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1.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071037

RESUMO

Knee osteoarthritis (KOA) represents a clinical challenge due to poor potential for spontaneous healing of cartilage lesions. Several treatment options are available for KOA, including oral nonsteroidal anti-inflammatory drugs, physical therapy, braces, activity modification, and finally operative treatment. Intra-articular (IA) injections are usually used when the non-operative treatment is not effective, and when the surgery is not yet indicated. More and more studies suggesting that IA injections are as or even more efficient and safe than NSAIDs. Recently, research to improve intra-articular homeostasis has focused on biologic adjuncts, such as platelet-rich plasma (PRP). The catabolic and inflammatory intra-articular processes that exists in knee osteoarthritis (KOA) may be influenced by the administration of PRP and its derivatives. PRP can induce a regenerative response and lead to the improvement of metabolic functions of damaged structures. However, the positive effect on chondrogenesis and proliferation of mesenchymal stem cells (MSC) is still highly controversial. Recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, significant progress has been made in understanding the mechanism of PRP action. In this review, we will discuss mechanisms related to inflammation and chondrogenesis in cartilage repair and regenerative processes after PRP administration in in vitro and animal studies. Furthermore, we review clinical trials of PRP efficiency in changing the OA biomarkers in knee joint.


Assuntos
Plasma Rico em Plaquetas , Animais , Células Cultivadas , Microambiente Celular , Condrócitos/efeitos dos fármacos , Condrogênese , Citocinas/administração & dosagem , Citocinas/uso terapêutico , Grânulos Citoplasmáticos/química , Cobaias , Humanos , Ácido Hialurônico/farmacologia , Ácido Hialurônico/uso terapêutico , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Injeções Intra-Articulares , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Neurotransmissores/administração & dosagem , Neurotransmissores/uso terapêutico , Osteoartrite do Joelho , Plasma Rico em Plaquetas/química , Resultado do Tratamento
2.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804203

RESUMO

Osteoarthritis (OA) is a common degenerative disease that results in joint inflammation as well as pain and stiffness. A previous study has reported that Cornus officinalis (CO) extract inhibits oxidant activities and oxidative stress in RAW 264.7 cells. In the present study, we isolated bioactive compound(s) by fractionating the CO extract to elucidate its antiosteoarthritic effects. A single bioactive component, morroniside, was identified as a potential candidate. The CO extract and morroniside exhibited antiosteoarthritic effects by downregulating factors associated with cartilage degradation, including cyclooxygenase-2 (Cox-2), matrix metalloproteinase 3 (Mmp-3), and matrix metalloproteinase 13 (Mmp-13), in interleukin-1 beta (IL-1ß)-induced chondrocytes. Furthermore, morroniside prevented prostaglandin E2 (PGE2) and collagenase secretion in IL-1ß-induced chondrocytes. In the destabilization of the medial meniscus (DMM)-induced mouse osteoarthritic model, morroniside administration attenuated cartilage destruction by decreasing expression of inflammatory mediators, such as Cox-2, Mmp3, and Mmp13, in the articular cartilage. Transverse microcomputed tomography analysis revealed that morroniside reduced DMM-induced sclerosis in the subchondral bone plate. These findings suggest that morroniside may be a potential protective bioactive compound against OA pathogenesis.


Assuntos
Cornus/química , Glicosídeos/farmacologia , Inflamação/tratamento farmacológico , Meniscos Tibiais/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Animais , Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Dinoprostona/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosídeos/química , Humanos , Interleucina-1beta/genética , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Meniscos Tibiais/patologia , Meniscos Tibiais/cirurgia , Camundongos , Osteoartrite/genética , Osteoartrite/patologia , Osteoartrite/cirurgia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Cultura Primária de Células , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
3.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924775

RESUMO

Calcium carbonate (CaCO3)-based materials have received notable attention for biomedical applications owing to their safety and beneficial characteristics, such as pH sensitivity, carbon dioxide (CO2) gas generation, and antacid properties. Herein, to additionally incorporate antioxidant and anti-inflammatory functions, we prepared tannylated CaCO3 (TA-CaCO3) materials using a simple reaction between tannic acid (TA), calcium (Ca2+), and carbonate (CO32-) ions. TA-CaCO3 synthesized at a molar ratio of 1:75 (TA:calcium chloride (CaCl2)/sodium carbonate (Na2CO3)) showed 3-6 µm particles, comprising small nanoparticles in a size range of 17-41 nm. The TA-CaCO3 materials could efficiently neutralize the acid solution and scavenge free radicals. In addition, these materials could significantly reduce the mRNA levels of pro-inflammatory factors and intracellular reactive oxygen species, and protect chondrocytes from toxic hydrogen peroxide conditions. Thus, in addition to their antacid property, the prepared TA-CaCO3 materials exert excellent antioxidant and anti-inflammatory effects through the introduction of TA molecules. Therefore, TA-CaCO3 materials can potentially be used to treat inflammatory cells or diseases.


