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1.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298988

RESUMO

This study evaluated the biocompatibility and biological performance of novel additive-manufactured bioabsorbable iron-based porous suture anchors (iron_SAs). Two types of bioabsorbable iron_SAs, with double- and triple-helical structures (iron_SA_2_helix and iron_SA_3_helix, respectively), were compared with the synthetic polymer-based bioabsorbable suture anchor (polymer_SAs). An in vitro mechanical test, MTT assay, and scanning electron microscope (SEM) analysis were performed. An in vivo animal study was also performed. The three types of suture anchors were randomly implanted in the outer cortex of the lateral femoral condyle. The ultimate in vitro pullout strength of the iron_SA_3_helix group was significantly higher than the iron_SA_2_helix and polymer_SA groups. The MTT assay findings demonstrated no significant cytotoxicity, and the SEM analysis showed cells attachment on implant surface. The ultimate failure load of the iron_SA_3_helix group was significantly higher than that of the polymer_SA group. The micro-CT analysis indicated the iron_SA_3_helix group showed a higher bone volume fraction (BV/TV) after surgery. Moreover, both iron SAs underwent degradation with time. Iron_SAs with triple-helical threads and a porous structure demonstrated better mechanical strength and high biocompatibility after short-term implantation. The combined advantages of the mechanical superiority of the iron metal and the possibility of absorption after implantation make the iron_SA a suitable candidate for further development.


Assuntos
Implantes Absorvíveis , Materiais Biocompatíveis , Âncoras de Sutura , Alanina Transaminase/sangue , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Fenômenos Biomecânicos , Nitrogênio da Ureia Sanguínea , Fosfatos de Cálcio/química , Fosfatos de Cálcio/toxicidade , Sulfato de Cálcio/administração & dosagem , Sulfato de Cálcio/química , Sulfato de Cálcio/toxicidade , Creatinina/sangue , Desenho de Equipamento , Fêmur/diagnóstico por imagem , Fêmur/ultraestrutura , Ferro , Lasers , Teste de Materiais , Microscopia Eletrônica de Varredura , Estrutura Molecular , Osseointegração , Polímeros/química , Polímeros/toxicidade , Porosidade , Coelhos , Distribuição Aleatória , Resistência à Tração , Vísceras , Microtomografia por Raio-X
2.
Nat Commun ; 12(1): 3413, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099701

RESUMO

Bottom-up approaches using building blocks of modules to fabricate scaffolds for tissue engineering applications have enabled the fabrication of structurally complex and multifunctional materials allowing for physical and chemical flexibility to better mimic the native extracellular matrix. Here we report a vapor-phased fabrication process for constructing three-dimensional modulated scaffold materials via simple steps based on controlling mass transport of vapor sublimation and deposition. We demonstrate the fabrication of scaffolds comprised of multiple biomolecules and living cells with built-in boundaries separating the distinct compartments containing defined biological configurations and functions. We show that the fabricated scaffolds have mass production potential. We demonstrate overall >80% cell viability of encapsulated cells and that modulated scaffolds exhibit enhanced cell proliferation, osteogenesis, and neurogenesis, which can be assembled into various geometric configurations. We perform cell co-culture experiments to show independent osteogenesis and angiogenesis activities from separate compartments in one scaffold construct.


Assuntos
Materiais Biomiméticos/química , Vapor , Engenharia Tecidual/métodos , Tecidos Suporte/química , Animais , Técnicas de Cultura de Células , Linhagem Celular , Proliferação de Células , Técnicas de Cocultura , Matriz Extracelular , Humanos , Hidrogéis/química , Camundongos , Neovascularização Fisiológica , Neurogênese , Osteogênese , Ratos
3.
BMC Musculoskelet Disord ; 22(1): 171, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33573634

