Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.090
Filtrar
1.
Yakugaku Zasshi ; 140(9): 1141-1150, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879246

RESUMO

Osteoarthritis is the most common joint disorder worldwide and one of the leading causes of disability in the elderly. We have reported that the novel sodium hyaluronate derivative chemically linked with diclofenac (DF), diclofenac etalhyaluronate (SI-613), exerted a potent and long-lasting analgesic effect in experimental arthritis models. In this study, we evaluated the properties of residual SI-613 in the knee joint after an intra-articular (IA) administration. After IA administration of fluorescent labeled SI-613 (FA-SI-613) or fluorescent labeled hyaluronic acid (FA-HA) to rabbits, fluorescence intensities in the synovial membrane and cartilage were higher in the FA-SI-613 group until 7 d after administration than in the FA-HA group. After IA administration of radiolabeled SI-613 (14C-SI-613) to rabbits, the radioactivity remained in the joint cavity and the joint tissues such as synovial membrane and cartilage until 84 d after administration. This residual radioactivity was identified mainly as HA linked with DF, since 14C-SI-613 was labeled at the benzene ring of DF and since more DF-linked HA oligomer was detected on metabolite analysis than free DF in the synovial membrane and synovial lavage fluid up to 28 d after administration. These results suggested that intra-articularly administered SI-613 remained for a longer time in the joint as HA linked with DF than when HA was administered. Therefore, SI-613 was considered to prolong the pharmacological effects of both HA and DF by remaining in the joint as HA linked with DF.


Assuntos
Diclofenaco/administração & dosagem , Diclofenaco/metabolismo , Ácido Hialurônico/análogos & derivados , Articulação do Joelho , Osteoartrite/tratamento farmacológico , Animais , Cartilagem/metabolismo , Modelos Animais de Doenças , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/metabolismo , Injeções Intra-Articulares , Articulação do Joelho/metabolismo , Masculino , Coelhos , Membrana Sinovial/metabolismo , Fatores de Tempo
2.
Medicine (Baltimore) ; 99(33): e21610, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872016

RESUMO

INTRODUCTION: Osteoarthritis (OA), a chronic and degenerative joint disease characterized by articular cartilage degeneration, sclerosis of subchondral bone, and osteophyte formation, is deemed a leading cause of activity limitation and disability among the elderly people. Serum uric acid (UA) is a terminal metabolite of purine compound, while hyperuricemia (HU) and UA crystals are recognized causes of gout. Several studies have investigated the correlations between HU, gout and OA, but the findings are inconclusive. We are also concerned whether the urate lowering therapy (ULT) can become a potential treatment for OA and intend to undertake this meta-analysis to clarify the related hypotheses. METHODS: Systematic literature search will be conducted on PubMed, Embase, and Web of Science to identify relevant studies up to February 2020 using appropriate search strategies. All citations and abstracts retrieved from literature search will be assessed by two reviewers independently. The Newcastle-Ottawa Scale or the Cochrane risk of bias assessment tool will be used as appropriate to assess the quality and the risk of bias of the included studies. The heterogeneity and the publication bias of the studies will be investigated accordingly. RESULTS: We propose to undertake this meta-analysis as a feasible approach to clarify the associations between HU, gout or ULT, and OA. DISCUSSIONS: This meta-analysis will help to strengthen our knowledge of the pathogenesis of OA and promote the development of preventive or treatment strategies. REGISTRATION: PROSPERO registration number CRD42020168769.


Assuntos
Gota/epidemiologia , Hiperuricemia/epidemiologia , Osteoartrite/epidemiologia , Ácido Úrico/sangue , Uricosúricos/administração & dosagem , Gota/tratamento farmacológico , Gota/prevenção & controle , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/prevenção & controle , Estudos Observacionais como Assunto , Osteoartrite/tratamento farmacológico , Osteoartrite/prevenção & controle , Projetos de Pesquisa
3.
Cochrane Database Syst Rev ; 9: CD008294, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32990945