Assuntos
Anti-Inflamatórios/química , Antioxidantes/química , Carbonato de Cálcio/química , Taninos/química , Antiácidos/química , Antiácidos/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Humanos
4.
Molecules ; 26(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799537

RESUMO

Kaempferia parviflora Wall. ex Baker (KP) has been reported to attenuate cartilage destruction in rat model of osteoarthritis. Previously, we demonstrated that KP rhizome extract and its active components effectively suppressed mechanisms associated with RA in SW982 cells. Here, we further evaluated the anti-arthritis potential of KP extract by using multi-level models, including a complete Freund's adjuvant-induced arthritis and a cartilage explant culture model, and to investigate the effects of KP extract and its major components on related gene expressions and underlying mechanisms within cells. In arthritis rats, the KP extract reduced arthritis indexes, with no significant changes in biological parameters. In the cartilage explant model, the KP extract exerted chondroprotective potential by suppressing sulfated glycosaminoglycans release while preserving high accumulation of proteoglycans. In human chondrocyte cell line, a mixture of the major components equal to their amounts in KP extract showed strong suppression the expression of genes-associated inflammatory joint disease similar to that of the extract. Additionally, KP extract significantly suppressed NF-κB and MAPK signaling pathways. The suppressing expression of necroptosis genes and promoted anti-apoptosis were also found. Collectively, these results provided supportive evidence of the anti-arthritis properties of KP extract, which are associated with its three major components.


Assuntos
Artrite/tratamento farmacológico , Extratos Vegetais/farmacologia , Zingiberaceae/metabolismo , Animais , Apoptose/efeitos dos fármacos , Artrite/genética , Artrite/imunologia , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Glicosaminoglicanos/metabolismo , Humanos , Inflamação/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , NF-kappa B/metabolismo , Cultura Primária de Células , Proteoglicanas/metabolismo , Ratos , Ratos Sprague-Dawley , Rizoma/metabolismo , Suínos , Fator de Transcrição RelA/metabolismo
5.
Oxid Med Cell Longev ; 2021: 8684725, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833854

RESUMO

Osteoarthritis (OA) is the most common degenerative joint disease with chronic joint pain caused by progressive degeneration of articular cartilage at synovial joints. Acteoside, a caffeoylphenylethanoid glycoside, has various biological activities such as antimicrobial, anti-inflammatory, anticancer, antioxidative, cytoprotective, and neuroprotective effect. Further, oral administration of acteoside at high dosage does not cause genotoxicity. Therefore, the aim of present study is to verify the anticatabolic effects of acteoside against osteoarthritis and its anticatabolic signaling pathway. Acteoside did not decrease the viabilities of mouse fibroblast L929 cells used as normal cells and primary rat chondrocytes. Acteoside counteracted the IL-1ß-induced proteoglycan loss in the chondrocytes and articular cartilage through suppressing the expression and activation of cartilage-degrading enzyme such as matrix metalloproteinase- (MMP-) 13, MMP-1, and MMP-3. Furthermore, acteoside suppressed the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, and prostaglandin E2 in the primary rat chondrocytes treated with IL-1ß. Subsequently, the expression of proinflammatory cytokines was decreased by acteoside in the primary rat chondrocytes treated with IL-1ß. Moreover, acteoside suppressed not only the phosphorylation of mitogen-activated protein kinases in primary rat chondrocytes treated with IL-1ß but also the translocation of NFκB from the cytosol to the nucleus through suppression of its phosphorylation. Oral administration of 5 and 10 mg/kg acteoside attenuated the progressive degeneration of articular cartilage in the osteoarthritic mouse model generated by destabilization of the medial meniscus. Our findings indicate that acteoside is a promising potential anticatabolic agent or supplement to attenuate or prevent progressive degeneration of articular cartilage.


Assuntos
Anti-Inflamatórios/farmacologia , Glucosídeos/farmacologia , Imunossupressores/farmacologia , Interleucina-1beta/metabolismo , Osteoartrite/metabolismo , Fenóis/farmacologia , Transdução de Sinais , Animais , Anti-Inflamatórios/uso terapêutico , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Linhagem Celular , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Glucosídeos/uso terapêutico , Imunossupressores/uso terapêutico , Metaloproteinases da Matriz/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite/tratamento farmacológico , Fenóis/uso terapêutico , Ratos , Ratos Sprague-Dawley
6.
Ecotoxicol Environ Saf ; 217: 112225, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33864983

