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1.
Mater Sci Eng C Mater Biol Appl ; 128: 112254, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474816

RESUMO

Numerous therapeutic strategies have been developed for osteoarthritis (OA) management, including intra-articular (IA) injections. The ideal IA formulation should control cartilage degradation and restore synovial fluid viscosity. To this end, we propose to combine thermo-sensitive polymers (poloxamers) with hyaluronic acid (HA) to develop suitable beta-lapachone (ßLap) loaded IA formulations. The development of IA formulations with these components entails several difficulties: low ßLap solubility, unknown ßLap therapeutic dose and the bonded commitment of easy administration and viscosupplementation. An optimized formulation was designed using artificial intelligence tools based on the experimental results of a wide variety of hydrogels and its therapeutic capacity was evaluated on an ex vivo OA model. The formulation presented excellent rheological properties and significantly decreased the secretion of degradative (MMP13) and pro-inflammatory (CXCL8) molecules. Therefore, the developed formulation is a promising candidate for OA treatment restoring the synovial fluid rheological properties while decreasing inflammation and cartilage degradation.


Assuntos
Ácido Hialurônico , Osteoartrite , Inteligência Artificial , Humanos , Hidrogéis , Inflamação/tratamento farmacológico , Osteoartrite/tratamento farmacológico
2.
Mater Sci Eng C Mater Biol Appl ; 128: 112345, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474895

RESUMO

Sulforaphane (SFN) is an isothiocyanate with anti-arthritic and immuno-regulatory activities, supported by the downregulation of NF-κB pathway, reduction on metalloproteinases expression and prevention of cytokine-induced cartilage degeneration implicated in OA progression. SFN promising pharmacological effects associated to its possible use, by intra-articular route and directly in contact to the site of action, highlight SFN as promising candidate for the development of drug-delivery systems. The association of poloxamers (PL) and hyaluronic acid (HA) supports the development of osteotrophic and chondroprotective pharmaceutical formulations. This study aims to develop PL-HA hybrid hydrogels as delivery systems for SFN intra-articular release and evaluate their biocompatibility and efficacy for osteoarthritis treatment. All formulations showed viscoelastic behavior and cubic phase organization. SFN incorporation and drug loading showed a concentration-dependent behavior following HA addition. Drug release profiles were influenced by both diffusion and relaxation of polymeric chains mechanisms. The PL407-PL338-HA-SFN hydrogel did not evoke pronounced cytotoxic effects on either osteoblast or chondrosarcoma cell lines. In vitro/ex vivo pharmacological evaluation interfered with an elevated activation of NF-κB and COX-2, increased the type II collagen expression, and inhibited proteoglycan depletion. These results highlight the biocompatibility and the pharmacological efficacy of PL-HA hybrid hydrogels as delivery systems for SFN intra-articular release for OA treatment.


Assuntos
Ácido Hialurônico , Osteoartrite , Cartilagem , Humanos , Hidrogéis , Isotiocianatos/farmacologia , Osteoartrite/tratamento farmacológico , Poloxâmero , Sulfóxidos
3.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445661

RESUMO

Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.


Assuntos
Adenosina/farmacologia , Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Membrana Sinovial/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Vasodilatadores/farmacologia , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/metabolismo , Osteoartrite/patologia , Sinoviócitos/metabolismo , Sinoviócitos/patologia
4.
BMJ Open ; 11(8): e048652, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380727

