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1.
Chem Biol Interact ; 319: 108984, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-32061742

RESUMEN

OBJECTIVES: As one of the main active ingredients of Chinese herbal medicine Andrographis paniculate, andrographolide is used in domestic clinical treatment for respiratory infections and inflammation. This study was designed to investigate the effects of andrographolide as an antioxidant on the level of oxidative stress, neutrophil accumulation and infiltration in joints and synovial tissue of arthritis rats induced by complete freund's adjuvant. METHODS: A rat model of rheumatoid arthritis was induced by subcutaneous injection of complete Freund's adjuvant in the footpad. The model was established 14 days after induction. The treatment was performed from 14th day to 35th day with different doses of andrographolide (25, 50, 100 mg/kg) and positive control methotrexate (3 mg/kg). The effects of andrographolide on oxidative stress, neutrophil accumulation and infiltration were measured by the paw swelling, arthritis score, the hot plate test, biochemical analysis, and histology. RESULTS: The medium and high-dose andrographolide (50, 100 mg/kg) group declined the levels of tumor necrosis factor-α, interleukin-6 and CXC chemokine ligand2, articular elastase and myeloperoxidase, and increased the levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione. The activity of malondialdehyde and nitrite/nitrate in andrographolide (50, 100 mg/kg) group was weakened than the model group. The degree of swelling and arthritis score of andrographolide group was lower than the model group. The results of hot plate test showed that high dose of andrographolide significantly improved the anti-injury ability of rats; Radiological and histological results showed that the joint osteoporosis, inflammatory cell infiltration, synovial hyperplasia and other phenomena in the andrographolide group were significantly improved. CONCLUSIONS: Andrographolide acts as a protective agent for the treatment of complete freund's adjuvant induced rheumatoid arthritis by inhibiting lipid peroxidation and nitrite/nitrate levels in a dose-dependent manner, enhancing antioxidant enzyme activity, reducing levels of chemokines and inflammatory factors, preventing neutrophil accumulation and infiltration.


Asunto(s)
Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Diterpenos/farmacología , Adyuvante de Freund/farmacología , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Artritis Experimental/metabolismo , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Catalasa/metabolismo , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/tratamiento farmacológico , Edema/metabolismo , Glutatión/metabolismo , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Articulaciones/efectos de los fármacos , Articulaciones/metabolismo , Masculino , Metotrexato/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
2.
Food Chem Toxicol ; 135: 110958, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31715307

RESUMEN

Nerolidol is naturally occurring sesquiterpene has wide range of biological properties including anti-inflammatory activity. However, it has high volatility with low solubility in nature. The present study aimed to develop and characterized nano-encapsulated nerolidol and evaluated its activity on zymosan-induced arthritis model. Nano-capsules were produced by interfacial deposition of preformed polymer method and characterized by particle size, pH, polydispersity index (PDI), zeta potential, drug content and transmission electron microscopy (TEM). In vitro cytotoxicity of formulations was evaluated by alamar blue and MTT assays. In vivo neutrophils migration assay was performed on intra-articular zymosan-induced arthritis model in mice. Nano-encapsulated nerolidol suspensions presented adequate properties: mean diameter of particles 219.5 ±â€¯8.4 nm, pH: 6.84 ±â€¯0.5, PDI≤0.2, the zeta potential was -20.3 ±â€¯3.6 mV and drug content 71,2 ±â€¯1.3%. The formulations did not demonstrated cytotoxicity under the conditions assessed. Nerolidol 300 mg/kg inhibited neutrophils migration into joint cavity by 18.8% remains compared with control group, and nano-encapsulated nerolidol 3 mg/kg inhibited (26.7% remains) similar to free nerolidol 10 mg/kg (27.4% remains). Histological, quantification of pro-inflammatory and anti-inflammatory cytokines proves the same results. In conclusion the data suggests that nanoencapsulation of nerolidol improved its anti-inflammatory effect on arthritis in mice.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Portadores de Fármacos/química , Nanocápsulas/química , Sesquiterpenos/uso terapéutico , Animales , Articulación del Tobillo/efectos de los fármacos , Articulación del Tobillo/patología , Artritis Experimental/inducido químicamente , Artritis Reumatoide/inducido químicamente , Línea Celular Tumoral , Femenino , Ratones , Tamaño de la Partícula , Zimosan
3.
Drug Deliv ; 26(1): 1140-1154, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31736366

RESUMEN

The current study aimed to encapsulate fluvastatin sodium (FVS), a member of the statins family possessing pleiotropic effects in rheumatoid arthritis (RA), into spanlastic nanovesicles (SNVs) for transdermal delivery. This novel delivery could surmount FVS associated oral encumbrances such as apparent first-pass effect, poor bioavailability and short elimination half-life, hence, accomplishing platform for management of RA. To consummate this objective, FVS-loaded SNVs were elaborated by thin film hydration method, utilizing either Span 60 or Span 80, together with Tween 80 or Brij 35 as an edge activator according to full factorial design (24). Applying Design-Expert® software, the influence of formulation variables on SNVs physicochemical properties and the optimized formulation selection were explored. Additionally, the pharmacokinetic studies were scrutinized in rats. Furthermore, in Freund's adjuvant-induced arthritis, rheumatoid markers, TNF-α, IL-10, p38 MAPK, and antioxidant parameters were measured. The optimum SNVs were nano-scaled spherical vesicles (201.54 ± 9.16 nm), having reasonable entrapment efficiency (71.28 ± 2.05%), appropriate release over 8 h (89.45 ± 3.64%) and adequate permeation characteristics across the skin (402.55 ± 27.48 µg/cm2). The pharmacokinetic study disclosed ameliorated bioavailability of the optimum SNVs gel by 2.79- and 4.59-fold as compared to the oral solution as well as the traditional gel, respectively. Moreover, it elicited a significant suppression of p38 MAPK expression and also significant improvement of all other measured biomarkers. Concisely, the foregoing findings proposed that SNVs can be auspicious for augmenting FVS transdermal delivery for management of RA.