RESUMO

Long-term exposure to excessive fluoride causes chronic damage in the body tissues and could lead to skeletal and dental fluorosis. Cartilage damage caused by excessive fluoride intake has gained wide attention, but how fluoride accumulation blocks the development of chondrocytes is still unclear. Here, we report a negative correlation between the length and growth plate width after NaF treatments via apoptosis and autophagy, with shrinkage of cells, nuclear retraction, dissolution of chondrocytes. Whereas, fluoride exposure had no significant effect on the number and distribution of the osteoclasts which were well aligned. More importantly, fluoride exposure induced apoptosis of tibial bone through CytC/Bcl-2/P53 pathways via targeting Caspase3, Caspase9, Bak1, and Bax expressions. Meanwhile, the Beclin1, mTOR, Pakin, Pink, and p62 were elevated in NaF treatment group, which indicated that long-term excessive fluoride triggered the autophagy in the tibial bone and produced the chondrocyte injury. Altogether, fluoride exposure induced the chondrocyte injury by regulating the autophagy and apoptosis in the tibial bone of ducks, which demonstrates that fluoride exposure is a risk factor for cartilage development. These findings revealed the essential role of CytC/Bcl-2/P53 pathways in long-term exposure to fluoride pollution and block the development of chondrocytes in ducks, and CytC/Bcl-2/P53 can be targeted to prevent fluoride induced chondrocyte injury.


Assuntos
Condrócitos/fisiologia , Patos/fisiologia , Fluoretos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Condrócitos/efeitos dos fármacos , Condrogênese , Fluoretos/metabolismo , Lâmina de Crescimento
7.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916312

RESUMO

Cartilage is a non-innervated and non-vascularized tissue. It is composed of one main cell type, the chondrocyte, which governs homeostasis within the cartilage tissue, but has low metabolic activity. Articular cartilage undergoes substantial stresses that lead to chondral defects, and inevitably osteoarthritis (OA) due to the low intrinsic repair capacity of cartilage. OA remains an incurable degenerative disease. In this context, several dietary supplements have shown promising results, notably in the relief of OA symptoms. In this study, we investigated the effects of collagen hydrolysates derived from fish skin (Promerim®30 and Promerim®60) and fish cartilage (Promerim®40) on the phenotype and metabolism of human articular chondrocytes (HACs). First, we demonstrated the safety of Promerim® hydrolysates on HACs cultured in monolayers. Then we showed that, Promerim® hydrolysates can increase the HAC viability and proliferation, while decreasing HAC SA-ß-galactosidase activity. To evaluate the effect of Promerim® on a more relevant model of culture, HAC were cultured as organoids in the presence of Promerim® hydrolysates with or without IL-1ß to mimic an OA environment. In such conditions, Promerim® hydrolysates led to a decrease in the transcript levels of some proteases that play a major role in the development of OA, such as Htra1 and metalloproteinase-1. Promerim® hydrolysates downregulated HtrA1 protein expression. In contrast, the treatment of cartilage organoids with Promerim® hydrolysates increased the neosynthesis of type I collagen (Promerim®30, 40 and 60) and type II collagen isoforms (Promerim®30 and 40), the latter being the major characteristic component of the cartilage extracellular matrix. Altogether, our results demonstrate that the use of Promerim® hydrolysates hold promise as complementary dietary supplements in combination with the current classical treatments or as a preventive therapy to delay the occurrence of OA in humans.


Assuntos
Condrócitos/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Cartilagem Articular/citologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Condrócitos/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Cultura Primária de Células
8.
Int J Mol Sci ; 22(5)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33804447

RESUMO

Interleukin (IL)-1ß is an important pro-inflammatory cytokine in the progression of osteoarthritis (OA), which impairs mitochondrial function and induces the production of nitric oxide (NO) in chondrocytes. The aim was to investigate if blockade of NO production prevents IL-1ß-induced mitochondrial dysfunction in chondrocytes and whether cAMP and AMP-activated protein kinase (AMPK) affects NO production and mitochondrial function. Isolated human OA chondrocytes were stimulated with IL-1ß in combination with/without forskolin, L-NIL, AMPK activator or inhibitor. The release of NO, IL-6, PGE2, MMP3, and the expression of iNOS were measured by ELISA or Western blot. Parameters of mitochondrial respiration were measured using a seahorse analyzer. IL-1ß significantly induced NO release and mitochondrial dysfunction. Inhibition of iNOS by L-NIL prevented IL-1ß-induced NO release and mitochondrial dysfunction but not IL-1ß-induced release of IL-6, PGE2, and MMP3. Enhancement of cAMP by forskolin reduced IL-1ß-induced NO release and prevented IL-1ß-induced mitochondrial impairment. Activation of AMPK increased IL-1ß-induced NO production and the negative impact of IL-1ß on mitochondrial respiration, whereas inhibition of AMPK had the opposite effects. NO is critically involved in the IL-1ß-induced impairment of mitochondrial respiration in human OA chondrocytes. Increased intracellular cAMP or inhibition of AMPK prevented both IL-1ß-induced NO release and mitochondrial dysfunction.


