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1.
Zhonghua Nei Ke Za Zhi ; 59(1): 47-51, 2020 Jan 01.
Artigo em Chinês | MEDLINE | ID: mdl-31887836

RESUMO

Objective: To study the influences of dihydrotestosterone (DHT) on the development of experimental autoimmune Graves disease (EAGD), and to observe the effect of DHT on cytokines in male BALB/c mice model. Methods: Male BALB/c mice aged 6-8 weeks were divided into 4 groups using random number table: (1) control group; (2) EAGD group; (3) placebo group; (4) DHT group. EAGD mice were induced with an adenovirus expressing the human thyroid stimulating hormone receptor antibody A-subunit (Ad-TSHR289). DHT (5mg) or a matching placebo were implanted one week before the first immunization. Thyroid hormones were detected with radioimmunoassay kit.. Cytokines [such as interferonγ (IFNγ), interleukin (IL)-4, IL-10, IL-9, and IL-17] producing cells from the spleen were detected using flow cytometry. Results: As expected Ad-TSHR289 treatment increased total thyroxine [EAGD group vs. control group: (117.76±32.69) nmol/L vs. (33.08±12.61) nmol/L, P<0.0001] and free thyroxine [EAGD group vs. control group: (15.01±11.55) pmol/L vs. (3.55±1.88) pmol/L, P<0.0001]. Treatment of DHT slightly lowered thyroid hormones [DHT group vs. placebo group: total thyroxine (114.80±44.27) nmol/L vs. (123.17±77.73) nmol/L; free thyroxine (13.48±6.01) pmol/L vs. (14.19±12.65) pmol/L], without significant difference (all P>0.05)]. However, the percentage of IL-10, but not IFN γ, IL-4, IL-9 and IL-17, secreted spleen cells increased in DHT group than in the placebo group [(7.11±3.29)% vs. (3.51±1.36)%, P<0.05]. Conclusion: The effects of DHT on thyroid hormone are mild. It might play an immunomodulatory role in the male mouse Graves disease model by up-regulating the cytokine IL-10.


Assuntos
Citocinas/efeitos dos fármacos , Di-Hidrotestosterona/farmacologia , Doença de Graves , Animais , Humanos , Interferon gama , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória
2.
J Environ Pathol Toxicol Oncol ; 38(3): 229-238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679310

RESUMO

Asthma has affected more than 300 million people worldwide and is considered one of the most debilitating global public health problems based on a recent statistical report from the Global Initiative for Asthma. Inflammation of the airways leads to the various interrelated mechanisms of innate and adaptive immunity acting mutually with the epithelium of the respiratory organ. Fucoxanthin is an orange or brown pigment which is naturally found in various seaweeds. To the best of our knowledge, there are no scientific claims or evidence of the curative effects of fucoxanthin against asthma. Hence, this present research was designed to investigate the curative activity of fucoxanthin against ovalbumin-induced asthma in a mouse model. Fucoxanthin (50 mg/kg) showed significant (P < 0.001) antiasthma activity. It effectively decreased intracellular secretion of reactive oxygen species and increased antioxidant enzyme activity. Fucoxanthin also decreased inflammatory cytokine markers in bronchoalveolar lavage fluid. Because fucoxanthin showed effective antiasthma activity against ovalbumin-induced asthma in experimental animals, further research on this natural antioxidant could lead to development of a novel drug for the treatment of asthma in humans.


Assuntos
Antiasmáticos/farmacologia , Antioxidantes/metabolismo , Asma/tratamento farmacológico , Citocinas/imunologia , Inflamação/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Xantofilas/farmacologia , Animais , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar/química , Citocinas/efeitos dos fármacos , Inflamação/induzido quimicamente , Masculino , Camundongos , Ovalbumina/toxicidade
3.
Medicine (Baltimore) ; 98(42): e17450, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626100

RESUMO

BACKGROUND: Cerebral aneurysm surgery has significant mortality and morbidity rate. Inflammation plays a key role in the pathogenesis of intracranial aneurysms, their rupture, subarachnoid hemorrhage and neurologic complications. Proinflammatory cytokine level in blood and cerebrospinal fluid (CSF) is an indicator of inflammatory response. Cytokines contribute to secondary brain injury and can worsen the outcome of the treatment. Lidocaine is local anesthetic that can be applied in neurosurgery as regional anesthesia of the scalp and as topical anesthesia of the throat before direct laryngoscopy and endotracheal intubation. Besides analgesic, lidocaine has systemic anti-inflammatory and neuroprotective effect.Primary aim of this trial is to determine the influence of local anesthesia with lidocaine on the perioperative levels of pro-inflammatory cytokines interleukin-1ß, interleukin-6, and tumor necrosis factor-α in plasma and CSF in cerebral aneurysm patients. METHODS: We will conduct prospective randomized clinical trial among patients undergoing craniotomy and cerebral aneurysm clipping surgery in general anesthesia. Patients included in the trial will be randomly assigned to the lidocaine group (Group L) or to the control group (Group C). Patients in Group L, following general anesthesia induction, will receive topical anesthesia of the throat before endotracheal intubation and also regional anesthesia of the scalp before Mayfield frame placement, both done with lidocaine. Patients in Group C will have general anesthesia only without any lidocaine administration. The primary outcomes are concentrations of cytokines interleukin-1ß, interleukin-6 and tumor necrosis factor-α in plasma and CSF, measured at specific timepoints perioperatively. Secondary outcome is incidence of major neurological and infectious complications, as well as treatment outcome in both groups. DISCUSSION: Results of the trial could provide insight into influence of lidocaine on local and systemic inflammatory response in cerebrovascular surgery, and might improve future anesthesia practice and treatment outcome. TRIAL IS REGISTERED AT CLINICALTRIALS.GOV:: NCT03823482.