RESUMO

INTRODUCTION: Symptomatic treatments for osteoarthritis (OA) provide only small-to-moderate efficacy over placebo in randomised controlled trials (RCTs). Treatment guidelines therefore have emphasised the need to identify predictors of treatment response through subgroup and multiple regression analysis. Individual participant data (IPD) meta-analysis is recommended as an efficient approach for this purpose. To our knowledge, this has not been undertaken for oral non-steroidal anti-inflammatory drugs (NSAIDs), including paracetamol, in OA. In this IPD meta-analysis, we aim to identify RCTs with specific mechanistic features related to OA pain, such as joint inflammation. We hypothesise that NSAIDs may work better for participants with joint inflammation, whereas paracetamol may not. METHODS AND ANALYSIS: A comprehensive literature search will be conducted on the databases of Web of Science, Embase, Medline, CINAHL, AMED and the Cochrane Library from 1 January 1998 to 1 December 2020. All RCTs related to oral NSAIDs or paracetamol including placebo-controlled trials in people with OA that have evaluated pain-related peripheral risk factors (eg, clinically detected knee effusion, synovial hypertrophy or effusion on imaging, knee morning stiffness, elevated serum C-reactive protein (CRP) level) and/or central pain risk factors (eg, pain elsewhere, depression, anxiety, sleep disturbance) will be retrieved. The outcome will be change in pain from baseline. Change in function and patient global assessment will also be included as outcomes if available. Investigators of all eligible trials will be contacted for IPD. Multilevel regression models will be used to identify predictors for the specific (active-placebo) and the overall treatment effect (change from baseline in active group). ETHICS AND DISSEMINATION: No identifiable data will be included in this study and no formal ethics approval is required as no new data collection will be processed. Results of this hypothesis-driven IPD meta-analysis will be disseminated through conference presentations and publication in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42020165098.


Assuntos
Osteoartrite , Preparações Farmacêuticas , Acetaminofen/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Humanos , Metanálise como Assunto , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico
5.
BMC Musculoskelet Disord ; 22(1): 724, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425806

RESUMO

BACKGROUND: The influence of the sympathetic nervous system (SNS) on metabolism of bone and cartilage expressing ß-adrenergic receptors (AR) was suggested. Here, we investigated whether the SNS functions as a modulator of cartilage metabolism induced by interleukin-1beta (IL-1ß). METHODS: Human articular chondrocytes and articular cartilage were collected from patients with osteoarthritis (OA). Chondrocyte monolayer and cartilage explant culture were stimulated with IL-1ß. The activity of ß-ARs was modulated by an agonist, norepinephrine (NE), and antagonists, including propranolol, atenolol, nebivolol, and nadolol. RESULTS: The levels of ß1-, ß2-, and ß3-AR in OA cartilage and IL-1ß-treated chondrocytes were lower than normal cartilage and untreated cells. Treatment of chondrocytes with IL-1ß and ß-blockers, including propranolol, atenolol, nebivolol, and nadolol, for 6 h significantly upregulated IL-1ß-induced expression of MMP-1, -3, and - 13, compared to chondrocytes treated with IL-1ß alone, indicating that antagonism of ß-AR confers catabolic signals. On the other hand, NE antagonized IL-1ß-induced catabolic response. In addition, NE significantly inhibited IL-1ß-induced release of glycosaminoglycan (GAG) from cartilage explant culture. In addition, ß-AR activity significantly affected IL-1ß-stimulated phosphorylation of JNK and ERK. These results indicate that ß-AR signal is associated with cartilage metabolism. CONCLUSIONS: Our findings showed that ß-ARs is a regulator of cartilage catabolism induced with IL-1ß.


Assuntos
Cartilagem Articular , Osteoartrite , Condrócitos , Humanos , Interleucina-1beta , Norepinefrina/farmacologia , Osteoartrite/tratamento farmacológico
6.
Ann Palliat Med ; 10(7): 7706-7720, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34353059