Assuntos
Condrócitos/efeitos dos fármacos , Inflamação/prevenção & controle , Interleucina-1beta/farmacologia , Mitocôndrias/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico/metabolismo , Osteoartrite do Joelho/prevenção & controle , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoartrite do Joelho/induzido quimicamente , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia
9.
Carbohydr Polym ; 261: 117869, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33766356

RESUMO

Osteoarthritis (OA) is an age-related joint disorder and one of the leading causes of physical disability. In this study, we designed and synthesized a new polysaccharide complex, carboxymethyl chitosan strontium (CMCS-Sr), which is believed to have positive effects on relieving OA. The synthesized CMCS-Sr was structurally verified by SEM, EDS, FTIR, etc. The therapeutic effects of CMCS-Sr were evaluated using various biological experiments. The cell viability and apoptosis results reveal that CMCS-Sr can significantly promote the proliferation and suppress OA chondrocytes apoptosis in vitro. The immunofluorescence staining results suggest that CMCS-Sr facilitates the promotion of the secretion of Type II collagen (Col-II). The transcriptomic results support the observed positive effects of CMCS-Sr on inhibiting chondrocytes apoptosis and alleviating inflammatory reactions. Moreover, animal study demonstrates that CMCS-Sr effectively reduced articular cartilage damage and subchondral bone degradation. Therefore, we propose the use of CMCS-Sr as a promising candidate for relieving OA.


Assuntos
Quitosana/análogos & derivados , Osteoartrite/tratamento farmacológico , Polímeros/síntese química , Polímeros/uso terapêutico , Estrôncio/química , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Células Cultivadas , Quitosana/síntese química , Quitosana/química , Quitosana/farmacologia , Quitosana/uso terapêutico , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Condrócitos/fisiologia , Humanos , Masculino , Osteoartrite/patologia , Polímeros/química , Polímeros/farmacologia , Cultura Primária de Células , Ratos , Estrôncio/farmacologia , Estrôncio/uso terapêutico
10.
Life Sci ; 274: 119324, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33711382

RESUMO

AIMS: Intervertebral Disc Degeneration (IDD) is a key factor involved in low back pain (LBP) which affects approximately 540 million individuals worldwide. Chlorogenic Acid (CGA), a natural compound, exerts anti-inflammatory property in several diseases. Here, we aim to investigate the biological effect of CGA on IDD and explore the underlying mechanism. MATERIALS AND METHODS: Lumbar spine instability (LSI) model in mice was utilized to mimic process of IDD. The effects of CGA in response to LSI were evaluated by luminescent imaging, micro-CT, histomorphology, and immunohistochemistry in vivo. Besides, the cytotoxicity of CGA on chondrocytes was detected by cell counting kit-8 (CCK-8) and the biological effects were assessed by polymerase chain reaction (PCR) in vitro. KEY FINDINGS: We found that CGA treatment dramatically suppressed the NF-κB activity in LSI mice. Moreover, administration of CGA mitigated cartilaginous endplate degeneration and postponed IDD development accompanying a decrease of inflammatory and catabolic mediators. Specifically, CGA ameliorated endplate degeneration might be related to its protective effects against endplate chondrocytes apoptosis and trans-differentiation. We further elucidated that CGA exerted these biological effects mainly by repressing NF-κB signaling in cartilage endplate. SIGNIFICANCE: Our study has illustrated, for the first time, the curative effects as well as the latent mechanism of CGA in IDD and our results suggested that CGA administration might be used as an alternative therapy for IDD.


Assuntos
Apoptose , Cartilagem/efeitos dos fármacos , Ácido Clorogênico/farmacologia , Condrócitos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Degeneração do Disco Intervertebral/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Animais , Cartilagem/patologia , Células Cultivadas , Condrócitos/patologia , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
Molecules ; 26(4)2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33562298

RESUMO

Osteoarthritis (OA) is considered one of the most common arthritic diseases characterized by progressive degradation and abnormal remodeling of articular cartilage. Potential therapeutics for OA aim at restoring proper chondrocyte functioning and inhibiting apoptosis. Previous studies have demonstrated that tauroursodeoxycholic acid (TUDCA) showed anti-inflammatory and anti-apoptotic activity in many models of various diseases, acting mainly via alleviation of endoplasmic reticulum (ER) stress. However, little is known about cytoprotective effects of TUDCA on chondrocyte cells. The present study was designed to evaluate potential effects of TUDCA on interleukin-1ß (IL-1ß) and tunicamycin (TNC)-stimulated NHAC-kn chondrocytes cultured in normoxic and hypoxic conditions. Our results showed that TUDCA alleviated ER stress in TNC-treated chondrocytes, as demonstrated by reduced CHOP expression; however, it was not effective enough to prevent apoptosis of NHAC-kn cells in either normoxia nor hypoxia. However, co-treatment with TUDCA alleviated inflammatory response induced by IL-1ß, as shown by down regulation of Il-1ß, Il-6, Il-8 and Cox2, and increased the expression of antioxidant enzyme Sod2. Additionally, TUDCA enhanced Col IIα expression in IL-1ß- and TNC-stimulated cells, but only in normoxic conditions. Altogether, these results suggest that although TUDCA may display chondoprotective potential in ER-stressed cells, further analyses are still necessary to fully confirm its possible recommendation as potential candidate in OA therapy.