RESUMO

BACKGROUND: We developed a porous Ti alloy/PEEK composite interbody cage by utilizing the advantages of polyetheretherketone (PEEK) and titanium alloy (Ti alloy) in combination with additive manufacturing technology. METHODS: Porous Ti alloy/PEEK composite cages were manufactured using various controlled porosities. Anterior intervertebral lumbar fusion and posterior augmentation were performed at three vertebral levels on 20 female pigs. Each level was randomly implanted with one of the five cages that were tested: a commercialized pure PEEK cage, a Ti alloy/PEEK composite cage with nonporous Ti alloy endplates, and three composite cages with porosities of 40, 60, and 80%, respectively. Micro-computed tomography (CT), backscattered-electron SEM (BSE-SEM), and histological analyses were performed. RESULTS: Micro-CT and histological analyses revealed improved bone growth in high-porosity groups. Micro-CT and BSE-SEM demonstrated that structures with high porosities, especially 60 and 80%, facilitated more bone formation inside the implant but not outside the implant. Histological analysis also showed that bone formation was higher in Ti alloy groups than in the PEEK group. CONCLUSION: The composite cage presents the biological advantages of Ti alloy porous endplates and the mechanical and radiographic advantages of the PEEK central core, which makes it suitable for use as a single implant for intervertebral fusion.


Assuntos
Fusão Vertebral , Titânio , Animais , Desenvolvimento Ósseo , Feminino , Cetonas , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Polietilenoglicóis , Porosidade , Suínos , Microtomografia por Raio-X
4.
Nat Commun ; 11(1): 4254, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848143

RESUMO

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFß1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFß1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.


Assuntos
Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Tiorredoxinas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Bleomicina/toxicidade , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Deleção de Genes , Humanos , Fibrose Pulmonar Idiopática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isomerases de Dissulfetos de Proteínas/genética , Dobramento de Proteína , Estabilidade Proteica , Fibrose Pulmonar/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I/química , Transdução de Sinais , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/genética , Regulação para Cima
5.
Cells ; 9(4)2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290085

RESUMO

Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1ß) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1ß increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1ß, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1ß increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1ß promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1ß and BMP-2, which prevents cartilage degeneration and OA development.


Assuntos
Proteína Morfogenética Óssea 2/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Interleucina-1beta/antagonistas & inibidores , Osteoartrite/metabolismo , Animais , Proteína Morfogenética Óssea 2/biossíntese , Proteína Morfogenética Óssea 2/metabolismo , Remodelação Óssea , Proteínas de Transporte/genética , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Linhagem Celular , Humanos , Interleucina-1beta/biossíntese , Interleucina-1beta/metabolismo , Masculino , Camundongos , Osteoartrite/genética , Osteoartrite/patologia , Ratos , Ratos Sprague-Dawley , Transcriptoma , Transfecção
6.
J Thorac Dis ; 10(6): 3722-3728, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30069370

RESUMO

Background: Pulmonary sequestration is a rare disease whose development begins in the embryonic stage. Surgery is the definitive treatment for eliminating respiratory symptoms and preventing complications. Reports of uniportal video-assisted thoracoscopic surgery (VATS) lobectomy and segmentectomy for pulmonary sequestration are limited in the literature. This study analyzes the perioperative results of the uniportal approach and compared them with those of the multiportal approach for pulmonary sequestration. Methods: We collected a VATS series in a single institute from 2007 to 2017. Adult patients diagnosed with pulmonary sequestration and who had received surgical intervention were included. The use of uniportal VATS began from 2016. The perioperative outcomes for uniportal and multiportal approaches were compared. Results: A total of 19 patients (7 in the uniportal group and 12 in the multiportal group) were included. VATS segmentectomy was performed significantly more in the uniportal group (P=0.033). Shorter operative time, less intraoperative blood loss, shorter pleural drainage time, and shorter postoperative hospital stay were found for the uniportal group; however, the differences compared with the multiportal group were not significant. There was also no significant difference in perioperative parameters among patients who underwent wedge resection, segmentectomy and lobectomy, respectively. All patients were symptom-free in the follow-up. Conclusions: The perioperative results for a series of uniportal VATS anatomical resections for pulmonary sequestration were found to be better than those obtained with the multiportal approach. Although a challenging procedure, uniportal VATS segmentectomy can be performed safely for pulmonary sequestration to preserve more healthy pulmonary parenchyma.