Assuntos
Anestesia Local/métodos , Anestésicos Locais/administração & dosagem , Citocinas/efeitos dos fármacos , Aneurisma Intracraniano/cirurgia , Lidocaína/administração & dosagem , Adolescente , Adulto , Idoso , Anestesia por Condução/métodos , Anestesia Geral/métodos , Craniotomia/métodos , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Feminino , Humanos , Aneurisma Intracraniano/sangue , Aneurisma Intracraniano/líquido cefalorraquidiano , Intubação Intratraqueal/métodos , Laringoscopia/métodos , Masculino , Pessoa de Meia-Idade , Faringe , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Couro Cabeludo , Resultado do Tratamento , Adulto Jovem
4.
Molecules ; 24(17)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461974

RESUMO

Within non-communicable diseases, chronic inflammatory conditions represent one of the biggest challenges for modern medicine. Traditional Chinese Medicine (TCM) has been practiced over centuries and has accumulated tremendous empirical knowledge on the treatment of such diseases. Huangqi Jianzhong Tang (HQJZT) is a famous TCM herbal formula composed of Radix Astragali, Ramulus Cinnamomi, Radix et Rhizoma Glycyrrhizae Praeparata cum Melle, Radix Paeoniae Alba, Rhizoma Zingiberis Recens, Fructus Jujubae and Saccharum Granorum (maltose), which has been used for the treatment of various chronic inflammatory gastrointestinal diseases. However, there is insufficient knowledge about its active constituents and the mechanisms responsible for its effects. The present study aimed at identifying constituents contributing to the bioactivity of HQJZT by combining in vitro cytokine production assays and LC-MS metabolomics techniques. From the HQJZT decoction as well as from its single herbal components, extracts of different polarities were prepared. Phytochemical composition of the extracts was analyzed by means of UPLC-QTOF-MS/MS. The inhibitory effects of the extracts on TNF-α, IL-1ß and IFN-γ production were studied in U937 cells. Phytochemical and pharmacological bioactivity data were correlated by orthogonal projection to latent structures discriminant analysis (OPLS-DA) in order to identify those HQJZT constituents which may be relevant for the observed pharmacological activities. The investigations resulted in the identification of 16 HQJZT constituents, which are likely to contribute to the activities observed in U937 cells. Seven of them, namely calycosin, formononetin, astragaloside I, liquiritigenin, 18ß-glycyrrhetinic acid, paeoniflorin and albiflorin were unambiguously identified. The predicted results were verified by testing these compounds in the same pharmacological assays as for the extracts. In conclusion, the anti-inflammatory activity of HQJZT could be substantiated by in vitro pharmacological screening, and the predicted activities of the OPLS-DA hits could be partially verified. Moreover, the benefits and limitations of MVDA for prediction pharmacologically active compounds contributing to the activity of a TCM mixture could be detected.


Assuntos
Anti-Inflamatórios/química , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/química , Lipopolissacarídeos/efeitos adversos , Metabolômica/métodos , Anti-Inflamatórios/farmacologia , Cromatografia Líquida , Citocinas/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Interleucina-1beta/metabolismo , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa/metabolismo , Células U937
5.
Saudi Med J ; 40(7): 657-668, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31287125

RESUMO

OBJECTIVES: To investigate the use of leukocyte-platelet rich fibrin on suppressing the porphyromonas gingivalis (PG-LPS)-induced secretion of proinflammatory cytokines. Methods:This quantitative experimental study was conducted at the School and Hospital of Stomatology, Jilin University, Changchun, China, between September 2017 and January 2019. A modified technique was used to obtain human gingival fibroblast cells (HGFCs). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Cell Counting Kit-8 tests were established to determine the proliferation rate. Human gingival fibroblast cells were treated by PG-LPS at different periods and the isolated mRNA was subjected to reverse transcription polymerase chain reaction and real time quantitative polymerase chain reaction. The release of platelet-derived growth factor and transforming-growth factor-ß1 at various time intervals was observed. Results: We successfully established a modified technique for the production of HGFCs culture. One µg/mL PG-LPS was the recommended concentration to inhibit fibroblast proliferation. The expression of the pro-inflammatory cytokines messenger ribnucleic acid was notably raised at 3 and 6 hours post-PG-LPS treatment. The cumulative release of growth factors peaked during the first 24 hours and the production continued for 10 days. However, the fibroblast expression of cytokines was significantly suppressed after treatment with leucocyte- and platelet-rich fibrin (L-PRF). Conclusion: This study provided a novel way of obtaining HGFCs and greater understanding of the clinical impacts through the assessment of the anti-inflammatory properties of L-PRF in vitro.


