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1.
Int. j. morphol ; 40(1): 122-128, feb. 2022. ilus
Artículo en Inglés | LILACS | ID: biblio-1385569

RESUMEN

SUMMARY: Induction of osteoarthritis (OA) following diabetes is characterized by a sever inflammation of the joints that can lead to disability. The cartilage content of proteoglycans can substantially be reduced, following the induction of diabetes mellitus associated with inflammation as well as knee joint injury, and the antidiabetic drug metformin combined with the anti-inflammatory agent resveratrol can prevent these deleterious effects. Therefore, insulin-independent diabetes, type 2 diabetes mellitus (T2DM) was induced in Albino rats by streptozotocin (STZ) injection (50 mg/kg) after being fed on a high carbohydrate and fat diets for 2 weeks. The protective group of rats which also received a single injection of STZ was treated daily with metformin (Met; 200 mg/kg) and resveratrol (Res; 30 mg/kg) for 12 weeks. Harvested knee joint tissues were prepared for basic histology stain and for proteoglycans staining using light microscopy. Histology images showed in diabetic rats (T2DM) OA development as demonstrated by profound injury to the knee joint and severe decrease of articular cartilage proteoglycans content, which were substantialy protected by Met+Res. Met+Res also significantly (p< 0.0001) decreased diabetes induced glycemia, dyslipidemia, and the inflammatory biomarkers, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high sensitivity C-reactive protein (hs-CRP). In addition, there was a significant correlation between OA and glycemia, dyslipidemia, and inflammation. Collectively, we demonstrate an association between knee joint damage and biomarkers of glycemia, dyslipidemia, and inflammation in diabetes-induced OA, with metformin plus resveratrol providing protective effects.


RESUMEN: La inducción de osteoartritis (OA) después de la diabetes se caracteriza por una inflamación severa de las articulaciones que puede conducir a la discapacidad. El contenido de cartílago de proteoglicanos se puede reducir sustancialmente, luego de la inducción de diabetes mellitus asociada con inflamación y lesión en la articulación de la rodilla sin embargo, el fármaco antidiabético metformina combinado con el agente antiinflamatorio resveratrol puede prevenir estos efectos nocivos. Por lo tanto, se indujo diabetes insulino dependiente, diabetes mellitus tipo 2 (T2DM) en ratas albinas mediante inyección de estreptozotocina (STZ) (50 mg/kg) después de haber sido alimentadas con dietas ricas en carbohidratos y grasas durante 2 semanas. El grupo protector de ratas que también recibió una inyección única de STZ fue tratado diariamente con metformina (Met; 200 mg/kg) y resveratrol (Res; 30 mg/kg) durante 12 semanas. Tejidos de la articulación de la rodilla fueon retirados y teñidos con histología básica y tinción de proteoglicanos usando microscopía óptica. Las imágenes histológicas en ratas diabéticas mostraban (T2DM) desarrollo de OA visualizadas por una lesión profunda en la articulación de la rodilla y una disminución severa del contenido de proteoglicanos del cartílago articular, los cuales estaban sustancialmente protegidos por Met+Res. Met+Res. También disminuyó significativamente (p< 0,0001) la glucemia inducida por la diabetes, la dislipidemia y los biomarcadores inflamatorios, el factor de necrosis tumoral alfa (TNF-α), la interleucina-6 (IL-6) y la proteína C reactiva de alta sensibilidad (PCR-hs). Además, hubo una correlación significativa entre la OA y la glucemia, la dislipidemia y la inflamación. En conjunto, demostramos una asociación entre el daño de la articulación de la rodilla y los biomarcadores de glucemia, dislipidemia e inflamación en la OA inducida por diabetes, con metformina más resveratrol que brindan efectos protectores.


Asunto(s)
Animales , Masculino , Ratas , Osteoartritis/prevención & control , Diabetes Mellitus Experimental , Resveratrol/administración & dosificación , Metformina/administración & dosificación , Proteoglicanos/efectos de los fármacos , Modelos Animales de Enfermedad , Hipoglucemiantes/administración & dosificación , Inflamación , Antiinflamatorios/administración & dosificación
2.
Sci Rep ; 11(1): 4115, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33603041

RESUMEN

Endometriosis is a painful gynecological condition characterized by ectopic growth of endometrial cells. Little is known about its pathogenesis, which is partially due to a lack of suitable experimental models. Here, we use endometrial stromal (St-T1b), primary endometriotic stromal, epithelial endometriotic (12Z) and co-culture (1:1 St-T1b:12Z) spheroids to mimic the architecture of endometrium, and either collagen I or Matrigel to model ectopic locations. Stromal spheroids, but not single cells, assumed coordinated directional migration followed by matrix remodeling of collagen I on day 5 or 7, resembling ectopic lesions. While generally a higher area fold increase of spheroids occurred on collagen I compared to Matrigel, directional migration was not observed in co-culture or in 12Z cells. The fold increase in area on collagen I was significantly reduced by MMP inhibition in stromal but not 12Z cells. Inhibiting ROCK signalling responsible for actomyosin contraction increased the fold increase of area and metabolic activity compared to untreated controls on Matrigel. The number of protrusions emanating from 12Z spheroids on Matrigel was decreased by microRNA miR-200b and increased by miR-145. This study demonstrates that spheroid assay is a promising pre-clinical tool that can be used to evaluate small molecule drugs and microRNA-based therapeutics for endometriosis.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Colágeno Tipo I/farmacología , Endometriosis/tratamiento farmacológico , Células del Estroma/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Colágeno/efectos de los fármacos , Colágeno/metabolismo , Combinación de Medicamentos , Endometriosis/metabolismo , Endometrio/efectos de los fármacos , Endometrio/metabolismo , Femenino , Humanos , Laminina/efectos de los fármacos , Laminina/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , MicroARNs/metabolismo , Proteoglicanos/efectos de los fármacos , Proteoglicanos/metabolismo
3.
J Ethnopharmacol ; 270: 113825, 2021 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-33460754

