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2.
Hum Genet ; 138(11-12): 1217-1225, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31606751

RESUMO

Pluripotent stem cell (PSC) cultures form an integral part of biomedical and medical research due to their capacity to rapidly proliferate and differentiate into hundreds of highly specialized cell types. This makes them a highly useful tool in exploring human physiology and disease. Genomic editing of PSC cultures is an essential method of attaining answers to basic physiological functions, developing in vitro models of human disease, and exploring potential therapeutic strategies and the identification of drug targets. Achieving reliable and efficient genomic editing is an important aspect of using large-scale PSC cultures. The CRISPR/Cas9 genomic editing tool has facilitated highly efficient gene knockout, gene correction, or gene modifications through the design and use of single-guide RNAs which are delivered to the target DNA via Cas9. CRISPR/Cas9 modification of PSCs has furthered the understanding of basic physiology and has been utilized to develop in vitro disease models, to test therapeutic strategies, and to facilitate regenerative or tissue repair approaches. In this review, we discuss the benefits of the CRISPR/Cas9 system in large-scale PSC cultures.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Técnicas de Inativação de Genes , Genômica/métodos , Células-Tronco Pluripotentes/fisiologia , Humanos , Células-Tronco Pluripotentes/citologia
3.
Pharmacol Res ; 148: 104414, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31449974

RESUMO

Atherosclerosis (AS) is one of the major causes leading to mortality of dysfunctional cardiovascular events in the menopausal women, which has long-term deficiency of estrogen. At present, the primary treatment for postmenopausal AS is hormone replacement therapy (HRT). However, it can increase the risks of ovarian and uterine cancers with long-term therapy. So seeking for a phytoestrogen which can overcome the disadvantages of HRT is a great mission. Dioscin, a traditional Chinese medicine, extracted from the roots of dioscorea nipponica, has anti-inflammatory, anti-tumor and anti-apoptosis activities. Especially, it also has estrogenic activity. Thus, this study aims to investigate the effects of dioscin on postmenopausal AS. Currently, ovariectomy (OVX) is the accepted model for AS associated with estrogen deficiency, and it can mimic the cessation of ovarian function that occurs in postmenopausal women as well. We used the high fat diet and ovariectomy(HFD-OVX)model to induce postmenopausal AS in the low-density lipoprotein receptor- deficient (LDLR-/-) mice. (1) The levels of TG, TC, LDL-C, HDLC, MDA, GSH, MDA and GSH in serum of HFD-OVX induced LDLR-/- mice were measured by colorimetric assay. (2) The artery injury of HFD-OVX induced LDLR-/- mice was detected with Oil Red O staining. (3) The protein expressions of NOX4, P22phox, IκB, p-p65, n-p65, ICAM-1, VCAM-1, caspase-3, caspase-9, bcl-2, PGC-1α, ERα, ERß in the arterial tissue of HFD-OVX induced LDLR-/- mice were detected by Western blot analysis. In vitro, the model of human aortic endothelial cells (HAECs) induced by oxidized low-density lipoprotein (ox-LDL) (150 µg /ml) was established, and the molecular mechanism of dioscin on atherosclerosis in postmenopausal women was investigated. (1) The levels of MDA, GSH, MDA and GSH in ox-LDL induced HAECs were measured by colorimetric assay. (2) Reactive Oxygen Species (ROS) of ox-LDL induced HAEC cells was detected by fluorescence staining. (3) The protein expressions of PGC-1α, ERα, ERß, NOX4, P22phox, IκB, p-p65, n-p65, ICAM-1, VCAM-1, caspase-3, caspase-9, bcl-2 and LC3 in ox-LDL induced HAECs were detected by Western blot analysis. (4) The autophagy level of ox-LDL induced HAECs was measured by transmission electron microscopy. (5) The applications of si-RNA transfection were used to explore whether dioscin could activate PGC-1α/ERα pathway to inhibit postmenopausal atherosclerosis. In vivo, we found that dioscin decreased the level of TG, TC, LDL-C and increased the level of HDLC in serum of HFD-OVX induced LDLR-/- mice, and it has protective effects to maintain the lipid homeostasis; The Oil Red O staining study showed that dioscin could significantly inhibit the formation of atherosclerotic plaques in HFD-OVX-treated LDLR-/- mice; Dioscin decreased the levels of NOX4, P22phox, p-p65, n-p65, ICAM-1, VCAM-1, caspase-3, caspase-9, but increased the levels of HDL-C, GSH, SOD, PGC-1α, ERα, ERß, IκB, Bcl-2 and elevated the autophagy level in arterial tissues of HFD-OVX induced LDLR-/- mice. It is particularly worth mentioning that the up-regulating effect of dioscin on ERα is stronger than ERß in OVX treated mice. In vitro, the results of colorimetric assay showed that dioscin decreased the level of MDA and LDH, increased the level of SOD and GSH in ox-LDL-induced HAEC cells; Dioscin also suppressed the release of ROS in ox-LDL-induced HAECs by fluorescence staining; Dioscin decreased the levels of NOX4, P22phox, p-p65, n-p65, ICAM-1, VCAM-1, caspase-3, caspase-9, but increased the levels of PGC-1α, ERα, ERß, IκB, Bcl-2 and the ratio of LC3-II/LC3-I in ox-LDL-induced HAECs; Dioscin significantly elevated the autophagy level of ox-LDL-induced HAECs by transmission electron microscopy analysis; In addition, by si-RNA transfection, we found that the inhibitory effects of dioscin on oxidative stress, inflammatory response and apoptosis might partly through PGC-1α/ERα pathway in ox-LDL induced HAECs. The data of dual-Luciferase reporter assay revealed that dioscin activated ERα at least partly through PGC-1α pathway. Dioscin significantly inhibited oxidative stress, inflammatory response, apoptosis and increased the level of autophagy in vivo and vitro. In addition, dioscin could regulate the balance of lipid metabolism. Moreover, we proved that the effects of dioscin attenuating postmenopausal atherosclerosis by inhibiting oxidative stress, inflammation and apoptosis were partly dependent on PGC-1α/ERα pathway. Therefore, dioscin, as a phytoestrogen, might become a drug for the treatment of atherosclerosis in postmenopausal women.