Assuntos
Citocinas/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Fibrina Rica em Plaquetas , Porphyromonas gingivalis/metabolismo , Estomatite , Animais , Técnicas de Cultura de Células , Proliferação de Células , Citocinas/genética , Citocinas/imunologia , Fibroblastos/imunologia , Gengiva/citologia , Humanos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Coelhos , Reação em Cadeia da Polimerase em Tempo Real
6.
J Appl Oral Sci ; 27: e20180529, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31166413

RESUMO

OBJECTIVES: Dental composites release unreacted resin monomers into the oral environment, even after polymerization. Periodontal cells are, therefore, exposed to substances that potentially elicit the immune inflammatory response. The underlying molecular mechanisms associated with the interaction between resin monomers and human immune cells found in the gingival crevicular fluid are not fully understood yet. This study investigated the ability of bisphenol A-glycidyl methacrylate (BISGMA), urethane dimethacrylate (UDMA) and triethylene glycol dimethacrylate (TEGDMA) to induce apoptosis and cytokine release by human leukocytes stimulated with a periodontal pathogen. METHODOLOGY: Peripheral blood mononuclear cells (PBMC) from 16 healthy individuals were included in this study. To determine the toxicity, the PBMC were incubated for 20 hours, with monomers, for the analysis of cell viability using MTT assay. To evaluate cell death in the populations of monocytes and lymphocytes, they were exposed to sub-lethal doses of each monomer and of heat-inactivated Porphyromonas gingivalis (P. gingivalis) for 5 hours. Secretions of IL-1ß, IL-6, IL-10 and TNF-α were determined by ELISA after 20 hours. RESULTS: UDMA and TEGDMA induced apoptosis after a short-time exposure. Bacterial challenge induced significant production of IL-1ß and TNF-α (p<0.05). TEGDMA reduced the bacterial-induced release of IL-1ß and TNF-α, whereas UDMA reduced IL-1ß release (p<0.05). These monomers did not affect IL-10 and IL-6 secretion. BISGMA did not significantly interfere in cytokine release. CONCLUSIONS: These results show that resin monomers are toxic to PBMC in a dose-dependent manner, and may influence the local immune inflammatory response and tissue damage mechanisms via regulation of bacterial-induced IL-1ß and TNF-α secretion by PBMC.


Assuntos
Bis-Fenol A-Glicidil Metacrilato/farmacologia , Citocinas/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Metacrilatos/farmacologia , Polietilenoglicóis/farmacologia , Ácidos Polimetacrílicos/farmacologia , Poliuretanos/farmacologia , Porphyromonas gingivalis/fisiologia , Análise de Variância , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/análise , Citocinas/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Humanos , Leucócitos Mononucleares/metabolismo , Necrose , Valores de Referência , Reprodutibilidade dos Testes , Estatísticas não Paramétricas , Fatores de Tempo
7.
J Neuroinflammation ; 16(1): 124, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186006

RESUMO

BACKGROUND: Spinal cord injury (SCI) usually causes a devastating lifelong disability for patients. After a traumatic lesion, disruption of the blood-spinal cord barrier induces the infiltration of macrophages into the lesion site and the activation of resident glial cells, which release cytokines and chemokines. These events result in a persistent inflammation, which has both detrimental and beneficial effects, but eventually limits functional recovery and contributes to the appearance of neuropathic pain. Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that regulate the expression of inflammatory genes by interacting with acetylated lysine residues. While BET inhibitors are a promising therapeutic strategy for cancer, little is known about their implication after SCI. Thus, the current study was aimed to investigate the anti-inflammatory role of BET inhibitors in this pathologic condition. METHODS: We evaluated the effectiveness of the BET inhibitor JQ1 to modify macrophage reactivity in vitro and to modulate inflammation in a SCI mice model. We analyzed the effects of BET inhibition in pro-inflammatory and anti-inflammatory cytokine production in vitro and in vivo. We determined the effectiveness of BET inhibition in tissue sparing, inflammation, neuronal protection, and behavioral outcome after SCI. RESULTS: We have found that the BET inhibitor JQ1 reduced the levels of pro-inflammatory mediators and increased the expression of anti-inflammatory cytokines. A prolonged treatment with JQ1 also decreased reactivity of microglia/macrophages, enhanced neuroprotection and functional recovery, and acutely reduced neuropathic pain after SCI. CONCLUSIONS: BET protein inhibition is an effective treatment to regulate cytokine production and promote neuroprotection after SCI. These novel results demonstrate for the first time that targeting BET proteins is an encouraging approach for SCI repair and a potential strategy to treat other inflammatory pathologies.