RESUMO

BACKGROUND: Osteoarthritis (OA) is a chronic joint disease characterized by cartilage destruction and periarticular osteophyte formation. One therapeutic option for this condition, the Wutou Decoction (WTD) Chinese medicine formula, is satisfactory in its efficacy. Here, we used bioinformatic and molecular docking techniques to investigate the mechanism of action of WTD in the treatment of OA. METHODS: The active compounds (and their target proteins) of 5 Chinese herbs in WTD were obtained by searching the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The action targets of WTD for OA were obtained by searching the Therapeutic Target Database and by mining the microarray data in the Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to identify key targets for OA treatment with the help of Database for Annotation, Visualization, and Integrated Discovery. Based on the Cytoscape software version 3.6.1, the visual networks of the "TCM drugs-Active Compounds-Targets-Diseases" and protein-protein interaction of the key targets of WTD for the treatment of OA were constructed. The core active compounds and the key targets obtained were molecularly docked and validated. RESULTS: Analyses revealed 140 active compounds in WTD, 123 of which had a total of 163 corresponding targets. In addition, 331 differentially expressed genes and 227 OA-related targets were obtained. The interaction networks among 32 key targets were identified. The biological processes of WTD in treating OA mainly involved regulation of inflammatory factors, transcription of genetic materials, cell cycle, angiogenesis, and endocrine regulation. The signaling pathways involved mainly included TNF signaling pathway, rheumatoid arthritis signaling pathway, cancer-related signals, vascular endothelial growth factor signaling pathway, and osteoclast differentiation signaling pathways. Molecular docking showed that 7 core compounds including quercetin and kaempferol had strong affinities with key target proteins for the WTD treatment of OA. CONCLUSIONS: WTD with multi-component can treats OA through multi-pathway. Its active compounds, including quercetin and kaempferol, can exert their therapeutic effects on OA by acting on TNF, PTGS2, MMP2, IL-6, IL-1ß, and other key targets to regulate inflammation, immunity, autophagy, and endocrine-related signaling pathways.


Assuntos
Medicamentos de Ervas Chinesas , Osteoartrite , Biologia Computacional , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Fator A de Crescimento do Endotélio Vascular
7.
RMD Open ; 7(2)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34215704

RESUMO

OBJECTIVES: Hand osteoarthritis (OA) is a condition characterised by cartilage degradation and frequently erosive changes. Analgesics and non-steroidal anti-inflammatory drugs are used for symptomatic relief but are often poorly tolerated or contraindicated. Previous publications suggest hydroxychloroquine (HCQ) as a possible treatment for hand OA. The OA-TREAT study aimed to investigate the efficacy and safety of HCQ in patients with inflammatory and erosive hand OA (EOA). METHODS: OA-TREAT was an investigator-initiated, multicentre, randomised, double-blind, placebo (PBO)-controlled trial. Patients with inflammatory and EOA, according to the ACR criteria, with radiographically erosive disease were randomised 1:1 to HCQ 200-400 mg/day or PBO for 52 weeks (W52). Both groups received stable standard therapy. The primary endpoint was Australian Canadian Hand Osteoarthritis Index (AUSCAN) for pain and hand disability at W52. RESULTS: 75 patients were randomised to HCQ and 78 to PBO. At W52, mean AUSCAN pain was 26.7 in HCQ and 26.5 in PBO patients (p=0.92). Hand disability measured by AUSCAN function (mean) was 48.1 in HCQ and 51.3 in PBO patients (p=0.36). Changes in radiographic scores did not differ significantly (p>0.05) between treatment groups. There were 7 serious adverse events in the HCQ and 15 in the PBO group. CONCLUSIONS: OA-TREAT is the first large randomised PBO controlled trial focusing on EOA. HCQ was no more effective than PBO for changes in pain, function and radiographic scores in the 52-week period. Overall safety findings were consistent with the known profile of HCQ.


Assuntos
Hidroxicloroquina , Osteoartrite , Austrália , Canadá , Humanos , Hidroxicloroquina/efeitos adversos , Osteoartrite/diagnóstico por imagem , Osteoartrite/tratamento farmacológico , Resultado do Tratamento
8.
Am J Vet Res ; 82(8): 611-618, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34296945