4.
Drug Des Devel Ther ; 13: 2503-2512, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440033

RESUMO

Background: Osteoarthritis (OA) is a common joint disease, which is characterized by degradation of articular cartilage. Evidence indicated that miR-23b-3p was upregulated in cartilage tissues of a patient with OA. However, the mechanism by which miR-23b-3p regulates the occurrence and development of OA remains unclear. Thus, this study aimed to investigate the role of miR-23b-3p in the progression of OA. Methods: In this study, qRT-PCR was used to measure the expression of miR-23b-3p in OA tissue samples and normal controls, respectively. Western blotting assay was performed to detect the levels of collagen II, aggrecan, Bax and active caspase 3 in CHON-001 cells. In addition, the dual-luciferase reporter system assay was used to detect the interaction between miR-23b-3p and COL11A2 in OA. Results: The levels of miR-23b-3p were upregulated, while the expressions of collagen II and aggrecan were decreased in OA tissues and in IL-1ß-treated CHON-001 cells. In addition, IL-1ß significantly induced apoptosis of CHON-001 cells via increasing the levels of Bax and active caspase 3. However, downregulation of miR-23b-3p markedly inhibited IL-1ß-induced apoptosis in CHON-001 cells via increasing the collagen II and aggrecan levels and decreasing Bax and active caspase 3 expressions. Meanwhile, dual-luciferase assay showed that COL11A2 was the direct target of miR-23b-3p in CHON-001 cells. Overexpression of miR-23b-3p markedly decreased the level of COL11A2 in cells. Moreover, downregulation of miR-23b-3p alleviated synovitis/cartilage destruction and reduced Osteoarthritis Research Society International scores and subchondral bone thickness in vivo. Conclusion: Downregulation of miR-23b-3p could alleviate the progression of OA through upregulating COL11A2 in vivo and in vitro. Therefore, downregulation of miR-23b-3p might be a potential therapeutic strategy for the treatment of OA.