Assuntos
Inflamação/tratamento farmacológico , Interleucina-1beta/genética , Osteoartrite/tratamento farmacológico , Ácido Tauroquenodesoxicólico/farmacologia , Fator de Transcrição CHOP/genética , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/crescimento & desenvolvimento , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Células Cultivadas , Condrócitos/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/patologia , Osteoartrite/genética , Osteoartrite/patologia , Ácido Tauroquenodesoxicólico/química , Tunicamicina/farmacologia
12.
Int J Mol Med ; 47(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33537813

RESUMO

The activation of oxidative stress is a primary cause of chondrocyte apoptosis in osteoarthritis (OA). The 78­kDa glucose­regulated protein (GRP78)/mammalian target of rapamycin (mTOR) signaling pathway has been demonstrated to be linked with the endoplasmic reticulum (ER) and autophagy. Hydrogen sulfide (H2S) has been reported to exert antioxidant effects. The present study investigated oxidative stress levels via 2',7'­dichlorofluorescin diacetate and MitoSOX staining, apoptosis rates via flow cytometry and the expression levels of ER stress­related proteins in GYY4137 (donor of H2S)­treated chondrocytes (CHs). CHs were isolated from the bilateral hip joints of male rats to examine mitochondrial permeability transition pore opening­ and mTOR signaling pathway­related proteins. The results demonstrated that tert­Butyl hydroperoxide (TBHP) increased CH apoptosis, and treatment with GYY4137 ameliorated TBHP­mediated the generation of ROS and CH apoptosis. Moreover, TBHP­treated CHs displayed elevated ER stress sensor expression levels and apoptotic rates; however, the TBHP­induced protein expression levels were decreased following GYY4137 treatment. In the present study, treatment with either GYY4137 or transfection with GRP78 siRNA both suppressed the activation of p­P70S6k and p­mTOR. H2S played an important role in regulating ER stress in TBHP­stimulated CHs. GYY4137 promoted autophagy, which was accompanied by the inhibition of ER stress. On the whole, the present study demonstrates that TBHP­induced oxidative stress stimulates ER interactions and CH apoptosis, which are suppressed by exogenous H2S via modulating the GRP78/mTOR signaling pathway.


Assuntos
Condrócitos/metabolismo , Condrócitos/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Sulfeto de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Condrócitos/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Masculino , Morfolinas/química , Morfolinas/farmacologia , Compostos Organotiofosforados/química , Compostos Organotiofosforados/farmacologia , Peróxidos/farmacologia , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Carbohydr Polym ; 258: 117692, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33593565

RESUMO

Osteoarthritis (OA) is the most prevalent articular chronic disease. Although, to date there is no cure for OA. Fucoidans, one of the main therapeutic components of brown algae, have emerged as promising molecules in OA treatment. However, the variability between fucoidans makes difficult the pursuit of the most suitable candidate to target specific pathological processes. By an in vitro experimental approach in chondrocytes and fibroblast-like synoviocytes, we observed that chemical composition of fucoidan, and specifically the phlorotannin content and the ratio sulfate:fucose, seems critically relevant for its biological activity. Nonetheless, other factors like concentration and molecular weight of the fucoidan may influence on its beneficial effects. Additionally, a cell-type dependent response was also detected. Thus, our results shed light on the potential use of fucoidans as natural molecules in the treatment of key pathological processes in the joint that favor the development of rheumatic disorders as OA.


Assuntos
Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Polissacarídeos/química , Sinoviócitos/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Antioxidantes/química , Apoptose/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/metabolismo , Feminino , Fibroblastos/metabolismo , Fucose/química , Fucus , Humanos , Técnicas In Vitro , Macrocystis , Masculino , Potencial da Membrana Mitocondrial , Pessoa de Meia-Idade , Oligossacarídeos/química , Osteoartrite/metabolismo , Floroglucinol/química , Espécies Reativas de Oxigênio , Doenças Reumáticas/imunologia , Sulfatos/química , Sinoviócitos/citologia , Undaria
14.
Vet Surg ; 50(3): 633-640, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33580729