RESUMO

BACKGROUND: Pine bark (Pinus spp.) extract is rich in bioflavonoids, predominantly proanthocyanidins, which are antioxidants. Commercially-available extract supplements are marketed for preventing or treating various chronic conditions associated with oxidative stress. This is an update of a previously published review. OBJECTIVES: To assess the efficacy and safety of pine bark extract supplements for treating chronic disorders. SEARCH METHODS: We searched three databases and three trial registries; latest search: 30 September 2019. We contacted the manufacturers of pine bark extracts to identify additional studies and hand-searched bibliographies of included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating pine bark extract supplements in adults or children with any chronic disorder. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data and assessed risk of bias. Where possible, we pooled data in meta-analyses. We used GRADE to evaluate the certainty of evidence. Primary outcomes were participant- and investigator-reported clinical outcomes directly related to each disorder and all-cause mortality. We also assessed adverse events and biomarkers of oxidative stress. MAIN RESULTS: This review included 27 RCTs (22 parallel and five cross-over designs; 1641 participants) evaluating pine bark extract supplements across 10 chronic disorders: asthma (two studies; 86 participants); attention deficit hyperactivity disorder (ADHD) (one study; 61 participants), cardiovascular disease (CVD) and risk factors (seven studies; 338 participants), chronic venous insufficiency (CVI) (two studies; 60 participants), diabetes mellitus (DM) (six studies; 339 participants), erectile dysfunction (three studies; 277 participants), female sexual dysfunction (one study; 83 participants), osteoarthritis (three studies; 293 participants), osteopenia (one study; 44 participants) and traumatic brain injury (one study; 60 participants). Two studies exclusively recruited children; the remainder recruited adults. Trials lasted between four weeks and six months. Placebo was the control in 24 studies. Overall risk of bias was low for four, high for one and unclear for 22 studies. In adults with asthma, we do not know whether pine bark extract increases change in forced expiratory volume in one second (FEV1) % predicted/forced vital capacity (FVC) (mean difference (MD) 7.70, 95% confidence interval (CI) 3.19 to 12.21; one study; 44 participants; very low-certainty evidence), increases change in FEV1 % predicted (MD 7.00, 95% CI 0.10 to 13.90; one study; 44 participants; very low-certainty evidence), improves asthma symptoms (risk ratio (RR) 1.85, 95% CI 1.32 to 2.58; one study; 60 participants; very low-certainty evidence) or increases the number of people able to stop using albuterol inhalers (RR 6.00, 95% CI 1.97 to 18.25; one study; 60 participants; very low-certainty evidence). In children with ADHD, we do not know whether pine bark extract decreases inattention and hyperactivity assessed by parent- and teacher-rating scales (narrative synthesis; one study; 57 participants; very low-certainty evidence) or increases the change in visual-motoric coordination and concentration (MD 3.37, 95% CI 2.41 to 4.33; one study; 57 participants; very low-certainty evidence). In participants with CVD, we do not know whether pine bark extract decreases diastolic blood pressure (MD -3.00 mm Hg, 95% CI -4.51 to -1.49; one study; 61 participants; very low-certainty evidence); increases HDL cholesterol (MD 0.05 mmol/L, 95% CI -0.01 to 0.11; one study; 61 participants; very low-certainty evidence) or decreases LDL cholesterol (MD -0.03 mmol/L, 95% CI -0.05 to 0.00; one study; 61 participants; very low-certainty evidence). In participants with CVI, we do not know whether pine bark extract decreases pain scores (MD -0.59, 95% CI -1.02 to -0.16; one study; 40 participants; very low-certainty evidence), increases the disappearance of pain (RR 25.0, 95% CI 1.58 to 395.48; one study; 40 participants; very low-certainty evidence) or increases physician-judged treatment efficacy (RR 4.75, 95% CI 1.97 to 11.48; 1 study; 40 participants; very low-certainty evidence). In type 2 DM, we do not know whether pine bark extract leads to a greater reduction in fasting blood glucose (MD 1.0 mmol/L, 95% CI 0.91 to 1.09; one study; 48 participants;very low-certainty evidence) or decreases HbA1c (MD -0.90 %, 95% CI -1.78 to -0.02; 1 study; 48 participants; very low-certainty evidence). In a mixed group of participants with type 1 and type 2 DM we do not know whether pine bark extract decreases HbA1c (MD -0.20 %, 95% CI -1.83 to 1.43; one study; 67 participants; very low-certainty evidence). In men with erectile dysfunction, we do not know whether pine bark extract supplements increase International Index of Erectile Function-5 scores (not pooled; two studies; 147 participants; very low-certainty evidence). In women with sexual dysfunction, we do not know whether pine bark extract increases satisfaction as measured by the Female Sexual Function Index (MD 5.10, 95% CI 3.49 to 6.71; one study; 75 participants; very low-certainty evidence) or leads to a greater reduction of pain scores (MD 4.30, 95% CI 2.69 to 5.91; one study; 75 participants; very low-certainty evidence). In adults with osteoarthritis of the knee, we do not know whether pine bark extract decreases composite Western Ontario and McMaster Universities Osteoarthritis Index scores (MD -730.00, 95% CI -1011.95 to -448.05; one study; 37 participants; very low-certainty evidence) or the use of non-steroidal anti-inflammatory medication (MD -18.30, 95% CI -25.14 to -11.46; one study; 35 participants; very low-certainty evidence). We do not know whether pine bark extract increases bone alkaline phosphatase in post-menopausal women with osteopenia (MD 1.16 ug/L, 95% CI -2.37 to 4.69; one study; 40 participants; very low-certainty evidence). In individuals with traumatic brain injury, we do not know whether pine bark extract decreases cognitive failure scores (MD -2.24, 95% CI -11.17 to 6.69; one study; 56 participants; very low-certainty evidence) or post-concussion symptoms (MD -0.76, 95% CI -5.39 to 3.87; one study; 56 participants; very low-certainty evidence). For most comparisons, studies did not report outcomes of hospital admissions or serious adverse events. AUTHORS' CONCLUSIONS: Small sample sizes, limited numbers of RCTs per condition, variation in outcome measures, and poor reporting of the included RCTs mean no definitive conclusions regarding the efficacy or safety of pine bark extract supplements are possible.


