapéutico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/clasificación , Carotenoides/química , Carotenoides/clasificación , Quimioterapia Adyuvante , Transición Epitelial-Mesenquimal/genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Aprendizaje Automático , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Medicina de Precisión , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Transducción de Señal , Inhibidores Tisulares de Metaloproteinasas/genética , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/genética , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
Intervertebral disc (IVD) degeneration with chronic low back pain is associated with neo-vascularisation into the deeper IVD regions. During this process, endothelial cells (ECs), which are primarily responsible for angiogenesis, interact with the adjacent annulus fibrosus (AF) cells, which are the first line of defence against the invasion of vascular structures into deeper IVD regions. However, the accumulation of inflammatory and catabolic enzymes that results from this interaction promotes matrix degradation and an inflammatory response. Thus, regulating the production of these mediators and catabolic enzymes could ameliorate IVD degeneration. Photobiomodulation (PBM) therapy is a non-invasive stimulation known to have biologically beneficial effects on wound healing, tissue repair, and inflammation. Here, we examined the effects of PBM, administered at various wavelengths (645, 525, and 465 nm) and doses (16, 32, and 64 J/cm2), on EC-stimulated human AF cells. Our results show that PBM selectively inhibited the EC-mediated production of inflammatory mediators, catabolic enzymes, and neurotrophins by human AF cells in a dose- and wavelength-dependent manner. These results suggest that PBM could be a superior and advanced treatment strategy for IVD degeneration.
Asunto(s)
Anillo Fibroso/citología , Medios de Cultivo Condicionados/química , Células Endoteliales/citología , Matriz Extracelular/metabolismo , Degeneración del Disco Intervertebral/metabolismo , Terapia por Luz de Baja Intensidad/métodos , Neovascularización Patológica/metabolismo , Adulto , Anillo Fibroso/metabolismo , Anillo Fibroso/efectos de la radiación , Células Cultivadas , Relación Dosis-Respuesta en la Radiación , Células Endoteliales/química , Matriz Extracelular/genética , Femenino , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/radioterapia , Masculino , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Persona de Mediana Edad , Modelos Biológicos , Neovascularización Patológica/radioterapiaRESUMEN
BACKGROUND: The photobiomodulation (PBM) effect has been applied to various clinical therapy for a long time. However, the mechanism related to the PBM effect in terms of wavelengths has been lack of in-depth study, except that ultraviolet radiation has attracted much attention due to its strong cell-killing effect. PURPOSE: To clarify the principle behind PBM and the main mechanism of improvement. METHODS: To carry on this study, we created light equipment using three LED chips, which emit 390 nm ultraviolet radiation, 415 nm blue light and 660 nm red light, respectively. We choose human fibroblasts (HF) to be irradiated by three different wavelengths for PBM test. In this study, we used cell counting kit (CCK-8) test to show the cell proliferation roughly and reported on a systematic RNA sequencing (RNA-seq) analysis at transcriptional expression levels from HF, which accepted PBM of different wavelengths of light. RESULTS: We found that 415 nm blue light inhibited cell proliferation and 660 nm red light stimulated cell proliferation while 390 nm ultraviolet radiation has little influence on cell proliferation. Furthermore, RNA-seq results showed that CSF1R, PPP3CC, ITGAL, ITGAM, IL2RB, and several other differentially expressed genes (DEGs) are involved in the cell proliferation. Relative DEGs values for matrix metalloproteinases (MMPs) gene family have shown a great difference in blue and red light radiation especially on MMP25, MMP9, MMP21, and MMP13. CONCLUSION: Taken together, the results provide a valuable resource to describe the variation of HFs under PBM of different light at gene level.