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Simiaowan (MSW) is a traditional Chinese medicine formula that is composed of six herbs. It has been widely used in the treatment of gouty arthritis. AIM OF THE STUDY: This study was designed to investigate the effect of MSW on gouty arthritis and explore the possible mechanisms. MATERIAL AND METHODS: The rat gouty arthritis model was established by intra-articular injection of Monosodium Urate (MSU) crystal, and then treated with MSW for 5 days. The perimeter of the knee joints was measured in a time-dependent manner and serum samples were collected for the detection of TNF-α, IL-1ß, and IL-6 protein levels by ELISA. The protein expressions of MMP-3, TIMP-3, STAT3, and p-STAT3 in cartilage tissues and C28/I2 cells were detected by Western blot, and the levels of proteoglycan in primary chondrocytes and cartilage tissues were determined by toluidine blue staining. In addition, AG490 and IL-6 were used in vitro to explore the function of IL-6/STAT3 pathway in the protective effect of MSU. RESULTS: MSW reduced the joint swelling rate in gouty arthritis model and inhibited MSU induced up-regulation of IL-1ß, TNF-α, and IL-6 protein levels in serum and synovial fluid. IL-1ß induced an increase in p-STAT3 and MMP-3 protein expression in C28/I2 cells, as well as a decrease in TIMP-3. MSW serum inhibited the protein expression changes induced by IL-1ß in vitro. Furthermore, inhibition of STAT3 signaling negated the effect of MSW serum on p-STAT3, MMP-3, and TIMP-3 protein levels in C28/I2 cells. MSW also increased the content of proteoglycan significantly both in vivo and in vitro. CONCLUSION: Our data indicated that MSW protected rats from MSU-induced experimental gouty arthritis and IL-1ß/IL-6/STAT3 pathway played an essential role in the protective effect of MSU against GA.


Asunto(s)
Artritis Gotosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Artritis Gotosa/inducido químicamente , Línea Celular , Condrocitos/efectos de los fármacos , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/tratamiento farmacológico , Humanos , Interleucina-1beta/toxicidad , Masculino , Proteoglicanos/efectos de los fármacos , Conejos , Ratas Sprague-Dawley , Ácido Úrico/toxicidad
4.
Arthritis Rheumatol ; 72(9): 1524-1533, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32336048

RESUMEN

OBJECTIVE: Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the formation of prostaglandin D2 (PGD2 ), which has important roles in inflammation and cartilage metabolism. We undertook this study to investigate the role of L-PGDS in the pathogenesis of osteoarthritis (OA) using an experimental mouse model. METHODS: Experimental OA was induced in wild-type (WT) and L-PGDS-deficient (L-PGDS-/- ) mice (n = 10 per genotype) by destabilization of the medial meniscus (DMM). Cartilage degradation was evaluated by histology. The expression of matrix metalloproteinase 13 (MMP-13) and ADAMTS-5 was assessed by immunohistochemistry. Bone changes were determined by micro-computed tomography. Cartilage explants from L-PGDS-/- and WT mice (n = 6 per genotype) were treated with interleukin-1α (IL-1α) ex vivo in order to evaluate proteoglycan degradation. Moreover, the effect of intraarticular injection of a recombinant adeno-associated virus type 2/5 (rAAV2/5) encoding L-PGDS on OA progression was evaluated in WT mice (n = 9 per group). RESULTS: Compared to WT mice, L-PGDS-/- mice had exacerbated cartilage degradation and enhanced expression of MMP-13 and ADAMTS-5 (P < 0.05). Furthermore, L-PGDS-/- mice displayed increased synovitis and subchondral bone changes (P < 0.05). Cartilage explants from L-PGDS-/- mice showed enhanced proteoglycan degradation following treatment with IL-1α (P < 0.05). Intraarticular injection of rAAV2/5 encoding L-PGDS attenuated the severity of DMM-induced OA-like changes in WT mice (P < 0.05). The L-PGDS level was increased in OA tissues of WT mice (P < 0.05). CONCLUSION: Collectively, these findings suggest a protective role of L-PGDS in OA, and therefore enhancing levels of L-PGDS may constitute a promising therapeutic strategy.


Asunto(s)
Artritis Experimental/genética , Cartílago Articular/patología , Condrocitos/metabolismo , Oxidorreductasas Intramoleculares/genética , Lipocalinas/genética , Osteoartritis/genética , Proteína ADAMTS5/metabolismo , Animales , Artritis Experimental/diagnóstico por imagen , Artritis Experimental/metabolismo , Artritis Experimental/patología , Huesos/diagnóstico por imagen , Cartílago Articular/metabolismo , Interleucina-1alfa/farmacología , Oxidorreductasas Intramoleculares/metabolismo , Lipocalinas/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Meniscos Tibiales/cirugía , Ratones , Ratones Noqueados , Osteoartritis/diagnóstico por imagen , Osteoartritis/patología , Prostaglandina D2/metabolismo , Proteoglicanos/efectos de los fármacos , Proteoglicanos/metabolismo , Rodilla de Cuadrúpedos/diagnóstico por imagen , Rodilla de Cuadrúpedos/metabolismo , Rodilla de Cuadrúpedos/patología , Microtomografía por Rayos X
5.
J Ethnopharmacol ; 256: 112664, 2020 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-32045685