RESUMO

OBJECTIVE: To assess whether the combination of hyaluronan, sodium chondroitin sulfate, and N-acetyl-d-glucosamine (HCSG) lubricates articular cartilage in vitro and modulates joint lubrication in vivo. ANIMALS: 16 healthy adult horses. PROCEDURES: The effects of HCSG injections on SF lubricant properties and joint health, immediately after injury and 2 weeks later, were analyzed by use an equine osteochondral fracture model of post-traumatic osteoarthritis (OA). Middle carpal joints of adult horses were randomly assigned to 1 of 4 surgical treatment groups as follows: normal nonsurgical group (n = 8), normal sham-surgical group (8), OA-induced surgical group with HCSG injection (8), or OA-induced surgical group with saline (0.9% NaCl) solution injection (8). Synovial fluid was aspirated periodically and analyzed for boundary lubrication function and lubricant molecules. At 17 days, joints were screened for gross pathological changes. RESULTS: Induction of OA led to an impairment of SF lubrication function and diminished hyaluronan concentration in a time-dependent manner following surgery, with HCSG injection lessening these effects. Certain friction coefficients approached those of unaffected normal equine SF. Induction of OA also caused synovial hemorrhage at 17 days, which was lower in joints treated with HCSG. CONCLUSIONS AND CLINICAL RELEVANCE: After induction of OA, equine SF lubricant function was impaired. Hyaluronan-sodium chondroitin sulfate-N-acetyl-d-glucosamine injection restored lubricant properties at certain time points and reduced pathological joint changes.


Assuntos
Cartilagem Articular , Doenças dos Cavalos , Osteoartrite , Animais , Doenças dos Cavalos/tratamento farmacológico , Cavalos , Lubrificação , Osteoartrite/tratamento farmacológico , Osteoartrite/veterinária , Líquido Sinovial , Viscossuplementos
9.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209222

RESUMO

Hyaluronan (HA) is a natural glycosaminoglycan present in many tissues of all vertebrates. HA has various biological functions, which are dependent on its molar mass. High-molar-mass HA has anti-angiogenic, immunosuppressive and anti-inflammatory properties, while low-molar-mass HA has opposite effects. HA has also antioxidative properties, however on the other hand it can be readily degraded by reactive oxygen species. For many years it has been used in treatment of osteoarthritis, cosmetics and in ophthalmology. In the last years there has been a growing interest of HA to also be applied in other fields of medicine such as skin wound healing, tissue engineering, dentistry and gene delivery. In this review we summarize information on modes of HA administration, properties and effects of HA in various fields of medicine including recent progress in the investigation of HA.


Assuntos
Cosméticos , Técnicas de Transferência de Genes , Ácido Hialurônico , Osteoartrite/tratamento farmacológico , Engenharia Tecidual , Cicatrização/efeitos dos fármacos , Cosméticos/química , Cosméticos/uso terapêutico , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/uso terapêutico
10.
Mater Sci Eng C Mater Biol Appl ; 127: 112234, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34225875

RESUMO

Osteoarthritis (OA) is a degenerative joint disease which is highly prevalent worldwide. However, no therapy for blocking OA pathogenesis is available currently. In this study, chondroitin sulfate (CS) E oligosaccharides were prepared and we identified disaccharide as the functional unit showing the strongest anti-complement activity and screened out complement C5 as its target in the complement system. We determined that CS-E disaccharide produced anti-inflammatory effects to treat OA by regulating the complement system: it inhibited the formation of complement-dependent complexes such as the membrane-attack complex (MAC) by targeting C5 and suppressed MAC-induced protein expression and the activation of downstream MAPK and NF-κB signaling pathways accordingly. By identifying CS-E disaccharide which could be regarded as a complement regulator or inhibitor exhibiting high anti-complement activity and revealing its OA-alleviating mechanism, this study not only provides a new strategy for OA treatment and drug development, but also potentially offers a promising C5 target therapy for other associated diseases.


Assuntos
Sulfatos de Condroitina , Osteoartrite , Sulfatos de Condroitina/farmacologia , Complemento C5 , Inativadores do Complemento , Humanos , Oligossacarídeos/farmacologia , Osteoartrite/tratamento farmacológico
11.
Curr Sports Med Rep ; 20(7): 345-350, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34234089

RESUMO

ABSTRACT: Cannabidiol and other cannabinoids are being used more frequently for sports medicine-related conditions. This review will help sports medicine clinicians answer questions that their athletes and active patients have about the potential effectiveness of cannabinoids on common sports medicine conditions. In the article, the authors compare cannabidiol and delta-9-tetrahydrocannabinol effects, noting the difference on the endocannabinoid and nonendocannabinoid receptors. The theoretical benefits of these two compounds and the current legality in the United States surrounding cannabidiol and delta-9-tetrahydrocannabinol use also are addressed.