Assuntos
Azepinas/farmacologia , Citocinas/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Receptores de Superfície Celular/antagonistas & inibidores , Traumatismos da Medula Espinal/metabolismo , Triazóis/farmacologia , Animais , Citocinas/biossíntese , Feminino , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Recuperação de Função Fisiológica/efeitos dos fármacos
8.
J Neuroinflammation ; 16(1): 126, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221190

RESUMO

BACKGROUND: Persistent and/or recurrent inflammatory processes are the main factor leading to multiple sclerosis (MS) lesions. The composite ultramicronized palmitoylethanolamide, an endogenous N-acylethanolamine, combined with the flavonoid luteolin, PEALut, have been found to exert neuroprotective activities in experimental models of spinal and brain injury and Alzheimer disease, as well as a clinical improvement in human stroke patients. Furthermore, PEALut enhances the expression of different myelin proteins in oligodendrocyte progenitor cells suggesting that this composite might have protective effects in MS experimental models. METHODS: The mouse model of experimental autoimmune encephalomyelitis (EAE) based on active immunization with a fragment of myelin oligodendrocyte glycoprotein (MOG35-55) was used. The daily assessment of clinical score and the expression of serum amyloid A (SAA1), proinflammatory cytokines TNF-α, IL-1ß, IFN-γ, and NLRP3 inflammasome, as well as TLR2, Fpr2, CD137, CD3-γ, and TCR-ζ chain, heterodimers that form T cell surface glycoprotein (TCR), and cannabinoid receptors CB1, CB2, and MBP, were evaluated in the brainstem and cerebellum at different postimmunization days (PIDs). RESULTS: Vehicle-MOG35-55-immunized (MOG35-55) mice developed ascending paralysis which peaked several days later and persisted until the end of the experiment. PEALut, given intraperitoneally daily starting on day 11 post-immunization, dose-dependently improved clinical score over the range 0.1-5 mg/kg. The mRNA expression of SAA1, TNF-α, IL-1ß, IFN-γ, and NLRP3 were significantly increased in MOG35-55 mice at 14 PID. In MOG35-55 mice treated with 5 mg /kg PEALut, the increase of SAA1, TNF- α, IL-1ß, and IFN-γ transcripts at 14 PID was statistically downregulated as compared to vehicle-MOG35-55 mice (p < 0.05). The expression of TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 receptors showed a significant upregulation in vehicle-MOG35-55 mice at 14 PID. Instead, CB1 and MBP transcripts have not changed in expression at any time. In MOG/PEALut-treated mice, TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 mRNAs were significantly downregulated as compared to vehicle MOG35-55 mice. CONCLUSIONS: The present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG35-55 model of EAE. The dose-dependent improvement of clinical score induced by PEALut was associated with a reduction in transcript expression of the acute-phase protein SAA1, TNF-α, IL-1ß, IFN-γ, and NLRP3 proinflammatory proteins and TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 receptors.


Assuntos
Encefalomielite Autoimune Experimental/patologia , Etanolaminas/farmacologia , Luteolina/farmacologia , Fármacos Neuroprotetores/farmacologia , Ácidos Palmíticos/farmacologia , Animais , Biomarcadores/análise , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL
9.
J Coll Physicians Surg Pak ; 29(5): 422-425, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31036110

RESUMO

OBJECTIVE: To determine the effect of irbesartan on the activity of oxidative stress parameters of glutathione (GSH), superoxide enzyme (SOD) and malondialdehyde (MDA), and concentration of serum inflammatory factors of macrophage chemokine-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor alpha (TNF-∝) in the renal tissue of type 2 diabetic rats. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: The First People's Hospital of Ningyang County, Shandong Province, China, from April 2017 to March 2018. METHODOLOGY: Thirty healthy male Sprague Dawley rats were randomly divided into a normal control group, a diabetic model group, and an irbesartan treatment group, 10 in each group. Rat models of type 2 diabetes were prepared by highsugar high-fat diet with low-dose streptozotocin injection. Changes in blood glucose and lipids, serum GSH, SOD, MDA, MCP-1, ICAM-1, and TNF-∝ levels were determined. RESULTS: Levels of FBG, TC, TG and LDL, activity of GSH, SOD and MDA, and levels of serum MCP-1, ICAM-1 and TNF-∝ among three groups were statistically significant (all p < 0.001). Compared with the diabetic model group, FBG, TC, TG and LDL levels, MDA activity, MCP-1, ICAM-1 and TNF-∝ levels all decreased in rats of the irbesartan treatment group (all p <0.001), and both GSH and SOD activity increased (both p<0.001). CONCLUSION: Irbesartan can improve blood glucose and lipid levels in type 2 diabetic rats, and reduce renal damage by improving oxidative stress and inhibiting the release of inflammatory cytokines.


Assuntos
Glicemia/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Irbesartana/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Glicemia/metabolismo , Citocinas/sangue , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Lipídeos/sangue , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
10.
Ann Anat ; 224: 153-160, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31108190

RESUMO

The effect of empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on the structure of endocrine pancreas in pre-diabetes (Pre-DM) is not yet elucidated. In the current study the relatively enlarged islets of Langerhans seen in the Pre-DM group was restored to control size by administration of EMPA. In addition the disbalance in the percentage of ß-cells and α-cells in islets of the Pre-DM was corrected in the Pre-DM + EMPA group with reversal of the significantly increased islet mass, ß-cell mass and neogenesis. Administrating EMPA in Pre-DM decreased level of caspase-3, increased that of Bcl-2 to control level and reduced the significantly increased inflammatory cytokines to levels approximated to those of the control group. In Pre-DM + EMPA group, EMPA had efficiently restored the significantly impaired glucose hemostasis to levels nearly similar to those of the control animals. This may indicate that the modulatory effect of EMPA on cells of the islets in Pre-DM is associated with a local pleotropic effect on inflammatory cytokines.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Experimental/patologia , Glucosídeos/uso terapêutico , Ilhotas Pancreáticas/efeitos dos fármacos , Estado Pré-Diabético/patologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Área Sob a Curva , Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Proliferação de Células , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Glucagon/sangue , Células Secretoras de Glucagon/citologia , Células Secretoras de Glucagon/efeitos dos fármacos , Teste de Tolerância a Glucose , Glucosídeos/farmacologia , Homeostase , Imuno-Histoquímica , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/patologia , Masculino , Estado Pré-Diabético/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
11.
Braz J Med Biol Res ; 52(6): e8273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31116257