Asunto(s)
Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/tratamiento farmacológico , Fluvastatina/administración & dosificación , Adyuvante de Freund/farmacología , Transducción de Señal/efectos de los fármacos , Piel/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Administración Cutánea , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , Disponibilidad Biológica , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Femenino , Tamaño de la Partícula , Permeabilidad , Ratas , Ratas Wistar , Absorción Cutánea
4.
Curr Med Sci ; 39(5): 784-793, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31612397

RESUMEN

Huai Qi Huang (HQH) exerts great effects in clinic, such as anti-inflammation, immune-regulation, anti-cancer, and so on. However, the mechanism by which HQH protects juvenile idiopathic arthritis (JIA) is obscure. Thus, we explored deeply the protective mechanisms in juvenile collagen-induced arthritis (CIA) rat model. Pyroptosis is Gasdermin D (GSDMD)-dependent programmed cell death, involved in many diseases, such as sepsis. We investigated whether GSDMD-induced pyroptosis take part in mechanisms of juvenile CIA arthritis. Juvenile Wistar rats (3-4 weeks) were injected intradermally with fully emulsified bovine type II collagen and complete Freund's adjuvant to establish CIA rat models. Later, the CIA rats received oral administration of HQH (4.16 g/kg) once a day from the day 21 of modeling, with the treatment lasting for 28 days. Varieties of indicators were measured for evaluation of anti-inflammation effect of HQH, including hind paw swelling, arthritis scores, micro CT, and histopathological changes and the level of pro-inflammatory cytokines in the serum, including tumor necrosis factor alpha (TNF-±) and interleukin-18 (IL-18). The expression of GSDMD and caspase-1 in the joint synovial tissues was detected. The results demonstrated that the expression of the pyroptotic protein GSDMD and its upstream caspase-1 was significantly increased in the synovial tissues of CIA rats. The treatment of HQH ameliorated the symptoms in CIA rats, reduced levels of pro-inflammatory cytokines and hind paw swelling, down-regulated the expression of GDSMD and caspase-1. GSDMD-induced pyroptosis participated in the pathogenesis of CIA rats. The study supported that HQH can effectively improve joints inflammation of juvenile collagen-induced arthritis rats by inhibiting pyroptosis pathway in the joint synovial tissues.


Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Piroptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Administración Oral , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Artritis Experimental/inducido químicamente , Artritis Experimental/genética , Artritis Experimental/inmunología , Caspasa 1/genética , Caspasa 1/inmunología , Bovinos , Colágeno Tipo II/administración & dosificación , Esquema de Medicación , Miembro Posterior , Interleucina-18/genética , Interleucina-18/inmunología , Masculino , Piroptosis/genética , Ratas , Ratas Wistar , Membrana Sinovial , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Microtomografía por Rayos X
5.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3441-3447, 2019 Aug.
Artículo en Chino | MEDLINE | ID: mdl-31602907

RESUMEN

To observe the effect of Tripterygium Glycosides Tablets on angiogenesis of rats with type Ⅱ collagen-induced arthritis( CIA) and on the tube formation of human umbilical vein endothelial cells( HUVEC) in vitro. The HUVEC were induced by 20 µg·L-1 vascular endothelial growth factor( VEGF) in vitro,and were treated with 0. 1,1,10 mg·L-1 Tripterygium Glycosides Tablets continuously for 7 hours. The numbers of branches of tube formation were measured. SD rats were immunized to establish CIA. CIA rats were treated with 9,18,36 mg·kg-1·d-1 Tripterygium Glycosides Tablets for 42 days. Histopathological examination( HE) was performed to observe the vascular morphology and vascular density in the synovial membrane of the inflamed joints. Immunohistochemistry and immunofluorescence were performed to observe the expression of platelets-endothelial cell adhesion molecule( CD31) and αsmooth muscle actin( αSMA) in synovial membrane. Immunohistochemistry and Western blot were performed to observe the expression of hypoxia-inducible factors 1α( HIF1α) and angiotensin 1( Ang1) in the synovial tissue. The results showed that the numbers of branches of tube formation of HUVEC induced by VEGF were improved,and declined significantly after treated by Tripterygium Glycosides Tablets. Compared with the normal group,the vascular density,CD31 positive expression,CD31 +/αSMA-immature and total vascular positive expression in the synovial membrane of the model group were significantly increased,and so as HIF1α and Ang1 in the synovium. Tripterygium Glycosides Tablets reduced the synovial vascular density and inhibited the positive expression of CD31,CD31+/αSMA-immature blood vessels and total vascular,but has no effect on CD31+/αSMA+mature blood vessels. Tripterygium Glycosides Tablets also inhibited the expression of HIF1α and Ang1 in synovial membrane of inflammatory joints. Our results demonstrated that Tripterygium Glycosides Tablets could inhibit the angiogenesis of synovial tissue in CIA rats and the tube formation of HUVEC,which is related to the down-regulation of HIF1α/Ang1 signal axis.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Glicósidos/farmacología , Tripterygium/química , Inhibidores de la Angiogénesis/farmacología , Angiotensina I/metabolismo , Animales , Artritis Experimental/inducido químicamente , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Membrana Sinovial/efectos de los fármacos , Comprimidos , Factor A de Crecimiento Endotelial Vascular
6.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3486-3493, 2019 Aug.
Artículo en Chino | MEDLINE | ID: mdl-31602913