7.
Sci Rep ; 8(1): 11190, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-30046042

RESUMO

NC-8 (ent-16-oxobeyeran-19-N-methylureido) is an isosteviol-derived analogue with multiple biological effects, including anti-inflammation and anti-bacterial activities and inhibition of HBV viral surface antigen gene expression. In this study, we explored the effects of NC-8 on the formation of osteoclasts from RAW 264.7 cells. We found that NC-8 exerts the novel effect of inhibiting osteoclast-like cell formation. Our experiments showed that RANKL-induced ERK, p38, and JNK phosphorylation were inhibited by NC-8. An ovariectomy-induced osteoporosis animal model was used to examine the protective effects of oral treatment with NC-8. Serum analysis was used to examine markers of osteoblasts, osteoclasts, and renal and hepatic function in rats. Micro CT scanning and histological analysis were used to measure bone loss in ovariectomized rats. Oral administration of NC-8 effectively decreased excess bone resorption and significantly antagonized trabecular bone loss in ovariectomized rats. Serum analysis of C-terminal telopeptide of type-I collagen, an osteoclast marker, also showed that NC-8 administration inhibited excess bone resorption. Furthermore, serum analysis showed that renal and liver function were not affected by these doses of NC-8 during long-term treatment. Our results demonstrate that NC-8 inhibits osteoclast differentiation and effectively ameliorates ovariectomy-induced osteoporosis.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Diterpenos do Tipo Caurano/administração & dosagem , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Animais , Reabsorção Óssea/sangue , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , MAP Quinase Quinase 4/genética , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoporose/sangue , Osteoporose/genética , Osteoporose/patologia , Ovariectomia/efeitos adversos , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/genética
8.
J Orthop Res ; 36(10): 2633-2640, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29727018

RESUMO

The interference screw is a widely used fixation device in the anterior cruciate ligament (ACL) reconstruction surgeries. Despite the generally satisfactory results, problems of using interference screws were reported. By using additive manufacturing (AM) technology, we developed an innovative titanium alloy (Ti6 Al4 V) interference screw with rough surface and inter-connected porous structure designs to improve the bone-tendon fixation. An innovative Ti6 Al4 V interference screws were manufactured by AM technology. In vitro mechanical tests were performed to validate its mechanical properties. Twenty-seven New Zealand white rabbits were randomly divided into control and AM screw groups for biomechanical analyses and histological analysis at 4, 8, and 12 weeks postoperatively; while micro-CT analysis was performed at 12 weeks postoperatively. The biomechanical tests showed that the ultimate failure load in the AM interference screw group was significantly higher than that in the control group at all tested periods. These results were also compatible with the findings of micro-CT and histological analyses. In micro-CT analysis, the bone-screw gap was larger in the control group; while for the additive manufactured screw, the screw and bone growth was in close contact. In histological study, the bone-screw gaps were wider in the control group and were almost invisible in the AM screw group. The innovative AM interference screws with surface roughness and inter-connected porous architectures demonstrated better bone-tendon-implant integration, and resulted in stronger biomechanical characteristics when compared to traditional screws. These advantages can be transferred to future interference screw designs to improve their clinical performance. The AM interference screw could improve graft fixation and eventually result in better biomechanical performance of the bone-tendon-screw construct. The innovative AM interference screws can be transferred to future interference screw designs to improve the performance of implants. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2633-2640, 2018.


Assuntos
Reconstrução do Ligamento Cruzado Anterior/instrumentação , Parafusos Ósseos , Tendões/cirurgia , Animais , Fenômenos Biomecânicos , Porosidade , Coelhos , Distribuição Aleatória , Titânio , Microtomografia por Raio-X
9.
Eur J Pharmacol ; 804: 94-101, 2017 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28315346

RESUMO

Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-matrix interaction. The vitronectin and osteopontin receptor αvß3 integrin has increased expression levels and is implicated in the adhesion, activation, and migration of osteoclasts on the bone surface as well as osteoclast polarization. αvß3 integrin plays an important role in osteoclast differentiation and resorption. In addition, Arg-Gly-Asp (RGD)-containing peptides, small molecular inhibitors, and antibodies to αvß3 integrin have been shown to inhibit bone resorption in vitro and in vivo. Here we examined the effects of a disintegrin HSA-ARLDDL a genetically modified mutant of rhodostomin conjugated with human serum albumin, which is highly selective of αvß3, on RANKL-induced osteoclastogenesis and ovariectomy (OVX)-induced osteoporosis. In RANKL-induced osteoclastogenesis, HSA-ARLDDL significantly inhibited osteoclast formation, and IC50 was at nM range. Post-treatment HSA-ARLDDL also inhibits osteoclast formation. Furthermore, weekly administration of HSA-ARLDDL significantly inhibits the increase in serum bone resorption marker levels and decrease in cancellous bone loss in tibia and femur induced by OVX. On the other hand, HSA-ARLDDL did not affect the differentiation and calcium deposition of osteoblasts. These results indicate that the highly selective and long-acting αvß3 integrin antagonists could be developed as effective drugs for postmenopausal osteoporosis.