Asunto(s)
Proliferación Celular/efectos de la radiación , Fibroblastos/fisiología , Terapia por Luz de Baja Intensidad , Metaloproteinasas de la Matriz/genética , Transducción de Señal/genética , Rayos Ultravioleta , Color , Humanos , Análisis de Secuencia de ARN , TranscriptomaRESUMEN
BACKGROUND: ß-Elemene is a natural agent extracted from the traditional Chinese herbal medicine Curcuma wenyujin that is a promising novel plant-derived drug with broad-spectrum anticancer activity. Our previous study identified an enhanced capacity for metastasis in multidrug resistant (MDR) gastric cancer and breast cancer cells. However, the anti-metastatic effects of ß-Elemene on MDR cancer cells remain unknown. PURPOSE: In this study, we posit the hypothesis that ß-elemene possesses antimetastatic effects on MDR cancer cells. METHODS: Cell viability assay was used to assess the resistance of SGC7901/ADR cells and the cytotoxic effects of ß-Elemene. Wound healing, transwell assay and lung metastatic mice model were used to the anti-metastasis effects of ß-Elemene. MicroRNA microarray analysis was used to explore potential regulated miRNAs. Luciferase reporter assay was used to identify the direct target. Human MMP antibody array, western blot, immunoprecipitation, qRT-PCR analyses and immunohistochemistry were conducted to investigate the underlying anti-metastasis mechanism of ß-Elemene. RESULTS: In this study, we found that ß-Elemene significantly inhibited the metastatic capacity of MDR gastric cells in vivo and in vitro. Mechanistically, we found that ß-Elemene regulated MMP-2/9 expression and reversed epithelial-mesenchymal transition. Further studies showed that ß-Elemene upregulated Cbl-b expression, resulting in inhibition of the EGFR-ERK/AKT pathways, which regulate MMP-2/9. Additionally, we confirmed that ß-Elemene upregulated Cbl-b by inhibiting miR-1323 expression. Finally, we found that numbers of metastatic tumor nodules were significantly decreased in the lungs of nude mice after ß-Elemene treatment. CONCLUSION: Our results suggested that ß-Elemene inhibits the metastasis of MDR gastric cancer cells by modulating the miR-1323/Cbl-b/EGFR signaling axis.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Sesquiterpenos/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Masculino , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Ratones Desnudos , MicroARNs/genética , Proteínas Proto-Oncogénicas c-cbl/genética , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/genéticaRESUMEN
Depression is often triggered by prolonged exposure to psychosocial stressors and associated with coronary heart disease (CHD). Matrix metalloproteinases (MMPs) are involved in the pathogenesis of various emotional and cardiovascular disorders. The purpose of this study was to investigate whether KaiXinSan (KXS), which may terminate the signaling of MMPs, exerts antidepressantlike and cardioprotective effects in a myocardial infarction (MI) plus depression rat model. Rats were randomly assigned to five groups: A normal control (control group), a celiscinjection of isopropyl adrenaline group (ISO group), depression (depression group), an ISO + depression (depression + ISO group), and an ISO + depression group treated with intragastric administration of 1,785 mg/kg KXS (KXS group). Behavioral changes, echocardiography, biochemical index, matrix metalloproteinase (MMP) and apoptosisrelated proteins were assessed. Compared with the depression + ISO group, KXS significantly improved stressinduced alterations of behavioral parameters and protected the heart by enlarging the left ventricular (LV) fractional shortening (FS) and LV ejection fraction (EF). Moreover, KXS significantly attenuated ISO + depressioninduced MMP2 and MMP9 expression at the mRNA and protein level and decreased TIMP in the heart compared to the complex model group. Myocardial apoptosis was significantly attenuated by KXS by regulating the Bcl2/Bax axis. These results indicated that MI comorbid with depression may damage the MMP balance in the central and peripheral system, and KXS may have a direct antidepressive and cardioprotective effect by regulating the level of MMPs and associated myocardial apoptosis. It is promising to further explore the clinical potential of KXS for the therapy or prevention of MI plus depression comorbidity disease.