RESUMEN

The aim of this paper was to observe the toxic effect of Tripterygium Glycosides Tablets( TG) on the reproductive system of Ⅱ type collagen induced arthritis( CIA) male rats,and to explore the toxic mechanism preliminarily. Fifty SD rats were randomly divided into normal control group( Con),model group( CIA),Tripterygium Glycosides Tablets clinical equivalent dose groups of 1,2,4 times( 9,18,36 mg·kg-1),10 rats in each group,and were given by gavage once a day for 42 days after the first immunization.The organ indexes of uterine and ovarian were calculated on days 21 and 42. Histopathological and morphological changes of uterine and ovarian were observed under optical microscope. The concentration of estradiol( E2),follicle-stimulating hormone( FSH),luteinizing hormone( LH),17α-hydroxylase( CYP17 A1) and cytochrome P450 19 A1( CYP19 A1) in serum were detected by ELISA. Immunohistochemistry was used to observe the expression of Bax and Bcl-2 related proteins in the apoptosis pathway of uterus and ovary. The results showed that compared with the Con group,CIA group could reduce the number of uterine glands( P<0.05),but no significant changes were observed in other groups. Compared with the CIA group,there were no significant changes in the coefficients of uterus and ovary in the Tripterygium Glycosides Tablets groups. The number of uterine glands,total follicles in the ovary,mature follicles and corpus luteum,the distribution of blood vessels and mitochondria had a certain inhibitory trend,and also slightly increased the number of atresia follicles,but the histopathological quantitative indicators were not statistically different. Except that 2 times clinical dose of Tripterygium Glycosides Tablets could significantly reduce the content of CYP19 A1( P<0. 05) after 42 d administration,there were no significant changes in serum estrogen E2,FSH,LH and estrogen synthesis key enzymes CYP17 A1 in each administration group. Medium and high doses of Tripterygium Glycosides Tablets could increase the expression of apoptotic protein Bax in uterine and ovarian tissues( P<0. 05,P<0. 01),and all the administration groups could inhibit the expression of apoptotic inhibiting protein Bcl-2( P <0. 05,P<0. 01,P<0.001),42 d was more obvious than 21 d. In conclusion,4 times and less than 4 times Tripterygium Glycosides Tablets did not cause obvious toxicity and histopathological changes in the reproductive organs of CIA rats,but it could reduce the level of serum estrogen synthesis key enzyme CYP19 A1 and affect the content of apoptosis-related proteins Bax and Bcl-2 in uterus and ovary tissues. The relevant mechanism needs further study.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Medicamentos Herbarios Chinos/toxicidad , Genitales Femeninos/efectos de los fármacos , Glicósidos/toxicidad , Tripterygium/química , Animales , Apoptosis , Aromatasa/metabolismo , Artritis Experimental/inducido químicamente , Medicamentos Herbarios Chinos/farmacología , Femenino , Glicósidos/farmacología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Comprimidos
7.
Life Sci ; 238: 116956, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31622607

RESUMEN

AIMS: The aim of our study was to study the pathological mechanisms induced by the rheumatoid arthritis (RA) on the Enteric Nervous System (ENS). MAIN METHODS: We evaluated the effect of the chronic arthritis and its treatment with 50 mg/kg quercetin alone (AQ) and combined with 17.5 mg/kg ibuprofen (AIQ) for 60 days on neurons, glial cells and intestinal wall. Other groups were used: control (C), arthritic (A) and arthritic treated with 17.5 mg/kg ibuprofen (AI). After 60 days, the jejunum was removed and processed for immunohistochemical techniques. Immunostainings were performed for HuC/D and S100 (myenteric and submucosal plexuses), and GFAP (only myenteric plexus), while immunolabeling for CD45 and CD20 lymphocytes was performed using cryosections. Western blot was performed for GDNF, S100 and GFAP. KEY FINDINGS: A group yielded a remarkable density decrease of the neurons and glial cells with morphometric changes in the myenteric and submucosal plexuses, reduction of the GDNF expression and GFAP-related parameters (GFAP expression, occupancy area and GFAP-expressing glial cells) and intestinal inflammation and atrophy of the mucosa and intestinal wall. AQ group substantially reversed most of these effects, except for intestinal atrophy of the jejunum. The AI and AIQ groups displayed lower beneficial results than AQ for parameters related to the neurons and glial cells, although AIQ did not prevent the inflammation of the mucosa. SIGNIFICANCE: The severe chronic rheumatoid arthritis induced severe effects on ENS and mucosa, and quercetin treatment continues to be an important antioxidant supplement preventing the progression of the RA severity.


Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental/complicaciones , Artritis Reumatoide/complicaciones , Inflamación/tratamiento farmacológico , Yeyuno/efectos de los fármacos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Quercetina/farmacología , Animales , Antioxidantes/farmacología , Artritis Experimental/inducido químicamente , Sistema Nervioso Entérico/efectos de los fármacos , Sistema Nervioso Entérico/patología , Inflamación/etiología , Inflamación/patología , Yeyuno/inmunología , Yeyuno/patología , Masculino , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Neuroprotección/efectos de los fármacos , Ratas , Ratas Sprague-Dawley
8.
Life Sci ; 236: 116860, 2019 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-31518605

RESUMEN

AIMS: Intrathecal injection of morphine presents analgesic and antiedematogenic effects in rats. However, it is unknown whether tramadol, which possess a mixed mechanism of action, can also produce analgesic and antiedematogenic effects similarly. MAIN METHODS: Male Wistar rats received carrageenan and LPS in the right knee joint. Tramadol (10 µg) was injected intrathecally 20 min before articular LPS injection. Incapacitation and articular edema were measured 5 h after LPS stimulation. Synovial fluid was collected for leukocyte counting and western blot analysis. Whole joint and lumbar spinal cord were also collected for histology and immunohistochemistry, respectively. Intrathecal pretreatments groups were with the NKCC1 blocker bumetanide, TRPV1 agonist resiniferatoxin, µ-opioid receptor antagonist CTOP and serotonergic neurotoxin 5,7-DHT, all previously to tramadol. KEY FINDINGS: Tramadol treatment caused the reduction of incapacitation and edema. It also reduced c-Fos protein expression in the spinal cord dorsal horn and slightly reduced TNF-α levels in synovial fluid, but neither reduced cell migration nor tissue damage. Bumetanide and resiniferatoxin prevented the analgesic and antiedematogenic effects of tramadol. CTOP prevented the analgesic and the antiedematogenic effects, but 5,7-DHT prevented only tramadol-induced analgesia. SIGNIFICANCE: Spinal NKCC1 cotransporter and peptidergic peripheral afferents seem to be important for the analgesic and antiedematogenic effects of tramadol, as well as µ-opioid receptor. However, the monoamine uptake inhibition effect of tramadol seems to be important only to the analgesic effect.


Asunto(s)
Analgésicos Opioides/administración & dosificación , Artralgia/prevención & control , Artritis Experimental/complicaciones , Artritis Reactiva/complicaciones , Edema/prevención & control , Lipopolisacáridos/toxicidad , Tramadol/administración & dosificación , Animales , Artralgia/etiología , Artralgia/patología , Artritis Experimental/inducido químicamente , Artritis Experimental/fisiopatología , Artritis Reactiva/inducido químicamente , Artritis Reactiva/fisiopatología , Modelos Animales de Enfermedad , Edema/etiología , Edema/patología , Inyecciones Espinales , Masculino , Ratas , Ratas Wistar
9.
Chem Biodivers ; 16(9): e1900294, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31381811

RESUMEN

Bawei Longzuan granule (BLG) is a representative Zhuang medicine preparation. The present work aims to characterize the chemical constituents of BLG and evaluate its anti-arthritic activity. The major chemical constituents of BLG were tentatively identified by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), which revealed the presence of some alkaloids (e. g., magnoflorine, sinomenine and nitidine) and flavonoids (e. g., hesperidin, diosmin and sinensetin) that may be partly responsible for the anti-arthritic effect of BLG. In addition, the collagen-induced arthritis (CIA) model in rats was induced by intradermal injection of bovine collagen-II in complete Freund's adjuvant at the base of tail. The CIA rats received oral administration of BLG (1.25, 2.5 and 5 g/kg) for 30 days. Then, various indicators were determined to evaluate its anti-arthritic activity, including paw swelling, arthritic score, body weight, knee joint pathology, thymus index and spleen index. Additionally, the serum levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1ß, IL-6, IL-4 and IL-10 were measured to determine the underlying mechanisms. The results showed that BLG efficiently ameliorated the severity of arthritis in CIA rats by decreasing paw swelling and arthritis score and improving the histological lesions of knee joint. Moreover, the serum levels of several pro-inflammatory cytokines (i. e., IL-1ß, TNF-α, IL-6 and IFN-γ) were downregulated, whereas two anti-inflammatory factors (i. e., IL-4 and IL-10) were upregulated after BLG administration. These results indicated that BLG possessed promising therapeutic effect on collagen-induced arthritis by inhibiting inflammatory responses. BLG can be used as a complementary or alternative traditional medicine to treat rheumatoid arthritis.


Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Medicamentos Herbarios Chinos/farmacología , Inflamación/tratamiento farmacológico , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/metabolismo , Colágeno , Citocinas/metabolismo , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Inflamación/metabolismo , Masculino , Medicina China Tradicional , Ratas , Ratas Wistar
10.
J Biochem Mol Toxicol ; 33(9): e22373, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31364231

RESUMEN

The purpose of the experiment was to study the effects of betulinic acid (BA) on adjuvant-induced arthritis in rats. The rat model of rheumatoid arthritis (AA) was established by Freund's complete adjuvant. Arthritis index, joint pathology, toe swelling, hemorheology, related cytokines and ROCK/NF-κB signaling pathway were measured in rats. BA can significantly inhibit the arthritis index, improve joint pathology, reduce toe swelling, improve blood rheology, improve synovial cell apoptosis, and restore related cytokine negative regulation of ROCK/NF-κB signaling pathways. BA has an obvious therapeutic effect on joint inflammation of toes in AA model rats, which may be due to the regulation of ROCK/NF-κB signaling pathway.