Assuntos
Desintegrinas/farmacologia , Integrina alfaVbeta3/antagonistas & inibidores , Mutação , Osteoporose/tratamento farmacológico , Peptídeos/genética , Animais , Desintegrinas/química , Desintegrinas/metabolismo , Desintegrinas/uso terapêutico , Feminino , Humanos , Masculino , Camundongos , Oligopeptídeos/química , Peptídeos/metabolismo , Domínios Proteicos , Ratos , Albumina Sérica/metabolismo
10.
Anesth Analg ; 124(3): 972-979, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28212183

RESUMO

BACKGROUND: Long-term opioid therapy for chronic pain may lead to analgesic tolerance, especially when administered intrathecally, thus preventing adequate pain relief. Discovering drug targets to treat opioid tolerance using a mechanism-based approach targeting opioid-induced neuroinflammation provides new therapeutic opportunities. In this study, we provide translational evidence that CXCL12/CXCR4 signaling contributes to the pathogenesis of opioid tolerance. METHODS: The CXCL12 levels in the cerebrospinal fluid of opioid-tolerant patients were compared with those of opioid-naive subjects. For further investigation, a rodent translational study was designed using 2 clinically relevant opioid delivery paradigms: daily intraperitoneal morphine injections and continuous intrathecal morphine infusion. We measured rats' tail flick responses and calculated the percentage of maximum possible effects (%MPE) to demonstrate opioid acute antinociception and the development of analgesic tolerance. The effects of exogenous CXCL12, CXCL12 neutralizing antibody, and receptor antagonist AMD3100 were investigated by intrathecal administration. Data were presented as mean ± SEM. RESULTS: CXCL12 was significantly upregulated in the cerebrospinal fluid of opioid-tolerant patients for 892 ± 34 pg/mL (n = 27) versus 755 ± 33 pg/mL (n = 10) in naive control subjects (P = .03). Furthermore, after 2 and 5 days of intrathecal morphine infusion, rat lumbar spinal cord dorsal horn CXCL12 messenger RNA levels were significantly upregulated by 3.2 ± 0.7 (P = .016) and 3.4 ± 0.3 (P = .003) fold, respectively. Results from the daily intraperitoneal morphine injection experiments revealed that administering an intrathecal infusion of CXCL12 for 24 hours before the first morphine injection did not decrease antinociception efficacy on day 1 but accelerated tolerance after day 2 (%MPE 49.5% vs 88.1%, P = .0003). In the intrathecal morphine coinfusion experiments, CXCL12 accelerated tolerance development (%MPE 9.4% vs 43.4% on day 1, P < .0001), whereas coadministration with CXCL12 neutralizing antibody attenuated tolerance (72.5% vs 43.4% on day 1, P < .0001; 47.6% vs 17.5% on day 2, P < .0001). Coadministration of receptor antagonist AMD 3100 can persistently preserve morphine analgesic effects throughout the study period (27.9% ± 4.1% vs 0.9% ± 1.6% on day 5, P = .03). CONCLUSIONS: The CXCL12/CXCR4 pathway contributes to the pathogenesis of opioid tolerance. Our study indicates that intervening with CXCL12/CXCR4 signaling has therapeutic potential for opioid tolerance.


Assuntos
Analgésicos Opioides/administração & dosagem , Quimiocina CXCL12/líquido cefalorraquidiano , Tolerância a Medicamentos/fisiologia , Morfina/administração & dosagem , Receptores CXCR4/metabolismo , Pesquisa Médica Translacional/métodos , Adulto , Idoso , Animais , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
11.
J Vis Surg ; 3: 149, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29302425

RESUMO

Uniportal video-assisted thoracoscopic surgery (VATS) makes a breakthrough in these years. Even we have gained more experience and surgical skills of uniportal VATS, some elements, such as calcified perivascular lymph nodes, make the surgery challenging. In this series, we used staged bronchial closure (cut the bronchus first and then close it with stapler after dividing the pulmonary artery with calcified lymph node) as an approach for dealing with this challenging issue. Though the rate of intraoperative vessel injury is relatively high, we obtained ideal surgical outcome by using this technique in different lobes and segment of the lung.