Asunto(s)
Depresión/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Infarto del Miocardio/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Depresión/inducido químicamente , Depresión/genética , Depresión/patología , Modelos Animales de Enfermedad , Epinefrina/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Humanos , Metaloproteinasas de la Matriz/genética , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocardio/metabolismo , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
The aim of this study was to identify the active compound responsible for the pharmacological activities of Manchurian spikenard (Aralia continentalis Kitag.). Interleukin (IL)-1ß-stimulated human chondrocytes and monoiodoacetate (MIA)-induced osteoarthritic rats were treated with the 50% ethanolic extract of spikenard or its major components, such as continentalic acid (ent-pimara-8(14),15-diene-19-oic acid) and kaurenoic acid (ent-kaura-16-en-19-oic acid). The spikenard extract significantly inhibited IL-1ß-stimulated production of IL-6, IL-8, metalloproteinase (MMP)-1, MMP-13, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and prostaglandin(PG)E2 in a dose-dependent manner but not MMP-3 production. The extract also inhibited the IL-1ß-induced translocation of NF-κB/p65 into the nucleus and dose-dependent phosphorylation levels of extracellular signal-regulated kinase (ERK), Jun amino-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase. Continentalic acid exhibited significant anti-arthritic activity corresponding exactly to that of the extract containing an equivalent amount of continentalic acid. On the other hand, kaurenoic acid exhibited a compatible activity at about a 10-times higher molar concentration than that of continentalic acid. In vitro anti-arthritic activities of the spikenard extract and continentalic acid were also confirmed in MIA-induced osteoarthritic rats. The 50% ethanolic extract of Manchurian spikenard exhibited promising anti-arthritic activities in the in vitro and in vivo osteoarthritis models, and continentalic acid, not kaurenoic acid, was most probably responsible for those activities.
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Antiinflamatorios/farmacología , Aralia/química , Condrocitos/efectos de los fármacos , Diterpenos/farmacología , Adulto , Células Cultivadas , Condrocitos/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Diterpenos/análisis , Femenino , Humanos , Interleucinas/genética , Interleucinas/metabolismo , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
Chlorogenic acid (CGA) is a widely applied traditional Chinese medicine ingredient which can be used for the treatment of osteoporosis. In this experiment, we investigated the potential therapeutic effect of chlorogenic acid on thiram-induced tibial dyschondroplasia (TD) and explored the underlying mechanisms that have been rarely mentioned by others yet. Performance indicator analysis and tibial parameter analysis showed that CGA exhibited a definite positive effect on thiram-induced TD chickens. In order to further explore the mechanisms underlying the positive actions of CGA, apoptotic, autophagic genes and MMPs involved in matrix mineralization of growth plate were evaluated in this study. The results showed that CGA decreased the expression of pro-apoptotic genes caspases-3 and caspases-9, leading to the reduction of apoptotic cells accumulated in growth plate. In addition, CGA also increased the level of BECN1, an important gene involved in autophagy, which benefits the survival of abnormal cells. Furthermore, CGA also increased the expression of MMP-9, MMP-10, and MMP-13, which can directly affect the ossification of bones. Altogether, these results demonstrate that CGA possesses a positive therapeutic effect on thiram-induced TD via modulating the expression of caspases and BECN1 and regulating the degradation of ECM (extracellular matrix).
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Beclina-1/metabolismo , Ácido Clorogénico/uso terapéutico , Matriz Extracelular/metabolismo , Osteocondrodisplasias/tratamiento farmacológico , Animales , Apoptosis , Autofagia , Beclina-1/genética , Caspasas/genética , Caspasas/metabolismo , Pollos , Ácido Clorogénico/farmacología , Matriz Extracelular/efectos de los fármacos , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Osteocondrodisplasias/etiología , Tiram/toxicidad , Tibia/efectos de los fármacos , Tibia/metabolismo , Tibia/patologíaRESUMEN
Skin aging is associated with increased reactive oxygen species (ROS) produced by human cells. These radicals are the main causes of skin aging, and skin cells have developed antioxidant enzymes for protection against ROS-induced damage. Antioxidants play critical roles to prevent ROS-induced aging symptoms. In this study, the antioxidant properties of Pourthiaea villosa (Thunb.) Decne. extract (PVDE) were studied. Human dermal fibroblast (HDF) cells were treated with PVDE to evaluate its antioxidant and antiaging activities and to investigate the underlying mechanisms. The identified compounds were polyols, and phenolic and flavonoid compounds from PVDE by UHPLC-LTQ-IT-MS/MS. PVDE exhibited significant antioxidant effects, as evaluated with reducing power, and ABTS and DPPH radical scavenging activity. Furthermore, PVDE treatment significantly increased antioxidant enzyme expressions and effectively blocked H2O2-induced matrix metalloproteinase activity through MAPK signaling pathways in HDFs. Therefore, these results showed that PVDE affords an advantage of being a functional natural material with antioxidant and antiaging effects for the skin.