5.
Int Immunopharmacol ; 75: 105762, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31357086

RESUMO

BACKGROUNDS: Up-regulated HIF-2α (hypoxia induced factor 2) had been demonstrated to contribute to Osteoarthritis (OA) development via inducing the expression of matrix-degrading enzymes. However, the HIF-2α also could promote primary cilia loss through HIF-2α/AURKA (Aurora kinase A)/NEDD9 pathway. And the primary cilia dysfunction is another characteristic of the OA. Thus, we investigated here whether the HIF-2α also contributes the OA development through mediating the primary cilia loss. METHODS: The primary chondrocytes were isolated from the experimental OA mice induced by destabilization of the medial meniscus (DMM). Chondrocytes were cultured under normoxia (21% O2) or hypoxia (2% O2) conditions. The HIF-1α and HIF-2α expressions were assessed by western blot. The cilia formation was counted by immuno-staining the acetylated tubulin. The contribution of HIF-1α or HIF-2α to the primary cilia loss was assessed by knocking-down the HIF-1α or HIF-2α individually. The HIF-2α/AURKA/NEDD9 pathway was validated through over-expressing or knocking-down specific components of the pathway and then counting the primary cilia number. Finally, the pathway was further confirmed in the OA mice. RESULTS: Hypoxia could induce the expression of both HIF-1α and HIF-2α, and also reduce the number of primary cilia on the chondrocytes isolated from the experimental OA mice. Knocking-down or over-expressing HIF-1α or HIF-2α individually showed that the HIF-2α could induce the primary cilia reduction rather than the HIF-1α. Manipulating the HIF-2α expression could positively affect the AURKA and NEDD9 expression. Manipulating the AURKA and NEDD9 expressions could reverse the function of HIF-2α on primary cilia. In the mice, knocking-down both AURKA and NEDD9 could alleviate the OA development significantly. CONCLUSION: Up-regulated HIF-2α contributes to the Osteoarthritis development through mediating the primary cilia loss, which might be developed as therapeutic targets for OA treatment.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cílios/fisiologia , Osteoartrite/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Cultivadas , Condrócitos/metabolismo , Técnicas de Silenciamento de Genes , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Articulação do Joelho/patologia , Lentivirus/genética , Masculino , Camundongos Endogâmicos C57BL , Osteoartrite/patologia , RNA Interferente Pequeno/genética , Regulação para Cima
6.
J Cell Biochem ; 120(6): 10812-10820, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30672021

RESUMO

Osteoarthritis (OA) is the most common degenerative joint disease and results from progressive loss and destruction of articular cartilage and the underlying bone. The disease affects millions of people worldwide with an associated risk of mobility disability. However, the molecular basis underlying OA initiation and progression is not well understood and, currently, there is no effective intervention available to decelerate disease progression or restore degraded cartilage. We have found that lncRNA long intergenic nonprotein coding RNA 341 (LINC00341) is aberrantly downregulated in OA patient tissues and cultured OA chondrocytes. This is likely responsible for the increased apoptosis of chondrocytes and pathological destruction of cartilage. Further investigation has revealed that LINC00341 interacts with miR-141 to suppress its functional binding to the 3'-untranslated region of YY1-associated factor 2 (YAF2) messenger RNA. Aberrant downregulation of LINC00341 thus may ultimately lead to inhibition of the YAF2 protein, which has been implicated to be an antiapoptotic factor. Our study has revealed a new noncoding RNA-mediated regulatory network that highly likely protects chondrocytes by preventing apoptosis under normal conditions. The results will help further explore the molecular details pertaining to the progression of OA and stimulate efforts to develop effective therapies.