RESUMO

OBJECTIVE: To quantitate bupivacaine concentration and formulation effects on chondrocyte viability in vitro. STUDY DESIGN: Controlled laboratory study. SAMPLE POPULATION: Primary canine chondrocyte isolates. METHODS: Cell passage 3 and 4 canine chondrocytes were exposed to 0.9% saline; canine chondrocyte growth medium; 0.4, 0.5, 0.6, 1.5, 2.5, 3.5, or 5 mg/mL preservative-free standard formulation bupivacaine (SFB); or 13.3 or 6.65 mg/mL liposomal encapsulated bupivacaine (LEB) for 1 hour. Chondrocyte viability and clonogenicity were quantitated with 3-(4,5-dimethylthiazol-2-31 yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenic assays, respectively. Differences among concentrations and formulations were assessed with Kruskal-Wallis and Dwass-Steel-Critchlow-Fligner post hoc tests. RESULTS: Growth medium had the highest cell viability based on MTT metabolism. Similarly, all LEB concentration groups had higher cell viability compared with SFB concentration cells treated with 3.5 or 5 mg/mL SFB (P < .03). Among SFB concentrations, cell viability was higher at 0.6 mg/mL compared with at 2.5 mg/mL or greater (P < .03). Cell clonogenicity was not significantly different between saline, culture medium, or 0.5 mg/mL SFB. Clonogenicity was lower with all tested LEB concentrations compared with saline or medium (P < .02). CONCLUSION: In vitro toxicity of SFB on canine chondrocytes is concentration dependent. Liposomal encapsulated bupivacaine may have time-dependent effects resulting in chondrotoxicity. CLINICAL SIGNIFICANCE: Clinically relevant concentrations of SFB after a single injection may not result in chondrotoxic effects in vitro. Liposomal encapsulated bupivacaine should not be used in the articular environment.


Assuntos
Anestésicos Locais/efeitos adversos , Bupivacaína/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Cães , Animais
15.
Vet Surg ; 50(3): 650-658, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33606293

RESUMO

OBJECTIVE: To evaluate relative cytotoxicity of antibiotics to normal canine joint tissues in vitro. STUDY DESIGN: Experimental in vitro study. SAMPLE POPULATION: Chondrocytes and synoviocytes (three dogs); cartilage explants (three dogs); six dogs total. METHODS: Chondrocytes and synoviocytes from normal femoropatellar joints of three dogs were plated on 24-well plates (50 000 cells/cm2 , triplicate, 48 hours) and exposed to antibiotics (ampicillin sulbactam, vancomycin, cefazolin, ceftazidime, amikacin, enrofloxacin; 0.39-25 mg/mL, 24 hours). Viability was assessed by using trypan blue dye exclusion. Antibiotic concentrations at which 50% cell death occurred (half-maximal inhibitory concentration) were determined to rank antibiotics for relative cytotoxicity. Occurrence of caspase-3 expression after antibiotic exposure was assessed as an indication of apoptosis induction. Cartilage explants from three different dogs were minced and exposed to antibiotics (amikacin, ceftazidime, cefazolin, enrofloxacin; 5 mg/mL, 72 hours). Live/dead staining was performed, and fluorescence was visualized by using confocal microscopy. Percentage of live vs dead cells was quantitated. RESULTS: Viability of chondrocytes and synoviocytes decreased with increasing antibiotic concentrations. Half-maximal inhibitory concentrations were determined for synoviocytes (vancomycin 13.77, ampicillin sulbactam 3.07, amikacin 2.26, ceftazidime 1.62, cefazolin 1.48, enrofloxacin 1.25 mg/mL) and chondrocytes (vancomycin 8.65, ampicillin sulbactam 8.63, ceftazidime 3.16, amikacin 2.74, cefazolin 1.67, enrofloxacin 0.78 mg/mL). Caspase-3 expression was upregulated, providing evidence that apoptotic pathways were active in cell death. CONCLUSION: Half-maximal inhibitory concentration data provided evidence of lower toxicity of vancomycin and ampicillin sulbactam to joint tissues in vitro. CLINICAL SIGNIFICANCE: These results provide evidence to justify future in vitro work with osteoarthritic joint tissues and in vivo clinical trials to evaluate safety and efficacy of intra-articular antibiotics to treat dogs with septic arthritis.