Assuntos
Canabidiol/uso terapêutico , Canabinoides/uso terapêutico , Medicina Esportiva , Desempenho Atlético , Concussão Encefálica/tratamento farmacológico , Canabidiol/efeitos adversos , Canabidiol/metabolismo , Canabinoides/efeitos adversos , Canabinoides/metabolismo , Cannabis/química , Cannabis/classificação , Dor Crônica/tratamento farmacológico , Dronabinol/metabolismo , Dronabinol/uso terapêutico , Endocanabinoides/metabolismo , Endocanabinoides/farmacologia , Humanos , Maconha Medicinal , Osteoartrite/tratamento farmacológico , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Canabinoides/metabolismo , Canais de Cátion TRPV/metabolismo , Estados Unidos
12.
ACS Appl Mater Interfaces ; 13(27): 31379-31392, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34197081

RESUMO

Osteoarthritis (OA) is treated with the intra-articular injection of steroids such as dexamethasone (DEX) to provide short-term pain management. However, DEX treatment suffers from rapid joint clearance. Here, 20 × 10 µm, shape-defined poly(d,l-lactide-co-glycolide)acid microPlates (µPLs) are created and intra-articularly deposited for the sustained release of DEX. Under confined conditions, DEX release is projected to persist for several months, with only ∼20% released in the first month. In a highly rigorous murine knee overload injury model (post-traumatic osteoarthritis), a single intra-articular injection of Cy5-µPLs is detected in the cartilage surface, infrapatellar fat pad/synovium, joint capsule, and posterior joint space up to 30 days. One intra-articular injection of DEX-µPL (1 mg kg-1) decreased the expression of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, and matrix metalloproteinase (MMP)-13 by approximately half compared to free DEX at 4 weeks post-treatment. DEX-µPL also reduced load-induced histological changes in the articular cartilage and synovial tissues relative to saline or free DEX. In sum, the µPLs provide sustained drug release along with the capability to precisely control particle geometry and mechanical properties, yielding long-lasting benefits in overload-induced OA. This work motivates further study and development of particles that provide combined pharmacological and mechanical benefits.


Assuntos
Cartilagem Articular/metabolismo , Dexametasona/química , Dexametasona/metabolismo , Portadores de Fármacos/química , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Animais , Biomarcadores/metabolismo , Preparações de Ação Retardada , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intra-Articulares , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Estresse Mecânico
13.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209006

RESUMO

Osteoarthritis (OA) is a common chronic disease with increasing prevalence in societies with more aging populations, therefore, it is causing more concern. S-Equol, a kind of isoflavones, was reported to be bioavailable and beneficial to humans in many aspects, such as improving menopausal symptoms, osteoporosis and prevention of cardiovascular disease. This study investigated the effects of S-Equol on OA progress in which rat primary chondrocytes were treated with sodium nitroprusside (SNP) to mimic OA progress with or without the co-addition of S-Equol for the evaluation of S-Equol's efficacy on OA. Results showed treatment of 0.8 mM SNP caused cell death, and increased oxidative stress (NO and H2O2), apoptosis, and proteoglycan loss. Furthermore, the expressions of MMPs of MMP-2, MMP-3, MMP-9, and MMP-13 and p53 were increased. The addition of 30 µM S-Equol could lessen those caused by SNP. Moreover, S-Equol activates the PI3K/Akt pathway, which is an upstream regulation of p53 and NO production and is associated with apoptosis and matrix degradation. As a pretreatment of phosphoinositide 3-kinases (PI3K) inhibitor, all S-Equol protective functions against SNP decrease or disappear. In conclusion, through PI3K/Akt activation, S-Equol can protect chondrocytes against SNP-induced matrix degradation and apoptosis, which are commonly found in OA, suggesting S-Equol is a potential for OA prevention.