Asunto(s)
Fibroblastos/efectos de los fármacos , Peróxido de Hidrógeno/efectos adversos , Photinia/química , Extractos Vegetales/farmacología , Envejecimiento de la Piel/efectos de los fármacos , Protectores Solares/farmacología , Antioxidantes/farmacología , Fibroblastos/metabolismo , Humanos , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Extractos Vegetales/química , Especies Reactivas de Oxígeno/metabolismo , Envejecimiento de la Piel/efectos de la radiación , Protectores Solares/química , Rayos Ultravioleta/efectos adversosRESUMEN
Carnosine is an endogenous dipeptide found in the vertebrate skeletal muscles that is usually obtained through the diet. To investigate the mechanism by which carnosine regulates the migration and intravasation of human colorectal cancer (CRC) cells, we used cultured HCT-116 cells as an experimental model in this study. We examined HCT-116 cell migratory and intravasive abilities and expression of epithelial-mesenchymal transition (EMT)-associated molecules and matrix metalloproteinases (MMPs) after carnosine treatment. The results showed that both migration and invasion were inhibited in cells treated with carnosine. We found significant decreases in Twist-1 protein levels and increases in E-cadherin protein levels in HCT-116 cells after carnosine exposure. Although plasminogen activator (uPA) and MMP-9 mRNA and protein levels were decreased, TIMP-1 mRNA and protein levels were increased. Furthermore, the cytosolic levels of phosphorylated I κ B (p-I κ B) and NF- κ B DNA-binding activity were reduced after carnosine treatment. These results indicate that carnosine inhibits the migration and intravasation of human CRC cells. The regulatory mechanism may occur by suppressing NF- κ B activity and modulating MMP and EMT-related gene expression in HCT-116 cells.
Asunto(s)
Carnosina/farmacología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/genética , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Neoplasias Colorrectales/irrigación sanguínea , Depresión Química , Células HCT116 , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Invasividad Neoplásica/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismoRESUMEN
Photoaging is generally the result of chronic exposure to the sun and ultraviolet (UV) radiation, which causes skin damage. In this study, we developed a UVB-induced hairless mouse model to determine whether Lactobacillus acidophilus IDCC 3302 tyndallizate (ACT3302) can enhance photodamaged skin repair. Mice (6 weeks old) were divided into six groups containing normal, UVB-treated vehicle, and UVB-treated ACT3302 (1 × 105, 1 × 106, 1 × 107, and 1 × 108 cells). Epidermal thickness was increased by UVB, but the thickening was lessened by ACT3302 as was the transepidermal water loss (TEWL). However, ACT3302 increased capacitance and decreased TEWL. Skin tissue staining to evaluate skin collagen increases in the number of skin collagen bundles in UVB-treated ACT3302 mice. UVB irradiation increased matrix metalloproteinase (MMP) and proinflammatory cytokine expression and activated mitogen-activated protein kinases in hairless mice; these changes were also attenuated by ACT3302. We conclude that ACT3302 effectively suppressed wrinkle formation induced by UVB irradiation through MMP downregulation. Therefore, ACT3302 potentially prevents skin photoaging and wrinkle formation.
Asunto(s)
Lactobacillus acidophilus/fisiología , Probióticos/administración & dosificación , Envejecimiento de la Piel/efectos de los fármacos , Envejecimiento de la Piel/efectos de la radiación , Piel/microbiología , Agua/metabolismo , Animales , Colágeno/metabolismo , Humanos , Masculino , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Pelados , Probióticos/efectos de la radiación , Regeneración/efectos de la radiación , Piel/metabolismo , Piel/fisiopatología , Piel/efectos de la radiación , Esterilización , Rayos UltravioletaRESUMEN
Intervertebral disc (IVD) degeneration is associated with imbalances between catabolic and anabolic responses, regulated by extracellular matrix (ECM)-modifying enzymes such as matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors of metalloproteinases (TIMPs). Potential contributing factors, such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, derived from infiltrated, activated macrophages within IVD tissues, can trigger abnormal production of ECM-modifying enzymes and progression of IVD degeneration. Novel therapies for regulating ECM-modifying enzymes can prevent or ameliorate IVD degeneration. Photobiomodulation (PBM), known to regulate wound repair, exhibits regenerative potential by modulating biological molecules. This study examined the effects of PBM, administered at various wavelengths (630, 525, and 465 nm) and energy densities (16, 32, and 64 J/cm2), on the production of ECM-modifying enzymes in replicated degenerative IVD. Our results showed that PBM selectively inhibited the production of ECM-modifying enzymes in a dose- and wavelength-dependent manner, suggesting that it could be a novel tool for treating symptomatic IVD degeneration.