Assuntos
Antibacterianos/toxicidade , Cartilagem/efeitos dos fármacos , Sobrevivência Celular , Condrócitos/efeitos dos fármacos , Cães , Sinoviócitos/efeitos dos fármacos , Animais , Cadáver , Cartilagem/transplante , Sobrevivência Celular/efeitos dos fármacos , Feminino , Masculino
16.
Int J Biol Macromol ; 172: 381-393, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476613

RESUMO

Current implantable materials are limited in terms of function as native tissue, and there is still no effective clinical treatment to restore articular impairments. Hereby, a functionalized polyacrylamide (PAAm)-alginate (Alg) Double Network (DN) hydrogel acting as an articular-like tissue is developed. These hydrogels sustain their mechanical stability under different temperature (+4 °C, 25 °C, 40 °C) and humidity conditions (60% and 75%) over 3 months. As for the functionalization, transforming growth factor beta-3 (TGF-ß3) encapsulated (NPTGF-ß3) and empty poly(lactide-co-glycolide) (PLGA) nanoparticles (PLGA NPs) are synthesized by using microfluidic platform, wherein the mean particle sizes are determined as 81.44 ± 9.2 nm and 126 ± 4.52 nm with very low polydispersity indexes (PDI) of 0.194 and 0.137, respectively. Functionalization process of PAAm-Alg hydrogels with ester-end PLGA NPs is confirmed by FTIR analysis, and higher viscoelasticity is obtained for functionalized hydrogels. Moreover, cartilage regeneration capability of these hydrogels is evaluated with in vitro and in vivo experiments. Compared with the PAAm-Alg hydrogels, functionalized formulations exhibit a better cell viability. Histological staining, and score distribution confirmed that proposed hydrogels significantly enhance regeneration of cartilage in rats due to stable hydrogel matrix and controlled release of TGF-ß3. These findings demonstrated that PAAm-Alg hydrogels showed potential for cartilage repair and clinical application.


Assuntos
Resinas Acrílicas/química , Alginatos/química , Materiais Biocompatíveis/química , Cartilagem Articular/efeitos dos fármacos , Hidrogéis/química , Nanopartículas/química , Fator de Crescimento Transformador beta3/farmacocinética , Implantes Absorvíveis , Animais , Materiais Biocompatíveis/farmacologia , Cartilagem Articular/crescimento & desenvolvimento , Cartilagem Articular/lesões , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/fisiologia , Composição de Medicamentos/métodos , Membro Posterior/efeitos dos fármacos , Masculino , Nanopartículas/ultraestrutura , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta3/química , Fator de Crescimento Transformador beta3/metabolismo , Resultado do Tratamento
17.
Life Sci ; 268: 118992, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417956

RESUMO

Osteoarthritis (OA) is a common chronic degenerative disease that affects the elderly. Thus far, no pharmacological therapy approved by regulators has shown a convincing effect on OA. Glabridin, a small molecule, is a well-known and powerful natural antioxidant, which has a strong scavenging effect on free radicals. This study attempted to explore the role and underlying mechanisms of Glabridin on OA both in vitro and in vivo. In the in vitro study, Glabridin was found to increase the expression levels of extracellular matrix (ECM) related genes, Collagen II, Aggrecan (ACAN), SRY-box 9 (SOX9) and proteoglycan 4 (PRG4). Moreover, Glabridin was observed to significantly reduce the level of oxidative stress in OA chondrocytes while effectively reducing the apoptosis of chondrocytes. Glabridin was also found to significantly increase the autophagy of human OA chondrocytes. During the in vivo study, intraarticular injection of Glabridin was observed to alleviate OA progression and protect chondrocytes against apoptosis following anterior cruciate ligament transection (ACLT) in rats. Furthermore, the mammalian target of rapamycin (mTOR) mediated autophagy was identified as one of the potential mediators of Glabridin activity. Overall, Glabridin protects articular cartilage from damage in rats with OA by protecting chondrocytes against oxidative stress, apoptosis and promoting mTOR mediated autophagy.


Assuntos
Condrócitos/efeitos dos fármacos , Isoflavonas/farmacologia , Osteoartrite do Joelho/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Animais , Ligamento Cruzado Anterior/patologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cartilagem Articular/patologia , Catalase/metabolismo , Condrócitos/metabolismo , Condrócitos/patologia , Proteínas da Matriz Extracelular/genética , Humanos , Injeções Intra-Articulares , Isoflavonas/administração & dosagem , Masculino , Osteoartrite do Joelho/etiologia , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Estresse Oxidativo/fisiologia , Fenóis/administração & dosagem , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Serina-Treonina Quinases TOR/metabolismo
18.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430111

RESUMO

Articular cartilage experiences mechanical constraints leading to chondral defects that inevitably evolve into osteoarthritis (OA), because cartilage has poor intrinsic repair capacity. Although OA is an incurable degenerative disease, several dietary supplements may help improve OA outcomes. In this study, we investigated the effects of Dielen® hydrolyzed fish collagens from skin (Promerim®30 and Promerim®60) and cartilage (Promerim®40) to analyze the phenotype and metabolism of equine articular chondrocytes (eACs) cultured as organoids. Here, our findings demonstrated the absence of cytotoxicity and the beneficial effect of Promerim® hydrolysates on eAC metabolic activity under physioxia; further, Promerim®30 also delayed eAC senescence. To assess the effect of Promerim® in a cartilage-like tissue, eACs were cultured as organoids under hypoxia with or without BMP-2 and/or IL-1ß. In some instances, alone or in the presence of IL-1ß, Promerim®30 and Promerim®40 increased protein synthesis of collagen types I and II, while decreasing transcript levels of proteases involved in OA pathogenesis, namely Htra1, and the metalloproteinases Mmp1-3, Adamts5, and Cox2. Both Promerim® hydrolysates also decreased Htra1 protein amounts, particularly in inflammatory conditions. The effect of Promerim® was enhanced under inflammatory conditions, possibly due to a decrease in the synthesis of inflammation-associated molecules. Finally, Promerim® favored in vitro repair in a scratch wound assay through an increase in cell proliferation or migration. Altogether, these data show that Promerim®30 and 40 hold promise as dietary supplements to relieve OA symptoms in patients and to delay OA progression.


Assuntos
Cartilagem Articular/efeitos dos fármacos , Colágeno/biossíntese , Organoides/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Animais , Cartilagem Articular/crescimento & desenvolvimento , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/efeitos dos fármacos , Cavalos , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Organoides/crescimento & desenvolvimento , Pele/química
19.
Food Funct ; 12(3): 1327-1337, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33443518

RESUMO

Osteoarthritis (OA) is a common degenerative joint disease characterized by articular cartilage degeneration and inflammation. Currently, there is hardly any effective treatment for OA due to its complicated pathology and the severe side effects of the treatment drugs used. It has been reported that maltol, a Maillard reaction product derived from ginseng, inhibits inflammation and oxidative stress in several animal models. However, the potential anti-inflammatory effects of maltol in OA treatment are unknown. This study aimed to evaluate the anti-inflammatory effects of maltol on interleukin (IL)-1ß-induced mouse chondrocytes and protective effects of maltol on these chondrocytes in medial meniscus destabilization (DMM) OA mouse models. Mice, randomly divided into maltol (n = 15), vehicle (n = 15) and control (n = 15) groups were treated with the same dose of maltol or saline, respectively. The cartilage tissues were extracted for histological analysis 8 weeks postoperative. For the in vitro studies, chondrocytes were treated with 10 ng mL-1 IL-1ß combined with maltol at different concentrations. In vitro assays showed that the maltol pre-treatment significantly inhibited the expressions of multiple inflammatory factors induced by IL-1ß, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nitric oxide (NO), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α). In addition, maltol alleviated the degradation of the extracellular matrix (ECM) by inhibiting the expressions of matrix metalloproteinase-13 (MMP13) and thrombospondin motif 5 (ADAMTS5), as well as reversing the degradation of aggrecan and collagen II. Moreover, maltol suppressed nuclear factor kappa B (NF-κB) signaling by activating the nuclear factor-erythroid 2-related factor-2 (Nrf2) in in vitro and in vivo studies. These findings indicate that maltol reduces the inflammation induced by IL-1ß in chondrocytes. Therefore, the results of this study indicated that maltol may be a potential drug for the effective treatment of OA.


Assuntos
Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Osteoartrite/prevenção & controle , Pironas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Matriz Extracelular , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fator 2 Relacionado a NF-E2/genética , Osteoartrite/etiologia
20.
Food Funct ; 12(4): 1590-1602, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33471008

RESUMO

Oxidative stress-mediated excessive apoptosis and senescence of chondrocytes are the main pathological alterations in the osteoarthritis (OA) development. The protective effects of theaflavin (TF), a common group of polyphenols in black tea, against many degenerative diseases by attenuating oxidative stress are well reported. Nevertheless, its role in the OA treatment is still scantily understood. In the current research, by applying enzyme-linked immunosorbent assay (ELISA) kits and immunofluorescent staining, TF treatment was found to inhibit tert-Butyl hydroperoxide (TBHP)-induced imbalance of anabolism and catabolism in primary mouse chondrocytes. Then, according to western blot, live-dead staining, and SA-ß-gal staining, the dramatically increased level of apoptosis and senescence of chondrocytes in response to TBHP was also found to be reduced by TF administration. With regard to upstream signaling investigation, the in vitro molecular binding analysis indicated that the beneficial effects of TF might be related to the regulation of the Keap1/Nrf2/HO-1 axis. Furthermore, the Silencing of Nrf2 resulted in the abolishment of the anti-apoptosis and anti-senescence effects of TF. In addition, the oral administration of TF was demonstrated to ameliorate osteoarthritis development in a surgically induced mouse OA model. Taken together, these results suggest that TF might be a promising therapeutic option for the treatment of OA.


Assuntos
Apoptose/efeitos dos fármacos , Biflavonoides/farmacologia , Catequina/farmacologia , Condrócitos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Osteoartrite/metabolismo , Animais , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia
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