12.
J Med Ultrasound ; 25(2): 68-70, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-30065462
13.
Taiwan J Obstet Gynecol ; 55(6): 804-809, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28040124

RESUMO

OBJECTIVE: The aim of this retrospective observational study was to determine the efficacy of carbetocin in reducing blood loss and primary postpartum hemorrhage (PPH) in vaginal and cesarean deliveries in a tertiary hospital in Taiwan. MATERIALS AND METHODS: Eligible gravid women (27-41 weeks) with available data were categorized into those treated prophylactically with and without carbetocin. The primary outcome was blood loss and incidence of primary PPH as measured by intrapartum/intraoperative and postpartum (recovery room) blood loss. RESULTS: A total of 1069 deliveries were evaluated. Maternal age (∼31 years of age), body mass index (∼27 kg/m2) and parity (∼1.4) were similar among those treated with and without carbetocin for both vaginal and cesarean deliveries. The majority [749/1069 (70.1%)] of deliveries were vaginal; a similar proportion of women undergoing vaginal [221/749 (29.5%)] and cesarean [110/320 (34.4%)] deliveries received prophylactic carbetocin for prevention of PPH. Among vaginal deliveries, there was no significant difference in intrapartum (p = 0.083) or postpartum (p = 0.925) blood loss, or incidence of PPH (p = 0.092) between women with versus without carbetocin prophylaxis. However, there was a significant reduction in the intraoperative and total blood loss among cesarean deliveries with versus without carbetocin prophylaxis (p < 0.001). The incidence of PPH was higher [84/320 (26.3%)] among cesarean than among vaginal deliveries [62/749 (8.3%)], but was significantly lower among cesarean deliveries with [18 (16.36%)] versus without [66 (30.45%); p = 0.003] carbetocin prophylaxis. CONCLUSION: In Taiwan, prophylactic use of carbetocin resulted in significantly less blood loss and incidence of PPH in cesarean than in vaginal deliveries.


Assuntos
Parto Obstétrico/efeitos adversos , Ocitócicos/administração & dosagem , Ocitocina/análogos & derivados , Hemorragia Pós-Parto/prevenção & controle , Administração Intravenosa , Adulto , Distribuição de Qui-Quadrado , Parto Obstétrico/estatística & dados numéricos , Feminino , Idade Gestacional , Humanos , Incidência , Ocitocina/administração & dosagem , Gravidez , Estudos Retrospectivos , Taiwan
14.
J Med Chem ; 58(12): 4954-63, 2015 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-25996239

RESUMO

As human beings live longer, age-related diseases such as osteoporosis will become more prevalent. Intolerant side effects and poor responses to current treatments are observed. Therefore, novel effective therapeutic agents are greatly needed. Here, pyrazole derivatives were designed and synthesized, and their osteoclastogenesis inhibitory effects both in vitro and in vivo were evaluated. The most promising compound 13 with a 2-(dimethylamino)ethyl group inhibited markedly in vitro osteoclastogenesis as well as the bone resorption activity of osteoclasts. Compound 13 affected osteoclast's early proliferation and differentiation more than later fusion and maturation stages. In ovariectomized (OVX) mice, compound 13 can inhibit the loss of trabecular bone volume, trabecular bone number, and trabecular thickness. Moreover, compound 13 can antagonize OVX-induced reduction of serum bone resorption marker and then compensatory increase of the bone formation marker. To sum up, compound 13 has high potential to be developed into a novel therapeutic agent for treating osteoporosis in the future.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/sangue , Reabsorção Óssea/imunologia , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , NF-kappa B/imunologia , Osteoclastos/patologia , Osteoporose/sangue , Osteoporose/imunologia , Osteoporose/patologia , Ovariectomia , Ligante RANK/antagonistas & inibidores , Ligante RANK/imunologia , Ratos Sprague-Dawley , Tíbia/efeitos dos fármacos , Tíbia/imunologia , Tíbia/patologia
16.
Anesthesiology ; 122(3): 666-76, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25383568