Assuntos
Antioxidantes/uso terapêutico , Doença Crônica/tratamento farmacológico , Flavonoides/uso terapêutico , Casca de Planta/química , Extratos Vegetais/uso terapêutico , Adolescente , Adulto , Asma/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Viés , Doenças Ósseas Metabólicas/tratamento farmacológico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Disfunção Erétil/tratamento farmacológico , Feminino , Humanos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Pinus , Ensaios Clínicos Controlados Aleatórios como Assunto , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Insuficiência Venosa/tratamento farmacológico
4.
Arthritis Care Res (Hoboken) ; 72(9): 1248-1256, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32754989

RESUMO

OBJECTIVE: To examine the risk of incident type 2 diabetes mellitus (DM) among patients with rheumatoid arthritis (RA) versus the risk among 4 different comparison cohorts. METHODS: Using a large US commercial insurance database, Optum Clinformatics Data Mart (2005-2017), we identified patients with RA based on ≥2 diagnoses for RA and use of ≥1 disease-modifying antirheumatic drug. We selected 4 comparison cohorts with ≥2 disease-specific diagnoses and ≥1 dispensing of disease-specific drugs: 1) general non-RA patients, 2) patients with hypertension, 3) patients with osteoarthritis (OA), and 4) patients with psoriatic arthritis (PsA). The index date was the disease-specific drug dispensing date. Patients with RA were matched to the comparator cohorts (except PsA) for age as of the index date, sex, and index date. The primary outcome was incident type 2 DM, defined as a new diagnosis of type 2 DM plus a new dispensing of antidiabetic drugs. A multivariable Cox proportional hazards model estimated hazard ratios of incident type 2 DM among RA versus each of the comparison cohorts, accounting for >40 baseline covariates. RESULTS: A total of 449,327 RA, general non-RA, hypertension, OA, or PsA patients were selected. During the median of 1.6 (range 0.6-3.3) years of follow-up, the incidence rate of type 2 DM was the lowest in the RA cohort (7.0 per 1,000 person-years) and highest (12.3 per 1,000 person-years) in the hypertension cohort. After adjusting for >40 baseline covariates, we found that RA was associated with a 24-35% lower risk of incident type 2 DM compared to 4 comparison groups. CONCLUSION: In this large population-based cohort study, patients with RA had a lower rate of incident type 2 DM compared to the general non-RA, hypertension, OA, and PsA cohorts.


Assuntos
Artrite Reumatoide/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Estudos de Coortes , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Estudos Retrospectivos , Risco
5.
Nat Commun ; 11(1): 4343, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859940

RESUMO

Osteoarthritis (OA), primarily characterized by articular cartilage destruction, is the most common form of age-related degenerative whole-joint disease. No disease-modifying treatments for OA are currently available. Although OA is primarily characterized by cartilage destruction, our understanding of the processes controlling OA progression is poor. Here, we report the association of OA with increased levels of osteoclast-associated receptor (OSCAR), an immunoglobulin-like collagen-recognition receptor. In mice, OSCAR deletion abrogates OA manifestations, such as articular cartilage destruction, subchondral bone sclerosis, and hyaline cartilage loss. These effects are a result of decreased chondrocyte apoptosis, which is caused by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in induced OA. Treatments with human OSCAR-Fc fusion protein attenuates OA pathogenesis caused by experimental OA. Thus, this work highlights the function of OSCAR as a catabolic regulator of OA pathogenesis, indicating that OSCAR blockade is a potential therapy for OA.


Assuntos
Apoptose/efeitos dos fármacos , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Osteoartrite/metabolismo , Osteoclastos/metabolismo , Receptores de Superfície Celular/metabolismo , Idoso , Animais , Cartilagem Articular/patologia , Condrócitos/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
6.
Nat Commun ; 11(1): 3427, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647171

RESUMO

The contribution of inflammation to the chronic joint disease osteoarthritis (OA) is unclear, and this lack of clarity is detrimental to efforts to identify therapeutic targets. Here we show that chondrocytes under inflammatory conditions undergo a metabolic shift that is regulated by NF-κB activation, leading to reprogramming of cell metabolism towards glycolysis and lactate dehydrogenase A (LDHA). Inflammation and metabolism can reciprocally modulate each other to regulate cartilage degradation. LDHA binds to NADH and promotes reactive oxygen species (ROS) to induce catabolic changes through stabilization of IκB-ζ, a critical pro-inflammatory mediator in chondrocytes. IκB-ζ is regulated bi-modally at the stages of transcription and protein degradation. Overall, this work highlights the function of NF-κB activity in the OA joint as well as a ROS promoting function for LDHA and identifies LDHA as a potential therapeutic target for OA treatment.