Asunto(s)
Matriz Extracelular/enzimología , Degeneración del Disco Intervertebral/terapia , Terapia por Luz de Baja Intensidad , Núcleo Pulposo/enzimología , Progresión de la Enfermedad , Matriz Extracelular/efectos de la radiación , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Interleucina-1beta/genética , Disco Intervertebral/enzimología , Disco Intervertebral/patología , Disco Intervertebral/efectos de la radiación , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/patología , Macrófagos/patología , Macrófagos/efectos de la radiación , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/efectos de la radiación , Núcleo Pulposo/patología , Núcleo Pulposo/efectos de la radiación , Cultivo Primario de Células , Inhibidores Tisulares de Metaloproteinasas/genética , Inhibidores Tisulares de Metaloproteinasas/efectos de la radiación , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
BACKGROUND: Epigallocatechin-3-gallate (EGCG), which is the principal component of green tea, has been shown to prevent atherosclerosis. However, the effect of EGCG on atherosclerotic plaque stability remains unknown. AIM: This study aimed to assess whether EGCG can enhance atherosclerotic plaque stability and to investigate the underlying mechanisms. METHODS: Apolipoprotein E-deficient mice fed a high-fat diet were injected intraperitoneally with EGCG (10 mg/kg) for 16 weeks. Cross sections of the brachiocephalic arteries were stained with haematoxylin and eosin for morphometric analyses or Masson's trichrome for collagen content analyses. Immunohistochemistry was performed to evaluate the percentage of macrophages and smooth muscle cells (SMCs). Protein expression and matrix metalloproteinase (MMP) activity were assayed by Western blot and gelatin zymography, respectively. Serum inflammatory cytokine levels were quantified by enzyme-linked immunosorbent assays. RESULTS: After 16 weeks of feeding the high-fat diet, there were clear atherosclerotic lesions in the proximal brachiocephalic artery segments according to HE staining. EGCG treatment significantly increased the thickness of the fibrous cap. In the atherosclerotic plaques of the EGCG group, the relative macrophage content was decreased, whereas the relative SMC and collagen contents were increased. The expression levels of MMP-2, MMP-9, and extracellular matrix metalloproteinase inducer (EMMPRIN) were significantly decreased by EGCG treatment. In addition, EGCG treatment decreased the circulat-ing tumour necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, and interferon-γ levels in apolipoprotein E-deficient mice. CONCLUSIONS: EGCG promotes atherosclerotic lesion stability in apolipoprotein E-deficient mice. Potentially, these effects are mediated through the inhibition of inflammatory cytokine, MMPs and EMMPRIN expression.
Asunto(s)
Basigina/genética , Catequina/análogos & derivados , Citocinas/sangre , Metaloproteinasas de la Matriz/genética , Placa Aterosclerótica/tratamiento farmacológico , Animales , Apolipoproteínas E/genética , Catequina/farmacología , Catequina/uso terapéutico , Dieta Alta en Grasa , Regulación de la Expresión Génica , Inflamación/sangre , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Transgénicos , Miocitos del Músculo Liso/metabolismo , Placa Aterosclerótica/sangre , Placa Aterosclerótica/metabolismo , Té/químicaRESUMEN
Cancer metastasis is a vital trait in malignancies with complicated early diagnosis and therapeutic management. Therefore, the development of new remedies and the utilization of natural medicines that target metastasis are of great interest and have been studied extensively. Chinese medicinal herbs have various anti-carcinogenesis properties; however, the in vitro effect and mechanism of Viola yedoensis on cancer cell metastasis remains poorly understood. V. yedoensis extracts (VYE) can suppress the invasion of a highly metastatic human lung cancer cell line, A549 cells. According to gelatin zymography and casein zymography assays, VYE inhibited the activities of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (u-PA). The results of reverse transcription-polymerase chain reaction and Western blotting revealed that VYE can alter the expression of proteinase inhibitor. VYE also suppressed the DNA binding activity of nuclear factor-kappa B. We concluded that VYE may inhibit tumor invasion by suppressing the activities of MMP and u-PA in lung cancer cells.