Assuntos
Condrócitos/citologia , Equol/farmacologia , Nitroprussiato/efeitos adversos , Osteoartrite/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Modelos Biológicos , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos
14.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298867

RESUMO

The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS); PUGNAc, an inhibitor of O-GlcNAcase; or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, "fueling" the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Doenças das Cartilagens/tratamento farmacológico , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Glucosamina/farmacologia , Hexosaminas/metabolismo , Uridina Difosfato N-Acetilglicosamina/farmacologia , Biomarcadores/metabolismo , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Doenças das Cartilagens/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo II/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Glicosilação/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Fosforilação/efeitos dos fármacos
15.
Aging (Albany NY) ; 13(13): 17690-17706, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34237707

RESUMO

Inflammation and extracellular matrix (ECM) degradation have been implicated in the pathological process of osteoarthritis (OA). α-Cyperone is the main active component of the traditional Chinese medicine Cyperus rotundus L. In this study, we found that α-Cyperone abolished the IL-1ß-induced production of inflammatory cytokines in isolated rat chondrocytes, such as cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS), in a dose-dependent manner (0.75, 1.5 or 3 µM). Also, the results showed that α-Cyperone downregulated the expression of metalloproteinases (MMPs) and thrombospondin motifs 5 (ADAMTS5), and upregulated the expression of type-2 collagen. Mechanistically, molecular docking tests revealed that α-Cyperone stably and effectively binds to p65, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). α-Cyperone inhibited NF-κB activation by blocking its nuclear transfer, and decreasing the phosphorylation of mitogen-activated protein kinase (MAPKs). In addition, in vivo studies based on a mouse model of arthritis showed that α-Cyperone prevented the development of osteoarthritis. Therefore, α-Cyperone may be a potential anti-OA drug.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Matriz Extracelular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Osteoartrite/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Condrócitos/efeitos dos fármacos , Cyperus , Regulação para Baixo , Matriz Extracelular/patologia , MAP Quinases Reguladas por Sinal Extracelular , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Osteoartrite/patologia , Osteoartrite/prevenção & controle , Ratos
16.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299264

RESUMO

Inflammation has a fundamental impact on the pathophysiology of osteoarthritis (OA), a common form of degenerative arthritis. It has previously been established that curcumin, a component of turmeric (Curcuma longa), has anti-inflammatory properties. This research evaluates the potentials of curcumin on the pathophysiology of OA in vitro. To explore the anti-inflammatory efficacy of curcumin in an inflamed joint, an osteoarthritic environment (OA-EN) model consisting of fibroblasts, T-lymphocytes, 3D-chondrocytes is constructed and co-incubated with TNF-α, antisense oligonucleotides targeting NF-kB (ASO-NF-kB), or an IkB-kinase (IKK) inhibitor (BMS-345541). Our results show that OA-EN, similar to TNF-α, suppresses chondrocyte viability, which is accompanied by a significant decrease in cartilage-specific proteins (collagen II, CSPG, Sox9) and an increase in NF-kB-driven gene proteins participating in inflammation, apoptosis, and breakdown (NF-kB, MMP-9, Cox-2, Caspase-3). Conversely, similar to knockdown of NF-kB at the mRNA level or at the IKK level, curcumin suppresses NF-kB activation, NF-kB-promotes gene proteins derived from the OA-EN, and stimulates collagen II, CSPG, and Sox9 expression. Furthermore, co-immunoprecipitation assay shows that curcumin reduces OA-EN-mediated inflammation and chondrocyte apoptosis, with concomitant chondroprotective effects, due to modulation of Sox-9/NF-kB signaling axis. Finally, curcumin selectively hinders the interaction of p-NF-kB-p65 directly with DNA-this association is disrupted through DTT. These results suggest that curcumin suppresses inflammation in OA-EN via modulating NF-kB-Sox9 coupling and is essential for maintaining homeostasis in OA by balancing chondrocyte survival and inflammatory responses. This may contribute to the alternative treatment of OA with respect to the efficacy of curcumin.