Assuntos
Condrócitos/metabolismo , Lactato Desidrogenase 5/metabolismo , Terapia de Alvo Molecular , Osteoartrite/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Aerobiose , Animais , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Citoproteção/efeitos dos fármacos , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/farmacologia , Articulação do Joelho/patologia , Meniscos Tibiais/cirurgia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos Endogâmicos C57BL , NAD/metabolismo , NF-kappa B/metabolismo , Osteoartrite/genética , Osteoartrite/patologia
7.
Travel Med Infect Dis ; 36: 101812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645478

RESUMO

BACKGROUND: Hydroxychloroquine (HCQ) is currently being examined for COVID-19. No previous meta-analysis has evaluated its side effects versus placebo. We conducted this meta-analysis to compare the safety of HCQ versus placebo. METHODS: Two authors independently searched PubMed and EMBASE databases for randomized controlled trials (RCTs) of adults comparing the adverse events (AEs) of HCQ versus placebo for any indication. Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs) were calculated based on random-effects models. The heterogeneity (I2) was assessed using Cochran's Q test. RESULTS: Nine RCTs (eight were double-blind) with a total of 916 patients were included. HCQ caused significantly more skin pigmentation than placebo (Peto OR, 4.64; 95% CI, 1.13 to 19.00; P-value = 0.033; I2 = 0%). The increase in other AEs did not reach statistical significance: rash (Peto OR, 1.11; 95% CI, 0.3 to 3.77; P-value = 0.03; I2 = 0%); gastrointestinal AEs (Peto OR, 1.43; 95% CI, 0.55 to 3.72; P-value = 0.46; I2 = 15.17%); headache (Peto OR, 1.94; 95% CI, 0.65 to 5.78; P-value = 0.23; I2 = 9.99%); dizziness (Peto OR, 1.32; 95% CI, 0.49 to 3.52; P-value = 0.58; I2 = 0%); fatigue (Peto OR, 2.13; 95% CI, 0.76 to 5.98; P-value = 0.15; I2 = 0%); and visual AEs (Peto OR, 1.61; 95% CI, 0.76 to 3.41; P-value = 0.22; I2 = 0%). Cardiac toxicity was not reported. CONCLUSIONS: This meta-analysis of RCTs found a significantly higher risk of skin pigmentation in HCQ users versus placebo. More data are needed to evaluate HCQ in the context of COVID-19 treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antirreumáticos/efeitos adversos , Urticária Crônica/tratamento farmacológico , Glomerulonefrite por IGA/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Hiperpigmentação/induzido quimicamente , Doenças Reumáticas/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Infecções Assintomáticas , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Tontura/induzido quimicamente , Exantema/induzido quimicamente , Fadiga/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Cefaleia/induzido quimicamente , Humanos , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
J Vis Exp ; (161)2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32716395

RESUMO

Autophagy is a central mechanism to regulate homeostasis. Alterations of autophagy contribute to aging-related diseases. Phenotypic methods to identify regulators of autophagy could be used for the identification of novel therapeutics. This article describes a cell-based imaging screening workflow developed to monitor autophagic flux using LC3 as a reporter of autophagic flux (mCherry-EGFP-LC3B) in human chondrocytes. Data acquisition is performed using an automated High Content Imaging Screening System microscope. An algorithm-based automated image analysis protocol was developed and validated to identify molecules activating autophagic flux. Critical steps, explanatory notes, and improvements over current autophagy monitoring protocols are reported. Physiologically relevant phenotypic screening approaches to target hallmarks of aging can facilitate more effective drug discovery strategies for age-related musculoskeletal diseases.


Assuntos
Autofagia/fisiologia , Bioensaio/métodos , Condrócitos/patologia , Citometria de Fluxo/métodos , Osteoartrite/patologia , Linhagem Celular Transformada , Condrócitos/efeitos dos fármacos , Descoberta de Drogas/métodos , Células HEK293 , Humanos , Proteínas Associadas aos Microtúbulos/farmacologia , Proteínas Associadas aos Microtúbulos/uso terapêutico , Osteoartrite/tratamento farmacológico , Osteoartrite/fisiopatologia
9.
Life Sci ; 256: 117924, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522568