7.
J Cell Biochem ; 120(3): 3989-3997, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30260030

RESUMO

OBJECTIVE: The aim of the study was to explore the mechanism of excessive apoptosis of nucleus pulposus cells induced by short hairpin RNA (shRNA) Piezo type mechanosensitive ion channel component 1 (Piezo1) under abnormal mechanical stretch stress. METHODS: In vitro mechanical stretch stress model of nucleus pulposus cells in vitro was established, in which the expression of Piezo1 was interfered by transfection of shRNA-Piezo1 interfering vector. Both messenger RNA and protein level of Piezo1 were measured by reverse-transcription polymerase chain reaction and Western blot analysis, respectively. Cytoplasmic Ca2+ was detected by Fluo3-AM kit, and changes of mitochondrial membrane potential in cells were detected using Cell Meter Assay kit. Finally, the apoptosis was evaluated with annexin V-fluorescein isothiocyanate kit. RESULTS: The highest transfection efficiency of lentivirus titer was 1 × 10 TU/mL and the nucleus pulposus cells were transfected with plural multiplicity of infection = 50. Homo-3201 sequence exhibited the most effective silencing effect and was used in subsequent experiments as the default sequence of shRNA-Piezo1. The calcium content in the cytoplasm of the tension stress group increased significantly compared with that in the blank control group ( q = 3.773; P < 0.05). The level of cytosolic calcium in shRNA-interference group was significantly lower than that in stretch stress group ( q = 5.159; P < 0.05). Stretch stress treatment resulted in an elevated ratio of mitochondrial membrane potential turnover as opposed to blank control group ( q = 4.332; P < 0.05), while shRNA-interference group showed smaller ratio of mitochondrial membrane potential turnover than that in stretch stress group ( q = 4.974; P < 0.05). Similar results were also observed in apoptosis rate analysis ( q = 3.175; P < 0.05). CONCLUSION: ShRNA-Piezo1 can protect cells by reducing the level of intracellular Ca2+ and the change of mitochondrial membrane potential.

8.
J Cell Physiol ; 234(4): 4472-4490, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30192012

RESUMO

Glucocorticoid-induced osteoporosis (GIO) is a secondary osteoporosis with extensive use of glucocorticoids (GCs). GCs can increase bone fragility and fracture via inhibiting osteoblastic proliferation and differentiation. Luteolin (LUT), a kind of plant flavonoid, has been reported to exhibit the antioxidant activity, but the effects of LUT on GIO still remain unclear. This study aimed to investigate the effects of LUT on GIO both in vivo and in vitro and elaborate the potential molecular mechanisms. LUT increased the superoxide dismutase activity, glutathione level and decreased reactive oxygen species (ROS) level and lactate dehydrogenase release in GIO. Meanwhile, LUT decreased caspase-3, caspase-9, and Bax protein expressions and increased Bcl-2 protein expression in GIO. LUT increased the ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor-κB Ligand (RANKL) messenger RNA (mRNA) expression and mRNA expression levels of osteogenic markers, including runt-related transcription factor 2, osterix, collagen type I, and osteocalcin. LUT also enhanced the extracellular signal-regulated kinases (ERK) phosphorylation, glycogen synthase kinase 3ß (GSK-3ß) phosphorylation, mRNA expression levels of lipoprotein-receptor-related protein 5 (Lrp-5) and ß-catenin. Further study revealed that Lrp-5 small interfering RNA (siRNA )and ERK-siRNA reduced the effects of LUT on GSK-3ß phosphorylation, alkaline phosphatase (ALP) activity and the ratio of OPG/RANKL mRNA expression. Moreover, ERK-siRNA decreased Lrp-5 mRNA expression in vitro. These results indicated that LUT promoted proliferation by attenuating oxidative stress and promoted osteoblastic differentiation by regulating the ERK/Lrp-5/GSK-3ß pathway in GIO. This study may bring to light the possible mechanisms involved in the action of LUT in GIO treatment, and benefit for further research on GIO.