Asunto(s)
Artritis Experimental/prevención & control , Adyuvante de Freund/toxicidad , Polisacáridos/farmacología , Esteroles/farmacología , Triterpenos/farmacología , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos
11.
BMC Vet Res ; 15(1): 309, 2019 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-31464629

RESUMEN

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are an important tool in the management of canine osteoarthritis, with the most recent introduction into the category being grapiprant, a piprant that selectively targets the EP4 prostaglandin receptor. To date there have been no efficacy studies comparing grapiprant with other NSAIDs. A randomized, two-sequence, assessor-blinded study involving two separate experiments was undertaken to measure the potency and persistence of acute pain control over 24 h resulting from a single oral dose of either firocoxib (Previcox®) or grapiprant (Galliprant®) in an acute arthritis model. RESULTS: Force-plate derived lameness ratios (0, no force recorded on the plate; 1, normal force) for the untreated group remained at 0 for most post-arthritis induction (PAI) assessments in both experiments. Throughout Experiment 1, mean PAI lameness ratios of the firocoxib-treated group remained at or above 0.80. In the grapiprant-treated group, ratios were 0 at 5 and 7 h PAI (7 and 9 h post-treatment), and 0.16 at 10 h PAI (12 h post-treatment). For lameness ratios, relative to the firocoxib group, the control and grapiprant group ratios were significantly lower at each PAI assessment (p ≤ 0.026 and p < 0.001, respectively), except at 1.5 h PAI at which acute pain was still not installed in untreated control dogs. In Experiment 2 the mean lameness ratios for the control group were 0 at 3, 5 and 7 h PAI, and in the grapiprant group at 5, 7 and 10 h PAI (i.e., 19, 21, and 24 h post-treatment). In the firocoxib group the lowest mean lameness ratio of 0.36 occurred at 3 h PAI (i.e. 17 h post-treatment). Except at 1.5 and 3 h PAI (i.e. 15.5 and 17 h post-treatment), due to the needed time for pain to install in the untreated control dogs, the lameness ratio differences between the firocoxib and both the control and grapiprant groups were significant at all assessments (p ≤ 0.033 for both groups). No significant differences were detected between the grapiprant and control groups in either experiment. CONCLUSIONS: Firocoxib treatment prior to induction of arthritis in dogs resulted in a high level of analgesia from the first post-treatment assessment at 1.5 h through 24 h post-treatment. The reduction in lameness provided by firocoxib was consistently superior to that provided by grapiprant, which was not significantly different from untreated controls.


Asunto(s)
4-Butirolactona/análogos & derivados , Artritis Experimental/veterinaria , Enfermedades de los Perros/tratamiento farmacológico , Sulfonas/uso terapéutico , Compuestos de Sulfonilurea/uso terapéutico , 4-Butirolactona/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Perros , Cojera Animal , Distribución Aleatoria , Ácido Úrico/toxicidad
12.
Phytomedicine ; 63: 153006, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31299594

RESUMEN

BACKGROUND: Bone destructive diseases like rheumatoid arthritis (RA), osteoporosis and bone metastatic tumors are mainly mediated by over-activated osteoclasts. Asperosaponin VI (AVI), isolated from the rhizome of Dipsacus asper, belongs to triterpenoid saponins. It has multiple physiological activities but its effects on RA, especially on osteoclast differentiation and activation are still unclear. PURPOSE: Explore the protective role of AVI on collagen induced arthritis (CIA) in vivo and RANKL induced osteoclastogenesis in vitro. METHODS: The effects of AVI on cell viability and RANKL-induced osteoclastogenesis, actin ring formation, bone resorption activity as well as on osteoclast specific gene and protein expression were tested using bone marrow derived monocytes (BMMs). Paws from CIA mice were used for micro-CT, HE and TRAP staining, real-time PCR and western blot. Sera were used for cytokine analysis by ELISA. The signaling pathways were detected using western blot, real-time PCR and immunofluorescence assay. RESULTS: AVI significantly inhibited RANKL-induced osteoclast formation and bone resorption activity by suppressing the formation of actin ring. It also inhibited the expression of various osteoclatogenesis marker genes and signaling pathways. AVI protected arthritis in vivo by suppressing inflammation and bone loss. CONCLUSION: AVI exerts its anti-osteoclastogenic activity both in vitro and in vivo by inhibiting RANKL-induced osteoclast differentiation and function. Thus, our studies demonstrate a potential therapeutic role for AVI in preventing or inhibiting RANKL-mediated osteolytic bone diseases.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Saponinas/farmacología , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Resorción Ósea/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Colágeno/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Osteoclastos/patología , Osteogénesis/fisiología , Ligando RANK/metabolismo , Ligando RANK/toxicidad , Transducción de Señal/efectos de los fármacos
13.
BMC Musculoskelet Disord ; 20(1): 335, 2019 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-31324245