RESUMO

AIMS: Osteoarthritis (OA) is a common degenerative joint disease characterized by cartilage degeneration and joint inflammation. As its pathogenesis remains unclear, there are no effective treatments established. Circular RNA (circRNA), microRNA (miRNA), and other noncoding RNAs participate in OA development; however, the effects and mechanisms of circRNA and miRNA in OA remain unknown. MAIN METHODS: Cartilage miRNA was examined in patients with and without OA. KEY FINDINGS: CircRNA-9119 and phosphatase and tensin homolog (PTEN) expression decreased in OA-affected cartilage and interleukin (IL)-1ß-induced chondrocytes, and miR-26a expression significantly decreased in normal cells and tissues. CircRNA-9119 overexpression restored chondrocyte growth, whereas IL-1ß treatment impaired chondrocyte growth. Annexin V-FITC & PI flow cytometry and Bcl-2/Bax ratio measurement indicated that the apoptosis of IL-1ß-treated articular chondrocytes was decreased by circRNA-9119 upregulation. Bioinformatic prediction and the dual-luciferase reporter assay indicated that circRNA-9119 served as a miR-26a sponge and that miR-26a targeted the 3'-UTR of PTEN. Transfection of chondrocytes with a circRNA-9119-overexpressing vector revealed downregulation of miR-26a expression. Furthermore, circRNA-9119 overexpression induced PTEN expression. In addition, a miR-26a mimic induced IL-1ß-induced chondrocyte apoptosis, and circRNA-9119 overexpression inhibited IL-1ß-induced chondrocyte apoptosis. SIGNIFICANCE: CircRNA-9119 is an important regulator of IL-1ß-treated chondrocytes through the miR-26a/PTEN axis, possibly contributing to OA development.


Assuntos
Condrócitos/metabolismo , Interleucina-1beta/metabolismo , Osteoartrite/tratamento farmacológico , Substâncias Protetoras/metabolismo , RNA Circular/metabolismo , Regiões 3' não Traduzidas , Apoptose/efeitos dos fármacos , Cartilagem/metabolismo , Cartilagem Articular/metabolismo , Linhagem Celular , Condrócitos/citologia , Regulação para Baixo , Matriz Extracelular/metabolismo , Humanos , MicroRNAs/genética , PTEN Fosfo-Hidrolase/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
11.
PLoS One ; 15(6): e0234972, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574222

RESUMO

OBJECTIVE: To evaluate prevalence of structural lesions, synovitis and bone marrow lesions (BMLs) on MRI performed with a 0.3T imaging system in patients with erosive hand osteoarthritis (EHOA) and to compare them to the anatomic radiographic Verbruggen-Veys score (VV). DESIGN: For this Cross-sectional study, fifty-five EHOA patients were studied with 0.3T contrast-enhanced MRI and radiography (RX) of their dominant hand. Structural lesions were scored according to the OMERACT Hand Osteoarthritis MRI Scoring System as follows: osteophytes and erosions were graded from 0 to 3. On joint destruction lesion synovitis and BMLs were graded from 0 to 1. And on MRI, we evaluated the presence of several structural features: N: normal, O: osteophytic lesions, E: erosive lesions, E/O: osteophytic and erosive lesions and D: joint destruction. RX was scored according to the VV system. Relations between MRI features and VV stages were analysed. RESULTS: MRI identified more structural lesions than RX (77.3% versus 74.8%) and particularly more erosive lesions (E or E/O) than VV Phase E (33.5% versus 20.2%). E/O and D were mostly found on MRI. Synovitis and BMLs were significantly associated with E/O and D with the following odds ratios (ORs): 8.4 (95% CI 1.8-13.6); OR: 13.7 (95% CI 2.9-21.0); OR: 15.7 (95% CI 3.2-23.5); OR: 38.5 (95% CI 9.5-57.0), respectively. CONCLUSION: MRI 0.3T appears completely relevant for EHOA lesion analysis. First, MRI shows more erosive lesions than RX in EHOA; second, it allows for the analysis of synovitis and BMLs to be associated with more specific structural MRI features (E/O and D).


Assuntos
Medula Óssea/patologia , Articulação da Mão/patologia , Imagem por Ressonância Magnética/estatística & dados numéricos , Osteoartrite/complicações , Radiografia/estatística & dados numéricos , Sinovite/epidemiologia , Idoso , Medula Óssea/diagnóstico por imagem , Estudos Transversais , Feminino , Articulação da Mão/diagnóstico por imagem , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Osteoartrite/diagnóstico por imagem , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Sinovite/diagnóstico por imagem , Sinovite/etiologia
12.
PLoS One ; 15(5): e0232989, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407402