Asunto(s)
Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Medicamentos Herbarios Chinos/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Invasividad Neoplásica/genética , Células A549 , Animales , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patología , Medicamentos Herbarios Chinos/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metaloproteinasas de la Matriz/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Péptido Hidrolasas/genética , Ratas , Activador de Plasminógeno de Tipo Uroquinasa/genéticaRESUMEN
This study aimed to determine whether photobiomodulation therapy (PBMT) could improve the bioavailability and chondroprotective benefits of mesenchymal stem cells injected into the knees of rats used as an experimental model of osteoarthritis (OA) as well as reduce the expression of matrix metalloproteinases (MMPs) and degradation of type II collagen (COL2-1) in the cartilage. Adipose-derived stem/stromal cells (ADSCs) were collected from three male Fischer 344 rats and characterized by flow cytometry. Fifty female Fischer 344 rats were distributed into five groups of 10 animals each. These groups were as follows: control, OA, OA PBMT, OA ADSC, and OA ADSC PBMT. OA was induced in the animals using a 4% papain solution. Animals from the OA ADSC and OA ADSC PBMT groups received an intra-articular injection of 10 × 106 ADSCs and were treated with PBMT by irradiation (wavelength: 808 nm, power: 50 mW, energy: 42 J, energy density: 71.2 J/cm2, spot size: 0.028). Euthanasia was performed 7 days after the first treatment. The use of PBMT alone and the injection of ADSCs resulted in downregulation of pro-inflammatory cytokines and MPs in cartilage compared to the OA group. PBMT and ADSCs caused upregulation of tissue inhibitors of MPs 1 and 2 and mRNA and protein expression of COL2-1 in cartilage compared to the OA group. The intra-articular injection of ADSCs and PBMT prevented joint degeneration resulting from COL2-1 degradation and modulated inflammation by downregulating cytokines and MMPs in the OA group.
Asunto(s)
Colágeno Tipo II/metabolismo , Terapia por Luz de Baja Intensidad , Metaloproteinasas de la Matriz/genética , Osteoartritis/radioterapia , Animales , Colágeno Tipo II/genética , Terapia Combinada , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Masculino , Metaloproteinasas de la Matriz/metabolismo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Osteoartritis/enzimología , Ratas , Ratas Endogámicas F344RESUMEN
Prunella vulgaris L., a well-known traditional Chinese herbal medicine, has anti-inflammatory and antioxidant activities. In the present study, the underlying molecular mechanisms of the protective effect of P. vulgaris extract (PVE) were investigated in UVB-irradiated normal human dermal fibroblasts (NHDFs). The mRNA expression of matrix metalloproteinases (MMPs), procollagen type I, and cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), was determined by reverse transcription-polymerase chain reaction. The expression of anti-photoaging-related signaling molecules in the NF-κB, MAPK/AP-1, and TGF/Smad pathways was assessed by western blot. We observed that PVE blocked the upregulated production of radical oxygen species induced in UVB-irradiated NHDFs in a dose-dependent manner. Treatment with PVE also significantly ameliorated the mRNA levels of MMPs, procollagen type I, TNF-α, and IL-6. In addition, the phosphorylation level of c-Jun and c-Fos was decreased through the attenuated expression levels of p-ERK and p-JNK after treatment with PVE. Furthermore, cells treated with PVE showed inhibited Smad 7 and increased Smad 2/3 expression in the TGF-ß/Smad signaling pathway. Hence, synthesis of procollagen type I, a precursor of collagen I, was promoted. These findings indicate that treatment with PVE has a potential protective effect against UVB-induced photoaging and photoinflammation.