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Orostachys japonicus A. Berger (O. japonicus), so-called Wa-song in Korea, a traditional food and medicine that grows on mountain rocks and roof tiles. Wa-song containing various phenolic compounds have been reported as a medicinal plant for prevention of fibrosis, cancer, inflammation, and oxidative damage. AIM OF THE STUDY: The present study was designed to examine the anti-angiogenic effects of cultivated Orostachys japonicus 70% ethanol extract (CE) in vascular endothelial growth factor (VEGF)-stimulated human umbilical vein endothelial cells (HUVECs). MATERIALS AND METHODS: CE was prepared with 70% ethanol. HUVECs, rat aortic rings, and matrigel plug in mice were treated with CE (10-20 µg/mL) and VEGF (20-50 ng/mL), and the anti-angiogenic activities of CE were analyzed by SRB, wound healing, trans-well invasion, capillary-like tubule formation, rat aortas, Western blot, and matrigel plug assay. Phenolic compounds in CE were analyzed using a high-performance liquid chromatography (HPLC)-PDA system. RESULTS: Treatment of CE (10-20 µg/mL) markedly suppressed proliferation of HUVECs in the presence (from 136.5% to 112.2%) or absence of VEGF (from 100.0% to 92.1%). The proliferation inhibitory effect of CE was caused by G0/G1 cell cycle arrest, and the decrease of CDK-2, CDK-4, Cyclin D1 and Cyclin E1. Furthermore, CE treatment showed significant angiogenesis inhibitory effects on motility, invasion and micro-vessel formation of HUVECs, rat aortic rings and subcutaneous matrigels under VEGF-stimulation condition. In HUVECs, CE-induced anti-angiogenic effect was regulated by inhibition of the PI3K/AKT/mTOR, MAPK/p38, MAPK/ERK, FAK-Src, and VEGF-VEGFR2 signaling pathways. CONCLUSION: This study demonstrated that CE might be used as a potential natural substance, multi-targeted angiogenesis inhibitor, functional food material.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Crassulaceae/química , Neovascularización Patológica/tratamiento farmacológico , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Inductores de la Angiogénesis/farmacología , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Colágeno/efectos de los fármacos , Colágeno/metabolismo , Combinación de Medicamentos , Fase G1/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Laminina/efectos de los fármacos , Laminina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Patológica/metabolismo , Proteoglicanos/efectos de los fármacos , Proteoglicanos/metabolismo , Ratas , Ratas Sprague-Dawley , Fase de Descanso del Ciclo Celular/efectos de los fármacos
6.
Anatol J Cardiol ; 22(5): 240-249, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31674929

RESUMEN

OBJECTIVE: Endocan, chemerin, and galectin-3 are discrete biomarkers associated with cardiovascular diseases and acting through different pathophysiological pathways. The aim of this study is to investigate and compare the effects of high doses of atorvastatin and rosuvastatin on serum endocan, chemerin, and galectin-3 levels in patients with acute myocardial infarction (AMI). METHODS: Sixty-three patients with AMI were randomized to receive atorvastatin (80 mg/day) or rosuvastatin (40 mg/day) after percutaneous revascularization. Serum levels of endocan, chemerin, and galectin-3 were evaluated at baseline and after 4-week therapy. RESULTS: Endocan levels were not decreased statistically significantly with atorvastatin 80 mg, but rosuvastatin 40 mg markedly decreased the levels of endocan according to baseline [from 110.27 (86.03-143.69) pg/mL to 99.22 (78.30-122.87) pg/mL with atorvastatin 80 mg and from 110.73 (77.28-165.22) pg/mL to 93.40 (70.48-115.13) pg/mL with rosuvastatin 40 mg, p=0.242 for atorvastatin 80 mg and p=0.014 for rosuvastatin 40 mg]. Chemerin levels significantly decreased in both groups according to baseline [from 264.90 (196.00-525.95) ng/mL to 135.00 (105.95-225.65) ng/mL with atorvastatin 80 mg and from 309.95 (168.87-701.27) ng/mL to 121.25 (86.60-212.65) ng/mL with rosuvastatin 40 mg, p<0.001, respectively, for both groups]. Galectin-3 levels did not change markedly with atorvastatin 80 mg, but they decreased with rosuvastatin 40 mg [from 17.00 (13.10-22.25) ng/mL to 19.30 (15.25-23.45) ng/mL with atorvastatin 80 mg, p=0.721, and from 18.25 (12.82-23.82) ng/mL to 16.60 (10.60-20.15) ng/mL with rosuvastatin 40 mg, p=0.074]. There were no significant between-group differences in terms of absolute and percentage changes of endocan, chemerin, and galectin-3 at 4 weeks. CONCLUSION: We reported that both statins similarly decreased the endocan levels, whereas rosuvastatin seems to have more prominent effects on the reduction of the chemerin and galectin-3 levels in patients with AMI.