Assuntos
Curcumina/farmacologia , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Apoptose/efeitos dos fármacos , Cartilagem/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Curcuma/metabolismo , Curcumina/metabolismo , Ciclo-Oxigenase 2/metabolismo , Humanos , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/metabolismo , Imidazóis/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Osteoartrite/fisiopatologia , Cultura Primária de Células , Quinoxalinas/farmacologia , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
17.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299024

RESUMO

Temporomandibular joint osteoarthritis (TMJ OA) is a low-inflammatory disorder with multifactorial etiology. The aim of this review was to present the current state of knowledge regarding the mechanisms of action and the efficacy of hyaluronic acid (HA), corticosteroids (CS) and platelet-rich plasma (PRP) in the treatment of TMJ OA.: The PubMed database was analyzed with the keywords: "(temporomandibular joint) AND ((osteoarthritis) OR (dysfunction) OR (disorders) OR (pain)) AND ((treatment) OR (arthrocentesis) OR (arthroscopy) OR (injection)) AND ((hyaluronic acid) OR (corticosteroid) OR (platelet rich plasma))". After screening of 363 results, 16 studies were included in this review. Arthrocentesis alone effectively reduces pain and improves jaw function in patients diagnosed with TMJ OA. Additional injections of HA, either low-molecular-weight (LMW) HA or high-molecular-weight (HMW) HA, or CS at the end of the arthrocentesis do not improve the final clinical outcomes. CS present several negative effects on the articular cartilage. Results related to additional PRP injections are not consistent and are rather questionable. Further studies should be multicenter, based on a larger group of patients and should answer the question of whether other methods of TMJ OA treatment are more beneficial for the patients than simple arthrocentesis.


Assuntos
Corticosteroides/uso terapêutico , Ácido Hialurônico/uso terapêutico , Osteoartrite/tratamento farmacológico , Plasma Rico em Plaquetas/metabolismo , Transtornos da Articulação Temporomandibular/tratamento farmacológico , Adolescente , Corticosteroides/farmacologia , Adulto , Humanos , Ácido Hialurônico/farmacologia , Injeções Intra-Articulares , Osteoartrite/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transtornos da Articulação Temporomandibular/metabolismo , Transtornos da Articulação Temporomandibular/fisiopatologia
18.
Bone ; 152: 116070, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34171516

RESUMO

BACKGROUND: Punicalagin (PUN) is a common anti-inflammatory polyphenol. However, the function and mechanism of PUN in osteoarthritis remains unknown. METHODS: Chondrocytes were isolated from rats, and confirmed by toluidine blue staining and immunofluorescence. Chondrocytes were challenged by lipopolysaccharide (LPS), and rat osteoarthritis model was established by Hulth method. The secretion of inflammatory factors, cell viability and apoptosis were tested via enzyme linked immunosorbent assay (ELISA), MTT and flow cytometry. The levels of forkhead box O1 (Foxo1), proteoglycan 4 (Prg4), hypoxia-inducible factor-3α (HIF3α), autophagy-related genes or extracellular matrix (ECM)-related proteins were examined via quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot or immunohistochemistry. The cartilage tissue damage was assessed via hematoxylin-eosin (HE) staining, toluidine blue staining and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (TUNEL) staining. RESULTS: LPS triggered inflammatory injury in chondrocytes. PUN promoted autophagy to mitigate LPS-induced inflammatory injury. Foxo1 silence attenuated the effect of PUN on LPS-mediated autophagy inhibition and inflammatory injury. Promotion of Prg4/HIF3α axis abolished the influence of Foxo1 knockdown on LPS-mediated chondrocytes injury. PUN mitigated the inflammatory injury in rat osteoarthritis model by promoting autophagy and inhibiting inflammation and ECM degradation via Foxo1/Prg4/HIF3α axis. CONCLUSION: PUN attenuates LPS-induced chondrocyte injury and osteoarthritis progression by regulating Foxo1/Prg4/HIF3α axis.