RESUMEN

BACKGROUND: Previous basic research and clinical studies examined the effects of mesenchymal stem cells (MSCs) on regeneration and maintenance of articular cartilage. However, our pilot study suggested that MSCs are more effective at suppressing inflammation and pain rather than promoting cartilage regeneration in osteoarthritis. Adipose tissue is considered a useful source of MSCs; it can be harvested easily in larger quantities compared with the bone marrow. The present study was designed to evaluate the anti-inflammatory, analgesic, and regenerative effects of intra-articularly injected processed lipoaspirate (PLA) cells (containing adipose-derived MSCs) on degenerative cartilage in a rat osteoarthritis model. METHODS: PLA cells were isolated from subcutaneous adipose tissue of 12-week-old female Sprague-Dawley rats. Osteoarthritis was induced by injection of monoiodoacetate (MIA). Each rat received 1 × 106 MSCs into the joint at day 7 (early injection group) and day 14 (late injection group) post-MIA injection. At 7, 14, 21 days after MIA administration, pain was assessed by immunostaining and western blotting of dorsal root ganglion (DRG). Cartilage quality was assessed macroscopically and by safranin-O and H&E staining, and joint inflammation was assessed by western blotting of the synovium. RESULTS: The early injection group showed less cartilage degradation, whereas the late injection group showed cartilage damage similar to untreated OA group. The relative expression level of CGRP protein in DRG neurons was significantly lower in the two treatment groups, compared with the untreated group. CONCLUSIONS: Intra-articular injection of PLA cells prevented degenerative changes in the early injection group, but had little effect in promoting cartilage repair in the late injection group. Interestingly, intra-articular injection of PLA cells resulted in suppression of inflammation and pain in both OA groups. Further studies are needed to determine the long-term effects of intra-articular injection of PLA cells in osteoarthritis.


Asunto(s)
Artralgia/terapia , Artritis Experimental/terapia , Cartílago Articular/patología , Trasplante de Células Madre Mesenquimatosas/métodos , Osteoartritis/terapia , Tejido Adiposo/citología , Animales , Artralgia/diagnóstico , Artralgia/etiología , Artritis Experimental/inducido químicamente , Biomarcadores/análisis , Femenino , Ganglios Espinales/patología , Humanos , Inyecciones Intraarticulares , Ácido Yodoacético/toxicidad , Articulación de la Rodilla/inervación , Articulación de la Rodilla/patología , Osteoartritis/inducido químicamente , Osteoartritis/patología , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento
14.
Physiol Int ; 106(2): 128-139, 2019 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-31262206

RESUMEN

AIM: This study aimed to evaluate the possible role of heat shock protein-70 (HSP70) induction by 17-allylaminodemethoxygeldanamycin (17-AAG) in collagen-induced arthritis in rats. MATERIAL AND METHODS: Male Wistar rats were divided into five groups (n = 10/group) and were treated intraperitoneally twice a week for 4 weeks, namely normal control (saline), arthritis control (AR; saline), AR + 17-AAG, AR + methotrexate (MTX), and AR + 17-AAG + MTX. At the end of the treatments, arthritic score was determined and then the animals were sacrificed. Erythrocyte sedimentation rate (ESR), serum levels of HSP70, interleukin-17 (IL-17), tumor necrosis factor-alpha (TNF-α), rheumatic factor (RF), C-reactive protein (CRP), malondialdehyde (MDA), glutathione peroxidase (GPx), and matrix metalloproteinase-9 (MMP-9) were determined. RESULTS: In the AR group, all parameters increased significantly, except for GPx, which showed a pronounced decrease. The 17-AAG and/or MTX treatments significantly reduced arthritic score, ESR, IL-17, TNF-α, RF, CRP, MDA, and MMP-9 with significant increase in GPx compared to the AR group. The HSP70 level was significantly higher in the AR + 17-AAG and the AR + 17-AAG + MTX groups but significantly lower in the AR + MTX group as compared to the AR group. Also, it was significantly lower in the AR + MTX group as compared to the AR + 17-AAG group. CONCLUSION: We concluded that HSP70 induction by 17-AAG attenuated the inflammatory process in a rheumatoid arthritis (RA) model induced by collagen, which suggested that HSP70 inducers can be promising agents in the treatment of RA.


Asunto(s)
Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/metabolismo , Colágeno/farmacología , Proteínas HSP70 de Choque Térmico/metabolismo , Animales , Sedimentación Sanguínea/efectos de los fármacos , Proteína C-Reactiva/metabolismo , Glutatión Peroxidasa/metabolismo , Interleucina-17/metabolismo , Masculino , Malondialdehído/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metotrexato/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo
15.
Pak J Pharm Sci ; 32(3 (Supplementary)): 1167-1173, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-31303586

RESUMEN

Medicinal plants are playing an imperative role in the therapy for treating various chronic ailments including arthritis. The present study was focused on finding in-vitro and in-vivo anti-arthritic potential of P. braunii roots. In vitro protein denaturation, membrane stabilization and anti-trypsinase assays were carried out to demonstrate anti-arthritic activity of the extracts. Furthermore, the extracts exerting promising in vitro anti-arthritic potential were tested orally at 150, 300 and 600mg/kg/day against formaldehyde induced arthritis in Wistar rats. The methanolic, aqueous and ethyl acetate extracts of the plant revealed noteworthy in vitro anti-arthritic activities while mitigating formaldehyde induced paw edema in dose dependent manner. Methanolic and aqueous extracts showed the highest inhibition (p<0.05) of paw edema, arthritic indices, reduced elevated level of platelets and leukocytes while increasing hemoglobin and body weight of arthritic rats. Anti-arthritic activity of the plant extracts may be due to inhibition of protein denaturation and lysosomal membrane stabilization. The plant exhibited good anti-arthritic potential.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Extractos Vegetales/farmacología , Plantas Medicinales/química , Polystichum/química , Albúminas/química , Albúminas/efectos de los fármacos , Animales , Artritis Experimental/inducido químicamente , Evaluación Preclínica de Medicamentos , Membrana Eritrocítica/efectos de los fármacos , Femenino , Formaldehído/toxicidad , Humanos , Masculino , Medicina Tradicional de Asia Oriental , Pakistán , Extractos Vegetales/química , Raíces de Plantas/química , Desnaturalización Proteica/efectos de los fármacos , Ratas Wistar , Albúmina Sérica Bovina/efectos de los fármacos
16.
Artículo en Inglés | MEDLINE | ID: mdl-31245305