Asunto(s)
Atorvastatina/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Infarto del Miocardio/sangre , Rosuvastatina Cálcica/farmacología , Angioplastia , Biomarcadores/sangre , Proteínas Sanguíneas , Quimiocinas/sangre , Quimiocinas/efectos de los fármacos , Femenino , Galectina 3/sangre , Galectina 3/efectos de los fármacos , Galectinas , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/terapia , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/efectos de los fármacos , Proteoglicanos/sangre , Proteoglicanos/efectos de los fármacos , Resultado del Tratamiento
7.
Inflammation ; 42(6): 1951-1956, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31267273

RESUMEN

The endothelial glycocalyx has been proved to be a polysaccharide protein complex covering the surface of vascular endothelial cells, playing an important role in vascular permeability, blood flow shear stress induction, and prevention of endothelial cell adhesion. The pathogenesis of PAH includes pulmonary arterial endothelial cell dysfunction and pulmonary arterial smooth muscle cell (PASMCs) proliferation. Based on the physicochemical properties of endothelial glycocalyx involving pathogenesis of pulmonary hypertension. We hypothesized that the endothelial glycocalyx is involved in the development of pulmonary hypertension; pulmonary hypertension can be regulated by protecting the integrity of glycocalyx. Expression of glycocalyx markers including heparin sulfate proteoglycan (HSPG), hyaluronan (HA), and syndecan-1 (SDC-1) was detected in monocrotaline (MCT)-induced PAH in rats and these components were detected when the PAH rats were treated with heparin that protected the role of glycocalyx. Results showed that plasma levels of HSPG, HA, and SDC-1 were increased in MCT group when compared with control group. However, rats in treatment group showed reduced levels of HSPG, HA, and SDC-1. Expression of HSPG, HA, and SDC-1 in pulmonary arteries was also reduced in MCT group when compared with those in the control group. By contrast, expression of HSPG, HA, and SDC-1 in pulmonary arteries increased in treatment group. In conclusion, destruction of glycocalyx was involved in the development of pulmonary hypertension. Pulmonary hypertension can be regulated by protecting the integrity of glycocalyx.


Asunto(s)
Glicocálix/metabolismo , Hipertensión Pulmonar/prevención & control , Animales , Biomarcadores/sangre , Modelos Animales de Enfermedad , Heparina/análogos & derivados , Heparina/sangre , Ácido Hialurónico/sangre , Hipertensión Pulmonar/inducido químicamente , Monocrotalina , Proteoglicanos/sangre , Proteoglicanos/efectos de los fármacos , Ratas , Sindecano-1/sangre
8.
Cartilage ; 10(3): 370-374, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-29582671

RESUMEN

OBJECTIVES: Staining with toluidine blue is a well-established procedure for the histological assessment of cartilaginous- and chondrogenic-differentiated tissues. Being a cationic dye, toluidine blue staining visualizes proteoglycans in a tissue because of its high affinity for the sulfate groups in proteoglycans. It is generally accepted that metachromatic staining with toluidine blue represents cartilaginous matrix and that the degree of positive staining corresponds with the amount of proteoglycans. DESIGN: Articular cartilage and pellets of chondrocytes or bone marrow stromal cells were analyzed with a standardized staining procedure for toluidine blue. RESULTS: In the present study, we illustrate why such an assumption is invalid unless a detailed description of the procedure and/or reference to a detailed published method are provided. This is because the staining specificity and intensity depend, as we have shown, on the pH of the staining solution, the use of dehydration, and on staining time. CONCLUSIONS: We can, therefore, suggest a well-controlled standardized protocol for toluidine blue staining, which provides an easy and simple selective staining technique for the assessment of cartilage tissue and proteoglycan development in chondrogenic differentiation. If this procedure is not used, then investigators must provide sufficient technical information concerning the staining protocol to allow an assessment of the validity of the staining results.


Asunto(s)
Condrogénesis/efectos de los fármacos , Colorantes/administración & dosificación , Coloración y Etiquetado/normas , Cloruro de Tolonio/administración & dosificación , Animales , Biopsia , Cartílago Articular/diagnóstico por imagen , Diferenciación Celular/fisiología , Condrogénesis/fisiología , Colorantes/normas , Células Madre Mesenquimatosas , Proteoglicanos/análisis , Proteoglicanos/efectos de los fármacos , Porcinos , Cloruro de Tolonio/normas
9.
Arthritis Rheumatol ; 69(9): 1784-1795, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28544596

RESUMEN

OBJECTIVE: D prostanoid receptor 1 (DP1), a receptor for prostaglandin D2 , plays important roles in inflammation and cartilage metabolism. However, its role in the pathogenesis of osteoarthritis (OA) remains unknown. This study was undertaken to explore the roles of DP1 in the development of OA in murine models and to evaluate the efficacy of a DP1 selective agonist in the treatment of OA. METHODS: The development of aging-associated OA and destabilization of the medial meniscus (DMM)-induced OA was compared between DP1-deficient (DP1-/- ) and wild-type (WT) mice. The progression of OA was assessed by histology, immunohistochemistry, and micro-computed tomography. Cartilage explants from DP1-/- and WT mice were treated with interleukin-1α (IL-1α) ex vivo, to evaluate proteoglycan degradation. The effect of intraperitoneal administration of the DP1 selective agonist BW245C on OA progression was evaluated in WT mice. RESULTS: Compared to WT mice, DP1-/- mice had exacerbated cartilage degradation in both models of OA, and this was associated with increased expression of matrix metalloproteinase 13 and ADAMTS-5. In addition, DP1-/- mice demonstrated enhanced subchondral bone changes. Cartilage explants from DP1-/- mice showed enhanced proteoglycan degradation following treatment with IL-1α. Intraperitoneal injection of BW245C attenuated the severity of DMM-induced cartilage degradation and bony changes in WT mice. CONCLUSION: These findings indicate a critical role for DP1 signaling in OA pathogenesis. Modulation of the functions of DP1 may constitute a potential therapeutic target for the development of novel OA treatments.