9.
BMC Musculoskelet Disord ; 19(1): 239, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30025527

RESUMO

BACKGROUND: The aim of this study was to determine the functional and radiological outcomes of arthroscopic treatment of anterior ankle impingement (AAI) in patients with chronic lateral ankle instability (CAI). METHODS: All patients with CAI between June 2012 and May 2015 were invited to participate in this investigation. All of them accepted open modified Broström repair of lateral ankle ligaments and were divided into two groups: AAI group (with anterior ankle impingement) and pure CAI group (without anterior ankle impingement). All of them were followed up using American Orthopaedic Foot and Ankle Society Score (AOFAS), Karlsson Ankle Functional Score and Tegner activity score. Ankle dorsiflexion was also examined. X-ray examination was applied to investigate anterior tibiotalar osteophytes. RESULTS: Finally, a total of 60 patients were followed up at a mean of 37 ± 10 months, including 22 patients in the AAI group and 38 patients in the pure CAI group. Preoperatively, the AAI group had significant lower AOFAS score (62.9 ± 11.7 vs 72.9 ± 11.1; p = 0.002) and Tegner activity score (1.5 ± 0.8 vs 2.1 ± 1.0; p = 0.04) respectively when compared with the pure CAI group. The ankle dorsiflexion of the AAI group (13 ± 2.1) was also significantly lower than that of the pure CAI group (26.2 ± 2.1) (p = 0.001). However, there was no significant difference in the AOFAS score or the Karlsson score or the Tegner score or the Ankle dorsiflexion between the two groups postoperatively. The postoperative X-ray images demonstrated complete osteophyte resection in all patients, and no recurrence of osteophyte. CONCLUSION: The functional outcome scores and dorsiflexion had significantly improved postoperatively. Combined treatment of chronic ankle instability and anterior ankle impingement produced satisfactory surgical outcomes in patients with CAI accompanied by anterior ankle impingement symptom.


Assuntos
Artroscopia/métodos , Desbridamento/métodos , Instabilidade Articular/diagnóstico por imagem , Instabilidade Articular/cirurgia , Ligamentos Laterais do Tornozelo/diagnóstico por imagem , Ligamentos Laterais do Tornozelo/cirurgia , Adulto , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/cirurgia , Doença Crônica , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
10.
Oxid Med Cell Longev ; 2018: 2876350, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30046372

RESUMO

Catalpol, an iridoid glucoside, has been found present in large quantities in the root of Rehmannia glutinosa L. and showed a strong antioxidant capacity in the previous study. In the present work, the protective effect of catalpol against AS via inhibiting oxidative stress, DNA damage, and telomere shortening was found in LDLr-/- mice. This study also shows that activation of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)/telomerase reverse transcriptase (TERT) pathway, which is the new link between mitochondria and telomere, was involved in the protective effects of catalpol. Further, by using PGC-1α or TERT siRNA in oxLDL-treated macrophages, it is proved that catalpol reduced oxidative stress, telomere function, and related DNA damage at least partly through activating the PGC-1α/TERT pathway. Moreover, dual luciferase activity assay-validated catalpol directly enhanced PGC-1α promoter activity. In conclusion, our study revealed that the PGC-1α/TERT pathway might be a possible therapeutic target in AS and catalpol has highly favorable characteristics for the treatment of AS via modulating this pathway.


Assuntos
Glucosídeos Iridoides/farmacologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Telomerase/metabolismo , Telômero/efeitos dos fármacos , Telômero/metabolismo , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Western Blotting , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Glucosídeos Iridoides/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Células THP-1 , Telomerase/genética
11.
Zhongguo Gu Shang ; 31(6): 550-555, 2018 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-29945412

RESUMO

OBJECTIVE: To explore the expression characteristics of new mechanosensitive ion channel Piezo1 protein in stress models of human degenerative chondrocytes. METHODS: The stress stimulation model of human degenerative chondrocytes in vitro was constructed. Multi-channel cell stretch stress loading system FX-4000T was used to treat chondrocytes. According to the results of pre-test, the loading frequency of 0.5 Hz and the cell elongation of 20% were loaded. According to cell processing time, it was divided into 0 h, 2 h, 12 h, 24 h and 48 h mechanical stress group. The RT-PCR and Western-blot were used to test the expression of the Piezo1, also the Laser scanning confocal microscope (LSCM) was used to test the intensity of the fluorescence of the Piezo1. RESULTS: (1)The result of the RT-PCR showed that the expression of the Piezo1 in the 2 h group was higher than the 0 h group(F=13.917, q=0.037 1, P<0.05). The expression of the piezo1 in the 24 h group was the highest. While the expression of the piezo1 in the 48 h group was lower than the expression of the piezo1 in the 24 h group(F=13.917, q=0.049 5, P<0.05). (2)The result of the Western-blot showed that the 2 h group was higher than the 0 h group(F=19.341, q=0.037 1, P<0.05). The expression of the 24 h had the highest expression which was higher than the 48 h group(F=19.341, q=0.017 7, P<0.05). (3)The Piezo1 protein was extensively expressed in the cytoplasm and nucleus of the nucleus pulposus cells. And with the increase of stress processing time, the fluorescence intensity of the protein also increased. CONCLUSIONS: In human degeneration cartilage cells, the new mechanio sensitive ion channel Piezo1 protein has a trace expression. After loading periodic mechanical tensile force, the expression of Piezo1 protein increases with time dependence.