RESUMO

Multi drug treatments are increasingly used in the clinic to combat complex and co-occurring diseases. However, most drug combination discovery efforts today are mainly focused on anticancer therapy and rarely examine the potential of using more than two drugs simultaneously. Moreover, there is currently no reported methodology for performing second- and higher-order drug combination analysis of secretomic patterns, meaning protein concentration profiles released by the cells. Here, we introduce COMBSecretomics (https://github.com/EffieChantzi/COMBSecretomics.git), the first pragmatic methodological framework designed to search exhaustively for second- and higher-order mixtures of candidate treatments that can modify, or even reverse malfunctioning secretomic patterns of human cells. This framework comes with two novel model-free combination analysis methods; a tailor-made generalization of the highest single agent principle and a data mining approach based on top-down hierarchical clustering. Quality control procedures to eliminate outliers and non-parametric statistics to quantify uncertainty in the results obtained are also included. COMBSecretomics is based on a standardized reproducible format and could be employed with any experimental platform that provides the required protein release data. Its practical use and functionality are demonstrated by means of a proof-of-principle pharmacological study related to cartilage degradation. COMBSecretomics is the first methodological framework reported to enable secretome-related second- and higher-order drug combination analysis. It could be used in drug discovery and development projects, clinical practice, as well as basic biological understanding of the largely unexplored changes in cell-cell communication that occurs due to disease and/or associated pharmacological treatment conditions.


Assuntos
Combinação de Medicamentos , Descoberta de Drogas/métodos , Metabolômica/métodos , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Simulação por Computador , Descoberta de Drogas/estatística & dados numéricos , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Humanos , Técnicas In Vitro , Metabolômica/estatística & dados numéricos , Modelos Biológicos , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Proteômica/métodos , Proteômica/estatística & dados numéricos , Software
13.
Proc Natl Acad Sci U S A ; 117(22): 12029-12040, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32404427

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is a uniformly fatal condition that is especially prevalent in skin, cardiovascular, and musculoskeletal systems. A wide gap exists between our knowledge of the disease and a promising treatment or cure. The aim of this study was to first characterize the musculoskeletal phenotype of the homozygous G608G BAC-transgenic progeria mouse model, and to determine the phenotype changes of HGPS mice after a five-arm preclinical trial of different treatment combinations with lonafarnib, pravastatin, and zoledronic acid. Microcomputed tomography and CT-based rigidity analyses were performed to assess cortical and trabecular bone structure, density, and rigidity. Bones were loaded to failure with three-point bending to assess strength. Contrast-enhanced µCT imaging of mouse femurs was performed to measure glycosaminoglycan content, thickness, and volume of the femoral head articular cartilage. Advanced glycation end products were assessed with a fluorometric assay. The changes demonstrated in the cortical bone structure, rigidity, stiffness, and modulus of the HGPS G608G mouse model may increase the risk for bending and deformation, which could result in the skeletal dysplasia characteristic of HGPS. Cartilage abnormalities seen in this HGPS model resemble changes observed in the age-matched WT controls, including early loss of glycosaminoglycans, and decreased cartilage thickness and volume. Such changes might mimic prevalent degenerative joint diseases in the elderly. Lonafarnib monotherapy did not improve bone or cartilage parameters, but treatment combinations with pravastatin and zoledronic acid significantly improved bone structure and mechanical properties and cartilage structural parameters, which ameliorate the musculoskeletal phenotype of the disease.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Modelos Animais de Doenças , Lamina Tipo A/genética , Progéria , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Fêmur/efeitos dos fármacos , Fêmur/patologia , Glicosaminoglicanos/análise , Articulações/efeitos dos fármacos , Articulações/patologia , Lamina Tipo A/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Fenótipo , Piperidinas/uso terapêutico , Pravastatina/uso terapêutico , Progéria/tratamento farmacológico , Progéria/genética , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Piridinas/uso terapêutico , Microtomografia por Raio-X , Ácido Zoledrônico/uso terapêutico
14.
Chem Biol Interact ; 326: 109136, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32417162

RESUMO

Osteoarthritis (OA) is a common degenerative joint disease that is closely associated with inflammation. Stachydrine (STA) is a bioactive alkaloid with anti-inflammatory activity. However, the role of STA in OA remains unknown. This study aimed to explore the effects of STA on OA chondrocytes in the presence of IL-1ß. Primary human OA chondrocytes were pretreated with various concentrations of STA for 2 h and then stimulated with IL-1ß for 24 h. Inflammatory mediators and cytokines including NO, PGE2, TNF-α and IL-6 in chondrocytes were detected to reflect inflammation status. Production of extracellular matrix (ECM) degrading enzymes including MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 in chondrocytes was measured using ELISA. The expression levels of iNOS, COX-2, p65, p-p65, p-IκBα, and IκBα were detected by Western blot analysis. Our results showed that STA significantly suppressed IL-1ß-induced inflammation with decreased levels of inflammatory mediators and cytokines including NO, PGE2, iNOS, COX-2, TNF-α and IL-6. Treatment with STA suppressed the production of ECM degrading enzymes including MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 in IL-1ß-induced chondrocytes. Furthermore, STA blocked the IL-1ß-mediated potentiation of NF-κB pathway in chondrocytes. In conclusion, these findings demonstrated that STA protected chondrocytes from IL-1ß-induced inflammation through the NF-κB signaling pathway.