Asunto(s)
Artritis Experimental/genética , Artritis Experimental/patología , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/patología , Receptores de Prostaglandina/deficiencia , Proteína ADAMTS5/metabolismo , Animales , Cartílago/efectos de los fármacos , Cartílago/patología , Progresión de la Enfermedad , Hidantoínas/farmacología , Interleucina-1alfa/farmacología , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteoglicanos/efectos de los fármacos
10.
Physiol Rep ; 4(15)2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27482070

RESUMEN

Pulmonary fibrosis is characterized by excessive accumulation of connective tissue, along with activated extracellular matrix (ECM)-producing cells, myofibroblasts. The pathological mechanisms are not well known, however serotonin (5-HT) and 5-HT class 2 (5-HT2) receptors have been associated with fibrosis. The aim of the present study was to investigate the role of 5-HT2B receptors in fibrosis, using small molecular 5-HT2B receptor antagonists EXT5 and EXT9, with slightly different receptor affinity. Myofibroblast differentiation [production of alpha-smooth muscle actin (α-SMA)] and ECM synthesis were quantified in vitro, and the effects of the receptor antagonists were evaluated. Pulmonary fibrosis was also modeled in mice by subcutaneous bleomycin administrations (under light isoflurane anesthesia), and the effects of receptor antagonists on tissue density, collagen-producing cells, myofibroblasts and decorin expression were investigated. In addition, cytokine expression was analyzed in serum. Lung fibroblasts displayed an increased α-SMA (P < 0.05) and total proteoglycan production (P < 0.01) when cultured with TGF-ß1 together with 5-HT, which were significantly reduced with both receptor antagonists. Following treatment with EXT5 or EXT9, tissue density, expression of decorin, number of collagen-producing cells, and myofibroblasts were significantly decreased in vivo compared to bleomycin-treated mice. Receptor antagonization also significantly reduced systemic levels of TNF-α and IL-1ß, indicating a role in systemic inflammation. In conclusion, 5-HT2B receptor antagonists have potential to prevent myofibroblast differentiation, in vitro and in vivo, with subsequent effect on matrix deposition. The attenuating effects of 5-HT2B receptor antagonists on fibrotic tissue remodeling suggest these receptors as novel targets for the treatment of pulmonary fibrosis.


Asunto(s)
Miofibroblastos/fisiología , Fibrosis Pulmonar/fisiopatología , Receptor de Serotonina 5-HT2B/fisiología , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Animales , Bleomicina , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Técnicas In Vitro , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/efectos de los fármacos , Proteoglicanos/efectos de los fármacos , Proteoglicanos/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Receptor de Serotonina 5-HT2B/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Factor de Necrosis Tumoral alfa/metabolismo
11.
Osteoarthritis Cartilage ; 24(1): 178-187, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26256766

RESUMEN

OBJECTIVE: To determine whether mandibular condylar cartilage degradation induced by experimentally abnormal occlusion could be ameliorated via systemic administration of strontium or NBD peptide. METHODS: Six-week-old female C57BL/6J mice were used. From the seventh day after mock operation or unilateral anterior crossbite (UAC) treatment, the control and UAC mice were further respectively pharmacologically treated for 2 weeks or 4 weeks of saline (CON + Saline and UAC + Saline groups), SrCl2 (CON + SrCl2 and UAC + SrCl2 groups) or NBD peptide (CON + NBD peptide and UAC + NBD peptide groups). Changes in condylar cartilage and subchondral bone were assessed 21 and 35 days after mock operation or UAC procedure by histology and micro-CT. Real-time PCR and/or immunohistochemistry (IHC) were performed to evaluate changes in expression levels of col2a1, aggrecan, ADAMTS-5, tnf-α, il-1ß, nfkbia, nuclear factor-kappaB phospho-p65 in condylar cartilage, and rankl/rank/opg in both condylar cartilage and subchondral bone. RESULTS: Cartilage degradation with decreased col2a1 and aggrecan expression, and increased ADAMTS-5, tnf-α/il1-ß, nfkbia and NF-κB phospho-p65 was observed in UAC + Saline groups. Subchondral bone loss with increased osteoclast numbers and decreased opg/rankl ratio was found in UAC + Saline groups compared to age-match CON + Saline groups. Cartilage degradation and subchondral bone loss were reversed by treatment of SrCl2 or NBD peptide while the same dosage in control mice induced few changes in condylar cartilage and subchondral bone. CONCLUSIONS: The results demonstrate reverse effect of systemic administration of strontium or NBD peptide on UAC-induced condylar cartilage degradation and subchondral bone loss.