RESUMO

Excessive pro-inflammatory cytokines result in adverse pregnancy outcomes, including preeclampsia-like phenotypes, and fetal growth restriction. Anti-inflammation might be an effective therapy. The aim of this research was to investigate whether Uncaria rhynchophylla alkaloid extract (URE), a highly safe anti-inflammation constituent of the herb, can inhibit inflammation and improve clinical characteristics of preeclampsia in a lipopolysaccharide (LPS)-induced preeclampsia rat model. The rat model was established by daily administration of LPS (1 µg/kg body weight per day) from gestational day (GD) 14 to 19. Different doses of URE (35, 70, and 140 mg/kg body weight per day) were administered from GD 14 to GD 19. The effects of URE on proteinuria, maternal hypertension, pregnancy outcomes, as well as pro-inflammatory cytokines levels in serum and placenta were measured. High-dose URE (HURE) treatment decreased LPS-induced mean 24-h proteinuria and systolic blood pressure, and increased fetal weight, placental weight, and the number of live pups (P<0.05). Moreover, increased serum and placental levels of interleukin (IL)-6, IL-1ß, tumor necrosis factor-α, and interferon-γ in the LPS-treated group were obviously inhibited after HURE administration (P<0.01). URE improved preeclampsia symptoms and mitigated inflammatory responses in the LPS-induced preeclampsia rat model, which suggests that the anti-inflammation effect of URE might be an alternative therapy for preeclampsia.


Assuntos
Anti-Inflamatórios/administração & dosagem , Inflamação/prevenção & controle , Extratos Vegetais/administração & dosagem , Pré-Eclâmpsia/prevenção & controle , Uncaria/química , Animais , Citocinas/sangue , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Lipopolissacarídeos , Pré-Eclâmpsia/induzido quimicamente , Gravidez , Ratos
12.
Life Sci ; 230: 121-131, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125565

RESUMO

AIMS: Cutaneous melanoma is the most aggressive skin cancer, derived from neoplastic transformation of melanocytes. Since several evidences highlighted the importance of a hierarchical model of differentiation among cancer cells, closely related to resistance mechanisms and tumor relapse, we investigated the effects of theophylline (Theo), a methylxanthine commonly used in treatment of respiratory diseases, on melanoma cells with different degree of differentiation, including patient-derived melanoma-initiating cells. MATERIALS AND METHODS: The antiproliferative and antimetastatic effects of Theo was demonstrated by cell counting, adhesion and migration assays on A375 and SK-MEL-30 cells. Further, Theo ability to reduce cell growth was highly significant in A375-derived spheroids and in two patient-derived melanoma-initiating cells (MICs). In order to identify pathways potentially involved in the antineoplastic properties of Theo, a comparative mass spectrometry proteomic analysis was used. Then, melanin content, tyrosinase and tissue transglutaminase activities as differentiation markers and actin re-organization through confocal microscopy were evaluated. Furthermore, a secretome profile of MICs after Theo treatments was performed by multiplex immunoassay. KEY FINDINGS: Obtained results demonstrate inhibitory effects of Theo on melanoma cell proliferation and migration, mainly in MICs, together with the induction of differentiation parameters. Moreover, our data indicate that the known anti-melanoma effect of Theo is due also to its ability to interfere with cytoskeleton dynamics and to induce the secretion of inflammatory molecules involved in recruitment of immunosuppressive cells in tumor microenvironment. SIGNIFICANCE: Data strongly suggest that Theo supplement, either as drug or as dietary supply, may represent a potent additional weapon against melanoma.


Assuntos
Melanoma/tratamento farmacológico , Melanoma/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Teofilina/farmacologia , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Humanos , Melanoma Experimental/patologia , Recidiva Local de Neoplasia , Proteômica , Neoplasias Cutâneas/patologia , Teofilina/metabolismo , Microambiente Tumoral/efeitos dos fármacos
13.
Drug Dev Res ; 80(5): 629-636, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31033006

RESUMO

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system. Although the exact etiology of the disease is largely unknown, it is identified that cytokines may play an important role in the pathogenesis of MS. In this study, the effects of curcumin has been investigated on the expression levels of selected cytokine coding genes as well as the extent of demyelination in the corpus callosum of C57BL/6 experimental autoimmune encephalomyelitis (EAE) model of MS. Gene expression analyses revealed that treatment with curcumin could lead to a significant reduction in the expression levels of pro-inflammatory cytokine coding genes including IL-6 (p = 0.001), IL-17 (p = 0.001), tumor necrosis factor (TNF)-α (p = 0.008), and interferon (IFN)-γ (p = 0.033) as well as a significant increase in the expression level of transforming growth factor (TGF)-ß (p = 0.006) as an anti-inflammatory cytokine. Moreover, the expression of glutathione peroxidase (GPX)-1 gene and the activity of anti-oxidant enzymes were significantly higher (p < 0.001) in curcumin-treated mice. Luxol fast blue staining also confirmed a significant reduction in the extent of demyelination in the curcumin-treated group (p < 0.001). Our results have confirmed that curcumin is an effective therapeutic agent that could ameliorate the severity of EAE.