Assuntos
Taninos Hidrolisáveis/farmacologia , Osteoartrite , Animais , Apoptose , Autofagia , Condrócitos , Taninos Hidrolisáveis/uso terapêutico , Proteínas do Tecido Nervoso , Osteoartrite/tratamento farmacológico , Proteoglicanas , Ratos , Fatores de Transcrição
19.
Biomaterials ; 275: 120967, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34153786

RESUMO

Although osteoarthritis (OA) is the most prevalent degenerative joint disease, there is no effective disease-modifying therapy. We report an empty self-assembled hyaluronic acid nanoparticle (HA-NP) as a potential therapeutic agent for OA treatment. In mouse primary articular chondrocytes, HA-NPs blocked the receptor-mediated cellular uptake of free low-molecular-weight HA, and the cellular uptake of HA-NPs increased by ectopic expression of CD44, using an adenoviral delivery system (Ad-Cd44). HA-NP showed in vitro resistance to digestion with hyaluronidase and in vivo long-term retention ability in knee joint, compared with free high-molecular-weight (HMW) HA. CD44 expression increased in the damaged articular cartilage of patients and mice with OA. Ad-Cd44 infection and IL-1ß treatment induced in vitro phenotypes of OA by enhancing catabolic gene expression in primary articular chondrocytes, and these effects were attenuated by HA-NP, but not HMW HA. Both Cd44 deficiency and intra-articular injection of HA-NP protected joint cartilage against OA development in the OA mouse model. NF-κB was found to mediate CD44-induced catabolic factor expression and HA-NP inhibited CD44-induced NF-κB activation in chondrocytes. Our results identify an empty HA-NP as a potential therapeutic agent targeting CD44 for OA treatment, and the CD44-NF-κB-catabolic gene axis as an underlying mechanism of destructive cartilage disorders.


Assuntos
Cartilagem Articular , Nanopartículas , Osteoartrite , Animais , Condrócitos , Humanos , Ácido Hialurônico , Camundongos , Osteoartrite/tratamento farmacológico
20.
J Biomed Nanotechnol ; 17(5): 859-872, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082872

RESUMO

Osteoarthritis is one of the most prevalent chronic diseases. Cartilage inflammation in osteoarthritis results from pain in articular joints. Anti-inflammatory drugs provide relief by hindering the production of pro-inflammatory cytokines and interleukin-6. Targeted delivery of anti-inflammatory drugs is very effective in the treatment of osteoarthritis. This approach reduces the usage of therapeutic drug dosages and unwanted side effects. Here, we fabricated a non-invasive and efficient targeted drug delivery system to reduce persistent inflammation in an osteoarthritis model. Temperature-sensitive hollow dextran/poly(N-isopropyl acrylamide) nanoparticles were synthesized by the destruction of N,N'-bis(acryloyl)cystamine crosslinked cores in imidazolium-based ionic liquids. The copolymerized 2-acrylamido-2-methylpropane sulfonic acid created sulfur functionalities that increase the loading of therapeutic KAFAK peptides. The chemical structure of the polymer nanoparticles was analyzed with UV-Visible, Fourier transform infrared, and X-ray photoelectron spectroscopy. The thermal responsive characteristics of the nanoparticles were determined with dynamic light scattering, scanning electron microscopy, and transmission electron microscopy analyses. Moreover, the synthesized nanoparticles were used as drug carriers to reduce inflammation in an Ex Vivo osteoarthritis model. The KAFAK-loaded hollow dextran/PNIPAM nanoparticles effectively delivered therapeutic peptides in cartilage explants to suppress inflammation. These thermoresponsive nanoparticles could be an effective drug delivery system to deliver anti-inflammatory therapeutic peptides in a highly osteoarthritic environment.


Assuntos
Líquidos Iônicos , Nanopartículas , Osteoartrite , Portadores de Fármacos/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Líquidos Iônicos/uso terapêutico , Osteoartrite/tratamento farmacológico , Peptídeos
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