Assuntos
Condrócitos , Núcleo Pulposo , Proliferação de Células , Humanos , Canais Iônicos , Estresse Mecânico
12.
Cell Stress Chaperones ; 23(3): 393-398, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29247272

RESUMO

Low levels of inflammation-induced expression of matrix metalloproteinase (MMP) play a crucial role in articular cartilage matrix destruction in osteoarthritis (OA) patients. Interferon regulatory factor-8 (IRF-8), an important member in the IRF family, plays a key role in regulating the inflammation-related signaling pathway. The aim of this study is to investigate the physiological roles of IRF-8 in the pathological progression of OA. We found that IRF-8 was expressed in human primary chondrocytes. Interestingly, the expression of IRF-8 was upregulated in OA chondrocytes. In addition, IRF-8 was increased in response to interleukin-1ß (IL-1ß) treatment, mediated by the Janus kinase 2 (JAK2) pathway. Overexpression of IRF-8 in human chondrocytes by transduction with lentiviral-IRF-8 exacerbated IL-1ß-induced expression of matrix metalloproteinase-13 (MMP-13) in human chondrocytes. In contrast, knockdown of IRF-8 inhibited IL-1ß-induced expression of MMP-13. Importantly, IRF-8 could bind to the promoter of MMP-13 and stimulate its activity. Additionally, overexpression of IRF-8 exacerbated IL-1ß-induced degradation of type II collagen. However, silencing IRF-8 abrogated the degradation of type II collagen. Taken together, our findings identified a novel function of IRF-8 in regulating articular cartilage matrix destruction by promoting the expression of MMP-13.


Assuntos
Condrócitos/metabolismo , Fatores Reguladores de Interferon/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Células Cultivadas , Colágeno Tipo II/metabolismo , Humanos , Interleucina-1beta/metabolismo , Janus Quinase 2/metabolismo , Metaloproteinase 13 da Matriz/genética , Osteoartrite/genética , Osteoartrite/patologia , Transdução de Sinais , Regulação para Cima
13.
Am J Cancer Res ; 7(6): 1270-1284, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28670490

RESUMO

Dehydrocostus lactone (DHE), a natural sesquiterpene lactone, has been used for treatment of various diseases with its anti-inflammatory activity. Recently, it has caused extensive interest in researchers due to it has anti-cancer abilities in some types of carcinomas. However, the anti-cancer effect and mechanism of DHE in glioma remains unclear. The present study conducted to determine the biological effects of DHE on the glioblastoma cells, as well as the mechanisms underlying these effects. After treatment with DHE, the glioblastoma (U118, U251 or U87) cells were significantly inhibited in their viability, proliferation and migration. At the meantime, DHE also induced mitochondria-mediated apoptosis by promoting the release of cytochrome c into cytosol, which activating caspase signaling pathway. Furthermore, our results fully demonstrate that DHE significantly suppressed COX-2 expression by inhibiting the phosphorylation of IKKß via targeting the ATP-binding site, thereby abrogating NF-κB binding and p300 recruitment to COX-2 promoter. Moreover, the current study firstly demonstrated that DHE can cross blood-brain barrier (BBB). In addition, treatment with DHE markedly inhibited neoplastic weight and volume without the notable adverse effects in the xenograft nude mice model, and these effects may be mediated through inhibition of the IKKß/NF-κB/COX-2 signaling pathway. These findings provide the pharmacological evidence for development of DHE as a potential agent against glioma.

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