Assuntos
Curcumina/administração & dosagem , Citocinas/genética , Encefalomielite Autoimune Experimental/tratamento farmacológico , Perfilação da Expressão Gênica/métodos , Glutationa Peroxidase/genética , Animais , Curcumina/farmacologia , Citocinas/efeitos dos fármacos , Encefalomielite Autoimune Experimental/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Interferon gama/genética , Interleucina-17/genética , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , Resultado do Tratamento , Fator de Necrose Tumoral alfa/genética
14.
Burns ; 45(3): 671-681, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31018913

RESUMO

Oxandrolone is a synthetic oral non-aromatizable testosterone derivative. This drug has been used successfully for several decades to safely treat growth delays in various diseases including Turner's syndrome. Currently the use of oxandrolone is under clinical testing in children with burn injury; the available data indicate that the anabolic steroid increases net muscle protein balance, maintains lean body mass, and reduces intensive care unit stay. Although oxandrolone is already in clinical trials in burn patients, preclinical burn-related studies with oxandrolone - especially those that go beyond muscle-related parameters and focus on burn-associated organ dysfunction, inflammatory response and wound healing - remain to be conducted. In the current project, using a well-characterized murine model of third-degree burn, we have tested the effect of oxandrolone on indices of organ injury, clinical chemistry parameters and plasma levels of inflammatory mediators. In oxandrolone-treated mice (1mg/kg/day for up to 21 days) there was a significant amelioration of burn-induced accumulation of myeloperoxidase levels in heart and lung (but not the liver and kidney) and significantly lower degree of malon dialdehyde accumulation in the liver (but not the heart, lung and kidney). Oxandrolone-treated mice showed a significant attenuation of the burn-induced elevation in circulating alkaline aminotransferase and amylase levels, while blood urea nitrogen and creatinine levels remained unaffected, indicative of protective effects of the anabolic hormone against burn-induced hepatic and pancreatic (but not renal) functional impairment. Multiple burn-induced inflammatory mediators (TNF-α, IL-1α, IL-1ß, IL-4, IL-6, IL-10, IL-12, IP-10, G-CSF, GM-CSF and interferon-γ) were significantly lower in the plasma of oxandrolone-treated animals after burn injury than in the plasma of controls subjected to burns. Finally, oxandrolone significantly accelerated burn wound healing. We conclude that oxandrolone improves organ function, modulates the systemic inflammatory response and accelerates wound healing in a murine model of burn injury.


Assuntos
Anabolizantes/farmacologia , Queimaduras/metabolismo , Citocinas/efeitos dos fármacos , Oxandrolona/farmacologia , Cicatrização/efeitos dos fármacos , Amilases/efeitos dos fármacos , Amilases/metabolismo , Animais , Queimaduras/imunologia , Queimaduras/patologia , Citocinas/imunologia , Coração/efeitos dos fármacos , Inflamação , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Malondialdeído/metabolismo , Camundongos , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Peroxidase/efeitos dos fármacos , Peroxidase/metabolismo
15.
Reprod Domest Anim ; 54(6): 917-923, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30972855

RESUMO

Developing alternate therapies for bovine endometritis is important in the context of drug residues in the milk and emergence of antimicrobial resistant bacteria. In this regard, we studied the immunomodulatory effect of curcumin 30 µM, on lipopolysaccharide- (LPS) and/or flagellin (100 ng/ml each)-induced prostaglandin E2 (PGE2 ) and proinflammatory cytokines (PIC) using primary bubaline endometrial stromal cells. After 24 hr treatment, the supernatant was assayed for PGE2 while cells were used for relative quantification of cytokines like IL-1ß, IL-6, IL-8 and TNF α transcripts using a control group as calibrator. LPS was found to possess potent stimulatory effect on PGE2 production, whereas the flagellin was not as potent as LPS in stimulating the PGE2 production either per se or in combination with LPS. LPS markedly up-regulated the transcripts of IL-8 and IL-6 as compared to IL-1ß and TNF α in the bubaline endometrial stromal cells. Except for IL-8, flagellin did not up-regulate other PICs. There was no additive effect between LPS and flagellin on the up-regulation of inflammatory cytokines. Curcumin inhibited the LPS-induced up-regulation of PIC with strong down-regulation of IL-8. The inhibitory effects of curcumin on the inflammatory mediators suggest a potential in the treatment of bovine endometritis.


Assuntos
Curcumina/farmacologia , Citocinas/efeitos dos fármacos , Dinoprostona/metabolismo , Endométrio/efeitos dos fármacos , Animais , Búfalos , Células Cultivadas , Citocinas/metabolismo , Endométrio/metabolismo , Feminino , Flagelina/farmacologia , Lipopolissacarídeos/farmacologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo
16.
Diabetes ; 68(6): 1210-1220, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30894367

RESUMO

Leptin resistance is a hallmark of obesity with unclear etiology. Celastrol, a compound found in the roots of the Tripterygium wilfordii and known to reduce endoplasmic reticulum (ER) stress, has recently emerged as a promising candidate to treat obesity by improving leptin sensitivity. However, the underlying neural mechanisms by which celastrol reduces obesity remain unclear. Using three different mouse models of obesity-diet-induced obesity (DIO), leptin receptor (LepR)-null, and melanocortin 4 receptor (MC4R)-null mice-in this study, we show that systemic celastrol administration substantially reduces food intake and body weight in MC4R-null comparable to DIO, proving the MC4R-independent antiobesity effect of celastrol. Body weight reduction was due to decreases in both fat and lean mass, and modest but significant body weight reduction was also observed in nonobese wild-type and LepR-null mice. Unexpectedly, celastrol upregulated proinflammatory cytokines without affecting genes involved in ER stress. Importantly, celastrol steadily increased sympathetic nerve activity to the brown fat and kidney with concordant increases of resting metabolic rate and arterial pressure. Our results suggest a previously unappreciated mechanism of action of celastrol in the regulation of energy homeostasis and highlight the need for careful consideration of its development as a safe antiobesity medication.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Obesidade/genética , Triterpenos/farmacologia , Perda de Peso/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/inervação , Animais , Pressão Arterial/efeitos dos fármacos , Metabolismo Basal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Citocinas/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Metabolismo Energético , Inflamação , Rim/efeitos dos fármacos , Rim/inervação , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Receptor Tipo 4 de Melanocortina/genética , Receptores para Leptina/genética , Sistema Nervoso Simpático/efeitos dos fármacos
17.
Inflammation ; 42(4): 1383-1388, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30848409

RESUMO

Modulation of the immune system has gathered more attention in the field of medicine due to the immense potential that it presents. Our immune system has important roles against cancer to infectious diseases, as well as in the development of autoimmune disorders. Therefore, being able to manipulate our immune system cells would enable us to determine the type and strength of the immune response to certain danger stimuli. Macrophages play an important role in the regulation of the immune system by producing cytokines, chemokines and by presenting antigens to other immune system cells to enable their activation; in our study, we focused on their in vitro activity in terms of pro-inflammatory cytokine production. In order to screen new immunomodulatory or immunostimulatory drug candidates, we examined the effect of ruthenium polypyridyl-based complex K30 that is used in solar cells as photosensitizer. Due to its electron transfer capacity, this material has potential to change the electron transfer reactions therefore could alter the function of the cells through metabolic changes at a cellular level. Our results suggest that K30 was differentially regulating the secretion levels of the pro-inflammatory cytokines by the LPS-activated mammalian macrophages, while it did not stimulate the macrophages by itself. K30 has an anti-inflammatory potential while lacking the immunostimulatory effect in our in vitro results and has potential to be used as anti-inflammatory drug molecule in metallic implants of the fractured bones to prevent damaging inflammatory environment and enable more efficient transplant and healing.


Assuntos
Complexos de Coordenação/química , Citocinas/efeitos dos fármacos , Inflamação/tratamento farmacológico , Macrófagos/metabolismo , Rutênio/química , Animais , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Citocinas/biossíntese , Descoberta de Drogas , Humanos , Interleucina-1beta , Interleucina-6 , Macrófagos/efeitos dos fármacos , Piridinas/química , Rutênio/uso terapêutico , Fator de Necrose Tumoral alfa
18.
BMC Vet Res ; 15(1): 68, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819151

RESUMO

BACKGROUND: Refractory diseases, including bacterial infections, are causing huge economic losses in dairy farming. Despite efforts to prevent and treat those diseases in cattle, including the use of antimicrobials, it is not well controlled in the field. Several inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), play important roles in disease progression; thus, blocking these cytokines can attenuate the acute and sever inflammation and may be a novel strategy for treatment. However, biological drugs targeting inflammatory cytokines have not been used in cattle. Therefore, in this study, bovine sTNFR1 and sTNFR2 IgG1 Fc-fusion proteins (TNFR1-Ig and TNFR2-Ig) were produced, and their anti-inflammatory functions were analyzed in vitro, to develop decoy receptors for bovine TNF-α. RESULTS: Both TNFR1-Ig and TNFR2-Ig were shown to bind with TNF-α, and TNFR2-Ig showed higher affinity toward TNF-α than TNFR1-Ig. We next stimulated murine fibroblast-derived cells (L929 cells) with TNF-α to induce cell death and analyzed cell viability in the presence of TNFR-Ig proteins. Both TNFR1-Ig and TNFR2-Ig suppressed TNF-α-induced cell death, significantly improving cell viability. In addition, cell death induced by TNF-α was suppressed, even at low TNFR2-Ig concentrations, suggesting TNFR2-Ig has higher activity to suppress TNF-α functions than TNFR1-Ig. Finally, to examine TNFR2-Ig's anti-inflammatory, we cultured peripheral blood mononuclear cells from cattle with TNF-α in the presence of TNFR2-Ig and analyzed the gene expression and protein production of the inflammatory cytokines IL-1ß and TNF-α. TNFR2-Ig significantly reduced the gene expression and protein production of these cytokines. Our results suggest that TNFR2-Ig inhibits inflammatory cytokine kinetics by blocking TNF-α to transmembrane TNFR, thereby attenuating excessive inflammation induced by TNF-α. CONCLUSIONS: Collectively, the findings of this study demonstrated the potential of TNFR2-Ig as a novel therapeutic for inflammatory diseases, such as bovine clinical mastitis. Further investigation is required for future clinical application.