RESUMEN

Rheumatoid arthritis (RA) is a common autoimmune disease linked to chronic inflammation. Dysbiosis of the gut microbiota has been proposed to contribute to the risk of RA, and a large number of researchers have investigated the gut-joint axis hypothesis using the collagen-induced arthritis (CIA) rats. However, previous studies mainly involved short-term experiments; very few used the CIA model to investigate changes in gut microbiota over time. Moreover, previous research failed to use the CIA model to carry out detailed investigations of the effects of drug treatments upon inflammation in the joints, hyperplasia of the synovium, imbalance in the ratios of Th1/Th2 and Th17/Treg cells, intestinal cytokines and the gut microbiota following long-term intervention. In the present study, we carried out a 16-week experiment to investigate changes in the gut microbiota of CIA rats, and evaluated the modulatory effect of total glucosides of paeony (TGP), an immunomodulatory agent widely used in the treatment of RA, after 12 weeks of administration. We found that taxonomic differences developed in the microbial structure between the CIA group and the Control group. Furthermore, the administration of TGP was able to correct 78% of these taxonomic differences, while also increase the relative abundance of certain forms of beneficial symbiotic bacteria. By the end of the experiment, TGP had reduced body weight, thymus index and inflammatory cell infiltration in the ankle joint of CIA rats. Furthermore, the administration of TGP had down-regulated the synovial content of VEGF and the levels of Th1 cells and Th17 cells in CIA rats, and up-regulated the levels of Th2 cells and Treg cells. The administration of TGP also inhibited the levels of intestinal cytokines, secretory immunoglobulin A (SIgA) and Interferon-γ (IFN-γ). In conclusion, the influence of TGP on dynamic changes in gut microbiota, along with the observed improvement of indicators related to CIA symptoms during 12 weeks of administration, supported the hypothesis that the microbiome may play a role in TGP-mediated therapeutic effects in CIA rats. The present study also indicated that the mechanism underlying these effects may be related to the regulation of intestinal mucosal immunity remains unknown and deserves further research attention.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Colágeno/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Glucósidos/farmacología , Paeonia/química , Animales , Articulación del Tobillo/patología , Artritis Experimental/inducido químicamente , Artritis Experimental/patología , Artritis Reumatoide/tratamiento farmacológico , Bacterias/clasificación , Bacterias/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Disbiosis , Heces/microbiología , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiología , Inmunidad , Inmunidad Mucosa , Inmunoglobulina A Secretora , Inmunomodulación , Inflamación , Interferón gamma/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Simbiosis , Linfocitos T Reguladores/efectos de los fármacos , Células TH1/efectos de los fármacos , Células Th17/efectos de los fármacos , Células Th2/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular
17.
J Avian Med Surg ; 33(2): 133-140, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-31251500

RESUMEN

The purpose of this study was to determine the efficacy of tramadol and meloxicam in an induced, temporary arthritis model in ducks as assessed by ground-reactive forces measured by a pressure-sensitive walkway (PSW) system. Twelve ducks (Cairina moschata domestica) were randomly separated into 3 equal groups of 4 birds each: water control, tramadol treatment, and meloxicam treatment. Baseline measurements were collected by having all ducks walk along a 3-m-long PSW in a custom-built corral before anesthesia and induction of arthritis. Arthritis was induced in all groups through injection, under anesthesia, of a 3% monosodium urate (MSU) solution into the intertarsal joint. One hour after MSU injection, birds were orally gavage fed 1 mL of tap water (control), tramadol (30 mg/kg), or meloxicam (1 mg/kg). After treatments, all ducks were reevaluated on the PSW at 1, 2, 3, 4, 8, and 24 hours post-MSU injection. The difference in maximum force was significantly greater in the control group than in both the tramadol- (P = .006) and meloxicam-treated (P = .03) individuals. Post hoc comparisons revealed differences between control and treated birds occurred only at the 3- and 4-hour time points after administration. No differences were found in the absolute difference in maximum force between tramadol- and meloxicam-treated birds at any time point (P > .05). Results of this study support the hypothesis that tramadol (30 mg/kg PO) and meloxicam (1 mg/kg PO) improve certain objective variables in an induced arthritis model in ducks. Our findings also support studies in other avian species that determined that both tramadol and meloxicam are effective analgesic drugs in some birds.


Asunto(s)
Artritis Experimental/veterinaria , Patos , Meloxicam/uso terapéutico , Tramadol/uso terapéutico , Analgésicos Opioides/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Ácido Úrico/toxicidad , Caminata
18.
Inflammopharmacology ; 27(4): 845-856, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31165333

RESUMEN

Previously, ginsenoside metabolite compound K (C-K) was able to reduce B cell proliferation and serum anti-type II collagen (anti-CII) antibody to normal levels in mice with collagen-induced arthritis (CIA); however, the mechanism by which C-K restores B cell balance is unclear. In the present work, C-K treatment not only alleviated the polyarthritis index, swollen joint count, pathological scores of spleen and joints, spleen index, B cell proliferation and the level of serum antibodies (IgG1, IgG2a and anti-collagen II), but C-K treatment also restored B cell subsets including regulatory B cells, plasma cells, memory B cells, mature B cells, and follicular B cells in CIA mice. Interestingly, C-K did not change the expression level of immunoglobulin D-type B-cell receptor (IgD-BCR) but promoted IgD-BCR endocytosis. C-K treatment enhanced ß-arrestin1 expression, facilitating the colocalization between IgD and ß-arrestin1, as well as colocalization between IgD and adaptor protein 2 (AP2). Inhibition of the ß-arrestin1-AP2 interaction with barbadin significantly reduced the ability of C-K to attenuate IgD-BCR plasma membrane localization. These results taken together depict that C-K ameliorates CIA in part by inhibiting B cell activation through the triggering of IgD-BCR internalization in a ß-arrestin1-AP2 dependent manner.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Linfocitos B/efectos de los fármacos , Endocitosis/efectos de los fármacos , Ginsenósidos/farmacología , Inmunoglobulina D/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Complejo 2 de Proteína Adaptadora/metabolismo , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Linfocitos B/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Colágeno/farmacología , Inmunoglobulina G/metabolismo , Articulaciones/efectos de los fármacos , Articulaciones/metabolismo , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Bazo/efectos de los fármacos , Bazo/metabolismo , beta-Arrestina 1/metabolismo
19.
Int J Rheum Dis ; 22(7): 1247-1254, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31155849

RESUMEN

AIM: The purpose of our investigation is to evaluate the anti-arthritic potential of isolated rosmarinic acid from the rind of Punica granatum. METHOD: Rosmarinic acid was isolated by bioactivity-guided isolation from butanolic fraction of Punica granatum and acute toxicity of rosmarinic acid was carried out. The experiment was conducted at doses of 25 and 50 mg/kg, in Freund's complete adjuvant (FCA)-induced arthritic rats. Various parameters, that is arthritic score, paw volume, thickness of paw, hematological, antioxidant and inflammatory parameters such as glutathione (GSH), superoxide dismutase (SOD), malonaldehyde (MDA) and tumor necrosis factor-α (TNF-α) were also estimated. RESULTS: Rosmarinic acid significantly decreased the arthritic score, paw volume, joint diameter, white blood cell count and erythrocyte sedimentation rate. It also significantly increased body weight, hemoglobin and red blood cells. The significantly decreased levels of TNF-α were observed in treated groups as compared to arthritic control rats (P < 0.001). At the same time antioxidant parameters (like GSH and SOD) were increased significantly while levels of MDA were significantly decreased (P < 0.001). CONCLUSION: The outcome of the present research concludes that rosmarinic acid showed significant anti-arthritic potential in FCA-induced arthritis in Wistar rats. This study represented the therapeutic role of rosmarinic acid from Punica granatum for the management of arthritis/rheumatoid arthritis/osteoarthritis and related inflammatory complications with negligible side effects which was still far from complete mitigation with available conventional medicines.


Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental/prevención & control , Cinamatos/farmacología , Depsidos/farmacología , Adyuvante de Freund , Articulaciones/efectos de los fármacos , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Artritis Experimental/patología , Glutatión/metabolismo , Mediadores de Inflamación/sangre , Articulaciones/metabolismo , Articulaciones/patología , Malondialdehído/metabolismo , Ratas Wistar , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/sangre
20.
Inflammation ; 42(5): 1595-1610, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31102126

RESUMEN

We analyzed the effects of a nanoencapsulated association of curcumin and vitamin D3 on purine metabolism enzymes in neutrophils, lymphocytes, and platelets in a model of adjuvant-induced arthritis (AIA) in rats. Following AIA induction, the animals were treated for 15 days with free and nanoencapsulated curcumin (4 mg/kg), nanocapsules of vitamin D3 (VD3) (15.84 IU/day), a nanoencapsulated combination of curcumin and VD3, vehicle, or blank nanocapsules. The animals were euthanized, and blood was collected to evaluate the activities of E-NTPDase, adenosine deaminase (ADA), and myeloperoxidase (MPO), as well as reactive oxygen species (ROS) levels and biochemical parameters. Also, the liver and kidney were collected for histological analysis. The changes in the activities of purinergic enzymes indicated that inflammation was significantly reverted by vitamin D3 and curcumin co-nanoencapsulation treatments in the arthritic rats. The reduction of inflammation was confirmed by the reduction in the signs and symptoms of AIA, as well as in MPO activity by all formulations. The treatments with nanocapsules reverted histological alterations in the kidney. Serum parameters were not altered by the induction or treatments. Our results suggest that co-nanoencapsulation of vitamin D3 and curcumin is an efficient alternative adjuvant treatment for rheumatoid arthritis as it reverts the changes in the purine metabolism and reduces arthritis-associated inflammation.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Colecalciferol/uso terapéutico , Curcumina/uso terapéutico , Inflamación/prevención & control , Purinas/metabolismo , Animales , Artritis Experimental/inducido químicamente , Cápsulas , Combinación de Medicamentos , Linfocitos/metabolismo , Neutrófilos/metabolismo , Ratas
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