Assuntos
Condrócitos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Osteoartrite/tratamento farmacológico , Prolina/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Linhagem Celular , Condrócitos/metabolismo , Humanos , Inflamação/metabolismo , Osteoartrite/metabolismo , Prolina/farmacologia
15.
N Z Med J ; 133(1515): 35-45, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32438375

RESUMO

AIMS: The changing medicolegal climate regarding the medicinal use of cannabinoids in New Zealand will increase the likelihood of patients consulting general practitioners (GPs) about these products. Arthritis is a common medical condition for which cannabis-based products are promoted and used; however, doctors' knowledge about the efficacy and safety of these products in the setting of arthritis may be limited. METHODS: We undertook a rapid review of the medical literature on cannabis-based medicinal products in arthritis. RESULTS: Animal studies have identified endocannabinoid pathways in arthritis that are potentially amenable to interventions. One randomised placebo-controlled trial of Sativex® in adults with rheumatoid arthritis has shown some improvements in pain but not in comparison with a standardised pharmacological treatment regimen. Systematic reviews of cannabis-based products in arthritis have determined that there is currently insufficient evidence to recommend cannabis-based medicines for routine clinical use. There were five ongoing registered clinical trials of cannabis-based products in arthritis, the results of which are yet to be reported. CONCLUSIONS: While animal models have identified possible endocannabinoid pathways in arthritis, there is no clear evidence of benefit in humans or comparative efficacy with current treatments. At this stage, there is little evidence to support GPs prescribing cannabis-based medicinal products for arthritis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Cannabis , Dor Musculoesquelética/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Animais , Endocanabinoides/metabolismo , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto
16.
Clin Pharmacol Ther ; 108(4): 719-729, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32438454

RESUMO

The pandemic spread of the new coronavirus disease 2019 (COVID-19) infection in China first, and all over the world at present, has become a global health emergency due to the rapidly increasing number of affected patients. Currently, a clear relationship between COVID-19 infection incidence and/or complications due to chronic or occasional treatments for other pathologies is still not clear, albeit the COVID-19 pandemic may condition the treatment strategy of complex disorders, such as osteoarthritis (OA). Importantly, OA is the most common age-related joint disease, affecting more than 80% of people older than the age of 55, an age burden also shared with the highest severity in COVID-19 patients. OA patients often show a large array of concomitant pathologies, such as diabetes, inflammation, and cardiovascular diseases that are again shared with COVID-19 patients and may therefore increase complications. Moreover, different OA treatments, such as NSAIDs, paracetamol, corticosteroids, opioids, or other molecules have a wide array of iatrogenic effects, potentially increasing COVID-19 secondary infection incidence or complications. In this review we critically analyze the evidence on either negative or positive effects of drugs commonly used to manage OA in this particular scenario. This would provide orthopedic surgeons in particular, and physicians, pharmacologists, and clinicians in general, a comprehensive description about the safety of the current pharmacological approaches and a decision-making tool to treat their OA patients as the coronavirus pandemic continues.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Gerenciamento Clínico , Osteoartrite/tratamento farmacológico , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Analgésicos não Entorpecentes/uso terapêutico , Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Infecções por Coronavirus/epidemiologia , Humanos , Imunossupressores/uso terapêutico , Osteoartrite/epidemiologia , Pneumonia Viral/epidemiologia
17.
Pain Res Manag ; 2020: 5759265, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32351639

RESUMO

Background: Tapentadol prolonged release (PR) has been shown effective and generally well tolerated in a broad range of chronic pain conditions. This subgroup analysis investigated its benefits for elderly patients with severe chronic osteoarthritis (OA) pain in routine clinical practice. Patients and Methods. Data of all patients with chronic OA pain were extracted from the database of a prospective, 3-month noninterventional tapentadol PR trial. The data of elderly OA patients (>65 years of age; n = 752) were compared with the data of younger OA patients (≤65 years; n = 282). Results: Almost all patients (elderly 98.7% and younger patients 99.3%) had received long-term analgesic medication prior to the start of tapentadol PR treatment but presented with severe pain accompanied by considerable impairments in sleep quality and quality of life measures. Tapentadol PR provided effective pain relief in both patient groups, with slightly better outcomes in younger patients. However, the mean baseline pain intensity of 7.1 (SD 1.5) was reduced by 3.8 points (p ≤ 0.001), and sleep and quality of life measures had also markedly improved in the elderly: quality of sleep by 3 points, quality of life by 3.4 points, social activities by 3 points, and independence by 2.7 points (p ≤ 0.001 for all measures; 11-point scale). At the end of observation, 68% of the elderly had clinically relevant pain reductions of at least 50% (vs baseline), and 87.9% attained either their intended pain reduction target and/or an additional individual treatment target (both predefined during baseline examination). Only 8.4% of the elderly experienced adverse drug reactions, most frequently nausea (2.7% of patients) and dizziness (1.5%). Conclusion: Tapentadol PR provided effective and well-tolerated treatment of severe chronic OA pain for elderly patients in routine clinical practice. The favorable tolerability profile in particular suggests tapentadol PR as a treatment option before classical strong opioids are considered.