Assuntos
Morte Celular/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Receptores Chamariz do Fator de Necrose Tumoral/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Apoptose/efeitos dos fármacos , Bovinos , Linhagem Celular , Células Cultivadas , Citocinas/metabolismo , Fibroblastos , Expressão Gênica , Fragmentos Fc das Imunoglobulinas/química , Fragmentos Fc das Imunoglobulinas/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Leucócitos Mononucleares , Camundongos , Receptores Tipo I de Fatores de Necrose Tumoral/química , Receptores Tipo I de Fatores de Necrose Tumoral/farmacologia , Receptores Tipo II do Fator de Necrose Tumoral/química , Receptores Tipo II do Fator de Necrose Tumoral/farmacologia
19.
Molecules ; 24(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866532

RESUMO

Baizhu Shaoyao San (BSS) is a crucial traditional Chinese medicinal formula widely applied for the treatment of painful diarrhea, diarrhea-predominant irritable bowel syndrome, ulcerative colitis, and some other gastrointestinal diseases. Corresponding to the clinical medication, the three medicinal herbs (Atractylodis Macrocephalae Rhizoma, Paeoniae Radix Alba, and Citri Reticulatae Pericarpium) included in BSS should be processed using some specific methods of stir-frying. To find the underlying correlations between serum chemical profiles and curative effects of crude and processed BSS on ulcerative colitis rats, and further explore for the effective material basis of processing, an UHPLC/Q-TOF-MS/MS technique coupled with gray correlation analysis (GCA) was developed. A total of 134 compounds were identified in rat sera after oral administration of BSS, among which 24 compounds were prototypes and 110 compounds were metabolites. Meanwhile, an ulcerative colitis model was established in rats by enema with 2,4,6-trinitrobenzene sulfonic acid, and the pharmacodynamic indicators for drug efficacies were evaluated as well. According to the results, processed BSS showed better efficacy than crude BSS. The top 10 potential effective components with high degree of correlation were identified based on GCA results, which were thought to be the crucial compounds that contributed to the enhancement of therapeutic effects in BSS after processing.


Assuntos
Análise Química do Sangue/métodos , Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Ácido Trinitrobenzenossulfônico/efeitos adversos , Animais , Cromatografia Líquida de Alta Pressão , Colite Ulcerativa/sangue , Colite Ulcerativa/induzido quimicamente , Citocinas/sangue , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Composição de Medicamentos , Medicamentos de Ervas Chinesas/farmacocinética , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
20.
Metab Brain Dis ; 34(2): 485-494, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30762138

RESUMO

Kaempferol (KFL), the major constituent of various fruits and vegetables, could attenuate oxidaitve stress and inflammation. The aims of the present study were to explore the ameliorative abilities of KFL on the depressive-like behaviors in a chronic social defeat stress (CSDS) mouse model, and to determine the potential mechanisms on oxidative stress, neuroinflammation, and AKT/ß-catenin signaling pathway. Three behavioral tests, sucrose preference test (SPT), social interaction test (SIT), and tail suspension test (TST), were used to evaluate the antidepressive effects of KFL in CSDS mice. Activity levels of antioxidant enzyme, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione s-transferase (GST), and concentrations of malonaldehyde (MDA) and protein carbonylation in the prefrontal cortex were assessed by commercial kits, respectively. Elisa was used to detect the levels of interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α). Q-PCR was used to determine the mRNA level of CD-11b. Furthermore, activity level of AKT/ß-catenin signaling in the prefrontal cortex of CSDS mice was investigated by western blot. In addition, LY294002, a PI3-K inhibitor, was used to investigate the role of AKT/ß-catenin signaling in the antidepressant effects of KFL. Social defeat stress reduced the bodyweights, sucrose consumptions, social interaction times, and the tail suspension mobility times in mice. CSDS mice were also exhibited remarkablely increased levels in oxidative stress markers, inflammatory mediators, and decreased activity of AKT/ß-catenin cascade in the prefrontal cortex, which were reversed by treatment with KFL. Interestingly, LY294002 appeared to partly inhibit the overall KFL-mediated protective effects in the CSDS mice. These results confirmed that KFL exerted antidepressive effects, which might be mediated, at least in part, by enhanced antioxidant abilities and anti-inflammation effects via up-regulation AKT/ß-catenin cascade activity in the prefrontal cortex of CSDS mice. Thus, KFL might be a promising, effective, and safe food medicine for depression treatment.


Assuntos
Antidepressivos/farmacologia , Quempferóis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Regulação para Cima/efeitos dos fármacos
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