Asunto(s)
Cartílago Articular/efectos de los fármacos , Maloclusión , Cóndilo Mandibular/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Péptidos/farmacología , ARN Mensajero/efectos de los fármacos , Estroncio/farmacología , Proteínas ADAM/efectos de los fármacos , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteína ADAMTS5 , Agrecanos/efectos de los fármacos , Agrecanos/genética , Agrecanos/metabolismo , Animales , Cartílago Articular/metabolismo , Colágeno Tipo II/efectos de los fármacos , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Oclusión Dental , Femenino , Proteínas I-kappa B/efectos de los fármacos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Inmunohistoquímica , Interleucina-1beta/efectos de los fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Cóndilo Mandibular/metabolismo , Cóndilo Mandibular/patología , Ratones , Ratones Endogámicos C57BL , Inhibidor NF-kappaB alfa , Osteoclastos/metabolismo , Osteoprotegerina/efectos de los fármacos , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Proteoglicanos/efectos de los fármacos , Proteoglicanos/metabolismo , Ligando RANK/efectos de los fármacos , Ligando RANK/genética , Ligando RANK/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Activador del Factor Nuclear kappa-B/efectos de los fármacos , Receptor Activador del Factor Nuclear kappa-B/genética , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Factor de Transcripción ReIA/efectos de los fármacos , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
12.
Int J Oral Maxillofac Implants ; 30(4): 953-8, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26252049

RESUMEN

PURPOSE: Autologous bone is used for augmentation in the course of oral implant placement. Bone grafts release paracrine signals that can modulate mesenchymal cell differentiation in vitro. The detailed genetic response of the bone-derived fibroblasts to these paracrine signals has remained elusive. Paracrine signals accumulate in bone-conditioned medium (BCM) prepared from porcine cortical bone chips. MATERIALS AND METHODS: In this study, bone-derived fibroblasts were exposed to BCM followed by a whole genome expression profiling and downstream quantitative reverse transciptase polymerase chain reaction of the most strongly regulated genes. RESULTS: The data show that ADM, IL11, IL33, NOX4, PRG4, and PTX3 were differentially expressed in response to BCM in bone-derived fibroblasts. The transforming growth factor beta (TGF-ß) receptor 1 antagonist SB431542 blocked the effect of BCM on the expression of the gene panel, except for IL33. CONCLUSION: These in vitro results extend existing evidence that cortical bone chips release paracrine signals that provoke a robust genetic response in mesenchymal cells that is not exclusively mediated via the TGF-ß receptor. The present data provide further insights into the process of graft consolidation.


Asunto(s)
Fibroblastos/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Adrenomedulina/análisis , Adrenomedulina/efectos de los fármacos , Animales , Benzamidas/farmacología , Huesos/citología , Proteína C-Reactiva/análisis , Proteína C-Reactiva/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Dioxoles/farmacología , Perfilación de la Expresión Génica/métodos , Sustancias de Crecimiento/análisis , Humanos , Interleucina-11/análisis , Interleucina-33/análisis , Interleucina-33/efectos de los fármacos , NADPH Oxidasas/análisis , NADPH Oxidasas/efectos de los fármacos , Comunicación Paracrina/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteoglicanos/análisis , Proteoglicanos/efectos de los fármacos , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Componente Amiloide P Sérico/análisis , Componente Amiloide P Sérico/efectos de los fármacos , Porcinos
13.
Diab Vasc Dis Res ; 12(4): 290-7, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25963575

RESUMEN

Pro-inflammatory conditions induced by products of protein glycation in diabetes substantially enhance the risk of endothelial dysfunction and related vascular complications. Endothelial cell specific molecule-1 (ESM-1) or endocan has been demonstrated as a potential biomarker in cancer and sepsis. Its role in diabetes-induced pathologies remains unknown. The expression of ESM-1 gene is under cytokine regulation, indicating its role in endothelium-dependent pathological disorders. In this study, we investigated the effect of advanced glycated human serum albumin (AGE-HSA) on the production of ESM-1. We show that AGE-HSA exerts a modulating role on the expression of ESM-1 in human umbilical vein endothelial cells. It up-regulates expression of ESM-1 protein in a dose-dependent manner which correlates with its messenger RNA (mRNA) transcription. RAGE and galectin-3, both AGE receptors, show antagonistic action on its expression. While gene silencing of RAGE has down-regulatory effect, that of galectin-3 has up-regulatory effect on AGE-induced expression of ESM-1. Inhibition of MAPKKK and JNK pathways did not alter the expression. In contrast, phosphatidylinositol 3 kinase (PI3K) inhibition significantly up-regulated ESM-1 expression. In conclusion, these results suggest that AGE-induced activation of human umbilical vein endothelial cells promotes formation of endocan which is an endothelial dysfunction marker and may be related to vascular disease in diabetes.


Asunto(s)
Diabetes Mellitus/fisiopatología , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Productos Finales de Glicación Avanzada/farmacología , Proteínas de Neoplasias/efectos de los fármacos , Proteoglicanos/efectos de los fármacos , Albúmina Sérica/farmacología , Diabetes Mellitus/metabolismo , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Galectina 3/efectos de los fármacos , Galectina 3/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Quinasas Quinasa Quinasa PAM/efectos de los fármacos , Quinasas Quinasa Quinasa PAM/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteoglicanos/genética , Proteoglicanos/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor para Productos Finales de Glicación Avanzada/efectos de los fármacos , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Albúmina Sérica Glicada
14.
J Pharm Pharmacol ; 67(7): 963-71, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25645065

RESUMEN

OBJECTIVES: We investigated whether inhibition of hedgehog (Hh) signal by cyclopamine attenuated inflammation and cartilage damage in adjuvant-induced arthritis (AIA) rats. METHODS: Cyclopamine (2.5, 5, 10 mg/kg) was given by intraperitoneal injection once daily from day 12 to 21 after AIA induction. Paw swelling (volume changes), serum pro-inflammatory cytokines levels (ELISA), histological analysis of joint damage (H&E staining), proteoglycans expression (Alcian blue staining), mRNA levels of sonic Hh (Shh), glioma-associated oncogene homologue 1 (Gli1), type II collagen (COII) and aggrecan in cartilage (real-time PCR) and articular chondrocyte apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) were measured respectively. KEY FINDINGS: Cyclopamine effectively attenuated inflammation and cartilage damage of AIA rats, as evidenced by reduced paw swelling, serum levels of tumor necrosis factors (TNF)-α, IL-1ß, IL-6 and histological scores of joint damage, increased proteoglycans expression and mRNA levels of COII and aggrecan in articular cartilage. Shh or Gli1 mRNA level was correlated negatively with COII and aggrecan mRNA levels, suggesting Hh signal inhibition was associated with promotion of cartilage extracellular matrix production. Furthermore, cyclopamine decreased the number of apoptotic articular chondrocytes of AIA rats, which might be partly related to its mechanisms on relieving cartilage damage. CONCLUSIONS: Our findings present some experimental evidence that Hh signal inhibition might be of potential clinical interest in rheumatoid arthritis treatment.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Cartílago Articular/efectos de los fármacos , Proteínas Hedgehog/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Alcaloides de Veratrum/farmacología , Animales , Artritis Experimental/metabolismo , Cartílago Articular/metabolismo , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Colágeno Tipo II/metabolismo , Modelos Animales de Enfermedad , Proteínas Hedgehog/metabolismo , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Proteínas Oncogénicas/metabolismo , Proteoglicanos/efectos de los fármacos , Proteoglicanos/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Transactivadores/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteína con Dedos de Zinc GLI1
16.
Georgian Med News ; (236): 102-5, 2014 Nov.
Artículo en Ruso | MEDLINE | ID: mdl-25541836

RESUMEN

Nitrates (salts of nitric acid) are very common substances in nature and are present in almost all living organisms. Relevance of research about features of various pathological processes in chronic nitric intoxication significantly associated with the fact that the intake of nitro compounds has significantly increased in recent years, especially in rural areas where local water sources are used. Investigations were carried out on 20 white Wistar rats. Two series of the experiment ware held: Group I - intact animals (10 animals); Group II - animals after administration of sodium nitrate at a dose of 200 mg/kg in the form of an aqueous solution intragastrically for 60 days (10 animals). Chronic nitrate intoxication leads to a significant increase of the level of serum chondroitin rats with permanent indicators glycoproteins indicates that the products disorganization of proteoglycans from the bone to the blood serum. Increasing of overall level glycosaminoglycans and the third fraction (heparan sulfate), and reducing of the 2-nd fraction (chondroitin-4-sulfate) glycosaminoglycans in serum may be indicative of a chronic lesion of sodium nitrite intoxication general connective tissue (including bone tissues and liver parenchymal).


Asunto(s)
Glicosaminoglicanos/sangre , Nitratos/toxicidad , Proteoglicanos/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Condroitín/sangre , Proteoglicanos/metabolismo , Ratas
17.
Eur J Oral Sci ; 122(2): 100-8, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24621258

RESUMEN

Temporomandibular joint disorders (TMDs) affect a significant portion of the population of the USA, with the majority of those seeking treatment being women of childbearing age. Owing to this striking sexual dimorphism it has been postulated that sex hormones play a role in the maintenance of normal temporomandibular joint (TMJ) function. Proteoglycan 4 (PRG4) is a secreted lubricating molecule required for maintaining low frictional levels within articular joints; however, its role in the TMJ is not well characterized. In this study we describe the development of immortalized baboon cells isolated from specific regions of the TMJ disc and their use in the investigation of PRG4 expression and localization patterns in the TMJ. We identified conserved estrogen response elements within the 5' flanking region of the PRG4 gene of several species, and found that treatment of baboon TMJ disc cells with estrogen led to reduced PRG4 promoter activity and reduced expression of PRG4 mRNA in vitro. The observed negative regulation of PRG4 by estrogen could lead to increased friction and degradation of joint components over time. This study, for the first time, provides evidence of the regulatory potential of estrogen on PRG4 gene expression and suggests a novel etiology for the gender disparity observed among TMD patients.


Asunto(s)
Estradiol/farmacología , Proteoglicanos/genética , Disco de la Articulación Temporomandibular/efectos de los fármacos , Transcripción Genética/genética , Región de Flanqueo 5'/genética , Empalme Alternativo , Animales , Técnicas de Cultivo de Célula , Línea Celular , Condrocitos/efectos de los fármacos , Secuencia Conservada/genética , Estrógenos/genética , Estrógenos/farmacología , Exones/genética , Femenino , Fibroblastos/efectos de los fármacos , Genes Reporteros/genética , Vectores Genéticos/genética , Papio , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Proteoglicanos/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , Elementos de Respuesta/genética , Retroviridae/genética , Disco de la Articulación Temporomandibular/citología , Transfección
18.
Int J Exp Pathol ; 94(6): 412-7, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23998420

RESUMEN

The field of study concerning promotion and/or inhibition of angiogenesis has gathered much attention in the scientific community. A great deal of work has been invested towards defining reproducible assays to gauge for promotion or inhibition of angiogenesis in response to drug treatments or growth conditions. Two common components of these assays were noted by our group to have an unexpected and previously unreported interaction. Suramin is a commercially available compound, commonly used as a positive control for in vitro angiogenic inhibition assays. Matrigel is a popular extracellular substrate that supports angiogenic network formation when endothelial cells are cultured on its surface. However, our group demonstrated that suramin alone (without the presence of cells) will actively dissolve Matrigel, causing the extracellular matrix to transition from the gel-like physical state to a more liquid state. This causes cells on the Matrigel to congregate and sink to the bottom of the well. Therefore, previous observations of inhibition of endothelial cell angiogenesis through the incubation with suramin (including previous observations made by our group) are, largely, an artefact caused by suramin and matrix interaction rather than suramin and cells interaction, as previously reported. Our results suggest that the presence of sulphate groups and amphiphilic properties of suramin are likely responsible for the disruption of the matrix layer. We believe that this information is of prime importance to anyone using similar in vitro models, or employing suramin in any therapy or drug development assays.


Asunto(s)
Artefactos , Bioensayo/métodos , Colágeno/efectos de los fármacos , Laminina/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Proteoglicanos/efectos de los fármacos , Suramina/farmacología , Tensoactivos/farmacología , Células Cultivadas , Combinación de Medicamentos , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/fisiología , Humanos , Técnicas In Vitro , Glicoproteínas de Membrana/efectos de los fármacos , Neovascularización Fisiológica/fisiología , Dodecil Sulfato de Sodio/farmacología , Suramina/química , Tensoactivos/química
19.
J Craniofac Surg ; 24(3): 1026-30, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23714939

RESUMEN

BACKGROUND: Despite advances in surgical technique, reconstruction of a mandibular condyle still causes significant donor-site morbidity. The purpose of this study was to compare the effect of 3 different growth factors and define optimal cell culture conditions for bone marrow-derived progenitor cells to differentiate into chondrocytes for mandibular condyle reconstruction. METHODS: Porcine bone marrow-derived progenitor cells (pBMPCs) were cultured as a pellet for 2, 3, and 4 weeks under the following conditions: group 1, TGF-ß3 + standard medium; group 2, TGF-ß3 + BMP-2 + standard medium; group 3, TGF-ß3 + IGF-1 + standard medium; and group 4, TGF-ß3 + BMP-2 + IGF-1 + standard medium. Chondrogenic differentiation was evaluated using 3 lineage differentiation markers. RESULTS: The mean type II collagen positive area increased over weeks 2, 3, and 4 in group 4 compared to all the other groups (ANOVA; P = 0.005). At week 4, there was significantly greater type II collagen production in group 4 compared to all the other groups (ANOVA; P = 0.003). The medium in group 4 produces the greatest amount of cartilage when compared to groups 1, 2, and 3, and that 4 weeks produces the greatest amount of type II collagen. CONCLUSIONS: The results of this study indicate that the most efficacious medium for chondrogenic differentiation of pBMPCs was group 4 medium and the most type II collagen was produced at 4 weeks.


Asunto(s)
Proteína Morfogenética Ósea 2/farmacología , Condrogénesis/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Factor de Crecimiento Transformador beta3/farmacología , Factor de Crecimiento Transformador beta/farmacología , Animales , Cartílago/efectos de los fármacos , Técnicas de Cultivo de Célula , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Separación Celular/métodos , Células Cultivadas , Condrocitos/efectos de los fármacos , Colágeno Tipo I/efectos de los fármacos , Colágeno Tipo II/efectos de los fármacos , Medios de Cultivo , Proteoglicanos/efectos de los fármacos , Proteínas Recombinantes/farmacología , Porcinos , Factores de Tiempo
20.
J Cell Physiol ; 228(9): 1884-96, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23460134

RESUMEN

The catabolic cytokine interleukin-1 (IL-1) and endotoxin lipopolysaccharide (LPS) are well-known inflammatory mediators involved in degenerative disc disease, and inhibitors of IL-1 and LPS may potentially be used to slow or prevent disc degeneration in vivo. Here, we elucidate the striking anti-catabolic and anti-inflammatory effects of bovine lactoferricin (LfcinB) in the intervertebral disc (IVD) via antagonism of both IL-1 and LPS-mediated catabolic activity using in vitro and ex vivo analyses. Specifically, we demonstrate the biological counteraction of LfcinB against IL-1 and LPS-mediated proteoglycan (PG) depletion, matrix-degrading enzyme production, and enzyme activity in long-term (alginate beads) and short-term (monolayer) culture models using bovine and human nucleus pulposus (NP) cells. LfcinB significantly attenuates the IL-1 and LPS-mediated suppression of PG production and synthesis, and thus restores PG accumulation and pericellular matrix formation. Simultaneously, LfcinB antagonizes catabolic factor mediated induction of multiple cartilage-degrading enzymes, including MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5, in bovine NP cells at both mRNA and protein levels. LfcinB also suppresses the catabolic factor-induced stimulation of oxidative and inflammatory factors such as iNOS, IL-6, and toll-like receptor-2 (TLR-2) and TLR-4. Finally, the ability of LfcinB to antagonize IL-1 and LPS-mediated suppression of PG is upheld in an en bloc intradiscal microinjection model followed by ex vivo organ culture using both mouse and rabbit IVD tissue, suggesting a potential therapeutic benefit of LfcinB on degenerative disc disease in the future.


Asunto(s)
Interleucina-1/metabolismo , Disco Intervertebral/metabolismo , Lactoferrina/metabolismo , Lipopolisacáridos/toxicidad , Dolor de la Región Lumbar/tratamiento farmacológico , Animales , Bovinos , Supervivencia Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1/antagonistas & inhibidores , Disco Intervertebral/citología , Disco Intervertebral/fisiopatología , Lactoferrina/química , Lactoferrina/farmacología , Dolor de la Región Lumbar/fisiopatología , Ratones , Técnicas de Cultivo de Órganos , Proteoglicanos/biosíntesis , Proteoglicanos/efectos de los fármacos , Conejos
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