Assuntos
Analgésicos Opioides/uso terapêutico , Preparações de Ação Retardada/uso terapêutico , Osteoartrite/tratamento farmacológico , Manejo da Dor/métodos , Tapentadol/uso terapêutico , Idoso , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Feminino , Humanos , Masculino , Osteoartrite/complicações , Estudos Prospectivos , Qualidade de Vida
18.
Yonsei Med J ; 61(4): 331-340, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32233176

RESUMO

PURPOSE: Osteoarthritis (OA) of the temporomandibular joint (TMJ) elicits cartilage and subchondral bone defects. Growth hormone (GH) promotes chondrocyte growth. The aim of this study was to evaluate the efficacy of intra-articular injections of GH to treat TMJ-OA. MATERIALS AND METHODS: Monosodium iodoacetate (MIA) was used to induce OA in the TMJs of rats. After confirming the induction of OA, recombinant human GH was injected into the articular cavities of rats. Concentrations of GH and IGF-1 were measured in the blood and synovial fluid, and OA grades of cartilage and subchondral bone degradation were recorded by histological examination and micro-computed tomography. RESULTS: MIA-induced OA in the rat TMJ upregulated insulin-like growth factor-1 (IGF-1) rather than GH levels. GH and IGF-1 concentrations were increased after local injection of GH, compared with controls. Locally injected GH lowered osteoarthritic scores in the cartilage and subchondral bone of the TMJ. CONCLUSION: Intra-articular injection of GH improved OA scores in rat TMJs in both cartilage and subchondral bone of the condyles without affecting condylar bone growth. These results suggest that intra-articular injection of human GH could be a suitable treatment option for TMJ-OA patients in the future.


Assuntos
Condrócitos/efeitos dos fármacos , Hormônio do Crescimento/administração & dosagem , Fator de Crescimento Insulin-Like I/administração & dosagem , Osteoartrite/tratamento farmacológico , Articulação Temporomandibular/efeitos dos fármacos , Idoso , Animais , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Hormônio do Crescimento/efeitos adversos , Hormônio do Crescimento Humano , Humanos , Injeções Intra-Articulares , Masculino , Osteoartrite/diagnóstico por imagem , Osteoartrite/patologia , Ratos , Líquido Sinovial , Articulação Temporomandibular/diagnóstico por imagem , Articulação Temporomandibular/fisiopatologia , Microtomografia por Raio-X
20.
Int J Nanomedicine ; 15: 2379-2390, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308389

RESUMO

Background: Osteoarthritis (OA) is the most common type of joint disease associated with cartilage breakdown. However, the role played by mitochondrial dysfunction in OA remains inadequately understood. Therefore, we investigated the role played by p66shc during oxidative damage and mitochondrial dysfunction in OA and the effects of p66shc downregulation on OA progression. Methods: Monosodium iodoacetate (MIA), which is commonly used to generate OA animal models, inhibits glycolysis and biosynthetic processes in chondrocytes, eventually causing cell death. To observe the effects of MIA and poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles, histological analysis, immunohistochemistry, micro-CT, mechanical paw withdrawal thresholds, quantitative PCR, and measurement of oxygen consumption rate and extracellular acidification rate were conducted. Results: p-p66shc was highly expressed in cartilage from OA patients and rats with MIA-induced OA. MIA caused mitochondrial dysfunction and reactive oxygen species (ROS) production, and the inhibition of p66shc phosphorylation attenuated MIA-induced ROS production in human chondrocytes. Inhibition of p66shc by PLGA-based nanoparticles-delivered siRNA ameliorated pain behavior, cartilage damage, and inflammatory cytokine production in the knee joints of MIA-induced OA rats. Conclusion: p66shc is involved in cartilage degeneration in OA. By delivering p66shc-siRNA-loaded nanoparticles into the knee joints with OA, mitochondrial dysfunction-induced cartilage damage can be significantly decreased. Thus, p66shc siRNA PLGA nanoparticles may be a promising option for the treatment of OA.


Assuntos
Mitocôndrias/patologia , Osteoartrite/tratamento farmacológico , RNA Interferente Pequeno/farmacologia , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Animais , Cartilagem Articular/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Ácido Iodoacético/toxicidade , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/uso terapêutico , Osteoartrite/induzido quimicamente , Osteoartrite/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , RNA Interferente Pequeno/administração & dosagem , Ratos Sprague-Dawley
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA