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1.
Chin J Physiol ; 66(4): 284-293, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37635488

RESUMO

Osteoarthritis (OA) is a form of chronic degenerative disease contributing to elevated disability rate among the elderly. Genkwanin is an active component extracted from Daphne genkwa possessing pharmacologic effects. Here, this study is designed to expound the specific role of genkwanin in OA and elaborate the probable downstream mechanism. First, the viability of chondrocytes in the presence or absence of interleukin-1 beta (IL-1ß) treatment was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used to assess cell apoptosis. Inflammatory response was estimated through enzyme-linked immunosorbent assay and Western blot. In addition, immunofluorescence staining and Western blot were utilized to measure the expression of extracellular matrix (ECM)-associated proteins. Dual-specificity protein phosphatase-1 (DUSP1) expression was tested by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot. Following DUSP1 elevation in genkwanin-treated chondrocytes exposed to IL-1ß, inflammatory response and ECM-associated factors were evaluated as forementioned. In addition, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide staining was to assess the mitochondrial membrane potential. Adenosine triphosphate (ATP) level was examined with ATP assay kit, and RT-qPCR was used to test mitochondrial DNA expression. Results indicated that genkwanin administration enhanced the viability while ameliorated the apoptosis, inflammatory response, and ECM degradation in IL-1ß-induced chondrocytes. Besides, genkwanin treatment fortified DUSP1 expression in IL-1ß-exposed chondrocytes. DUSP1 interference further offsets the impacts of genkwanin on the inflammation, ECM degradation, and mitochondrial dysfunction in IL-1ß-challenged chondrocytes. In short, genkwanin enhanced DUSP1 expression to mitigate mitochondrial dysfunction, thus ameliorating IL-1ß-elicited inflammation, apoptosis, and degradation of ECM in chondrocytes.


Assuntos
MicroRNAs , Osteoartrite , Humanos , Idoso , Condrócitos/metabolismo , Interleucina-1beta/farmacologia , Interleucina-1beta/metabolismo , Inflamação/tratamento farmacológico , Matriz Extracelular/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Apoptose , Mitocôndrias , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Trifosfato de Adenosina/uso terapêutico , MicroRNAs/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Fosfatase 1 de Especificidade Dupla/farmacologia
2.
Exp Ther Med ; 25(6): 303, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37229323

RESUMO

Osteoarthritis (OA) is a type of joint disease with a rising prevalence and incidence among the elderly across the global population. Chemokine-like factor 1 (CKLF1) is a human cytokine, which has been demonstrated to be involved in the progression of multiple human diseases. However, little attention has been paid to the impact of CKLF1 on OA. The present study was designed to identify the role of CKLF1 in OA and to clarify the regulatory mechanism. The expression levels of CKLF1 and its receptor CC chemokine receptor 5 (CCR5) were examined by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. A Cell Counting Kit-8 assay was used to estimate cell viability. The levels and expression of inflammatory factors were determined by ELISA and RT-qPCR, respectively. Apoptosis was investigated by TUNEL assays and the protein levels of apoptosis-related factors were analyzed by western blotting. RT-qPCR and western blotting were used to examine the expression of extracellular matrix (ECM) degradation-associated proteins and ECM components. Dimethylmethylene blue analysis was used to analyze the production of soluble glycosamine sulfate additive. A co-immunoprecipitation assay was used to confirm the protein interaction between CKLF1 and CCR5. The results revealed that CKLF1 expression was increased in IL-1ß-exposed murine chondrogenic ATDC5 cells. Furthermore, CKLF1 silencing enhanced the viability of IL-1ß-induced ATDC5 cells, while inflammation, apoptosis and degradation of the ECM were reduced. Additionally, CKLF1 knockdown led to decreased CCR5 expression in IL-1ß-challenged ATDC5 cells, and CKLF1 bound with CCR5. The enhanced viability, as well as the suppressed inflammation, apoptosis and degradation of the ECM, following CKLF1 knockdown in the IL-1ß-induced ATDC5 cells were all restored after CCR5 was overexpressed. In conclusion, CKLF1 might serve a detrimental role in the development of OA by targeting its receptor CCR5.

3.
J Appl Biomater Funct Mater ; 18: 2280800020962629, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33155513

RESUMO

BACKGROUND: Targeted delivery to the Rheumatoid arthritis (RA) which is characterized by destruction and degeneration of bones due to chronic inflammation is of great need. RA being a chronic autoimmune disorder might result in severe disability and morbidity. A targeted delivery system is designed to deliver methotrexate (MTX) for RA. METHODS: Here, we synthesized folic acid (FA) conjugated hydrophobically modified glycol chitosan (GC) self-assembled nanoparticles (FA-GC-SA) for the targeted delivery of MTX to RA. The FA conjugation and hydrophobic modification of GC by stearic acid (SA) was confirmed by Fourier-transform infrared spectroscopy (FTIR). The FA-GC-SA was exploited for developing targeted nanoparticles encapsulating MTX by the ionic gelation method. The particles were characterized and evaluated for their targeting potential in in vitro cell culture studies. Further their in vivo efficacy in arthritis induced rats using collagen was also evaluated. RESULTS: FTIR confirms the successful modification of GC-SA and FA-GC-SA. The FA-GC-SA-MTX of size 153 ± 9 nm were prepared with high encapsulation efficiency of MTX. The FA-GC-SA-MTX size was further confirmed by transmission electron microscopy (TEM). In vitro cell studies revealed the superior efficacy of FA-GC-SA-MTX in cell cytotoxicity. Also, significantly higher cellular uptake of FA functionalized FA-GC-SA-MTX was observed in comparison to non-functionalized GC-SA-MTX attributed to folate receptors (FRs) mediated endocytosis. In vivo results confirms the potential of FA-GC-SA-MTX which reduces reduces the pro-inflammatory cytokines, paw thickness, and arthritis score in collagen induced rats. CONCLUSION: The results shows that FRs targeted FA-GC-SA-MTX has superior efficacy in the treatment of RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Quitosana/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Metotrexato/administração & dosagem , Animais , Sobrevivência Celular , Colágeno/química , Endocitose , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Inflamação , Macrófagos/metabolismo , Camundongos , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Tamanho da Partícula , Células RAW 264.7 , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Ácidos Esteáricos/química
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