RESUMO

BACKGROUND: The pivotal role of glial activation and up-regulated inflammatory mediators in the opioid tolerance has been confirmed in rodents but not yet in humans. Here, the authors investigated the intraspinal cytokine and chemokine profiles of opioid-tolerant cancer patients; and to determine if up-regulated chemokines could modify opioid tolerance in rats. METHODS: Cerebrospinal fluid samples from opioid-tolerant cancer patients and opioid-naive subjects were compared. The cerebrospinal fluid levels of tumor necrosis factor-alpha, CXCL1, CXCL10, CCL2, and CX3CL1 were assayed. The rat tail flick test was utilized to assess the effects of intrathecal CXCL1 on morphine-induced acute antinociception and analgesic tolerance. RESULTS: CXCL1 level in cerebrospinal fluid was significantly up-regulated in the opioid-tolerant group (n = 30, 18.8 pg/ml vs. 13.2 pg/ml, P = 0.02) and was positively correlated (r = 0.49, P < 0.01) with opioid dosage. In rat experiment, after induction of tolerance by morphine infusion, the spinal cord CXCL1 messenger RNA was up-regulated to 32.5 ± 11.9-fold. Although CXCL1 infusion alone did not affect baseline tail-flick latency, the analgesic efficacy of a single intraperitoneal injection of morphine dropped significantly on day 1 to day 3 after intrathecal infusion of CXCL1. After establishing tolerance by intrathecal continuous infusion of morphine, its development was accelerated by coadministration of CXCL1 and attenuated by coadministration of CXCL1-neutralizing antibody or CXCR2 antagonist. CONCLUSIONS: CXCL1 is up-regulated in both opioid-tolerant patients and rodents. The onset and extent of opioid tolerance was affected by antagonizing intrathecal CXCL1/CXCR2 signaling. Therefore, the CXCL1/CXCR2 signal pathway may be a novel target for the treatment of opioid tolerance.


Assuntos
Analgésicos Opioides/administração & dosagem , Quimiocina CXCL1/líquido cefalorraquidiano , Tolerância a Medicamentos/fisiologia , Medição da Dor/efeitos dos fármacos , Pesquisa Médica Translacional/métodos , Adulto , Idoso , Animais , Feminino , Humanos , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley
17.
Int J Nanomedicine ; 9: 4485-94, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25278753

RESUMO

The blood-brain/tumor barrier inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time focused ultrasound (FUS) hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10-minute transcranial FUS hyperthermia on day 6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD + hyperthermia groups was measured using an IVIS spectrum system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD + hyperthermia compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers.


Assuntos
Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/patologia , Doxorrubicina/análogos & derivados , Hipertermia Induzida/métodos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/secundário , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Feminino , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos BALB C , Microbolhas , Nanopartículas/química , Nanopartículas/uso terapêutico , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Terapia por Ultrassom
18.
PLoS One ; 9(9): e107890, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25229347

RESUMO

The lipoxygenase isoform of 5-lipoxygenase (5-LOX) is reported to be overexpressed in human rheumatoid arthritis synovial tissue and involved in the progress of inflammatory arthritis. However, the detailed mechanism of how 5-lipoxygenase regulates the inflammatory response in arthritis synovial tissue is still unclear. The aim of this study was to investigate the involvement of lipoxygenase pathways in TNF-α-induced production of cytokines and chemokines. Human synovial fibroblasts from rheumatoid patients were used in this study. 5-LOX inhibitors and shRNA were used to examine the involvement of 5-LOX in TNF-α-induced cytokines and chemokines expression. The signaling pathways were examined by Western Blotting or immunofluorescence staining. The effect of 5-LOX inhibitor on TNF-α-induced chemokine expression and paw edema was also explored in vivo in C57BL/6 mice. Treatment with 5-LOX inhibitors significantly decreased TNF-α-induced pro-inflammatory mediators including interleukin-6 (IL-6) and monocyte chemo-attractant protein-1 (MCP-1) in human synovial fibroblasts. Knockdown of 5-LOX using shRNA exerted similar inhibitory effects. The abrogation of NF-κB activation was involved in the antagonizing effects of these inhibitors. Furthermore, 5-LOX inhibitor decreased TNF-α-induced up-regulation of serum MCP-1 level and paw edema in mouse model. Our results provide the evidence that the administration of 5-LOX inhibitors is able to ameliorate TNF-α-induced cytokine/chemokine release and paw edema, indicating that 5-LOX inhibitors may be developed for therapeutic treatment of inflammatory arthritis.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Fibroblastos/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa/efeitos adversos , Animais , Araquidonato 5-Lipoxigenase/deficiência , Araquidonato 5-Lipoxigenase/genética , Quimiocina CCL2/sangue , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Edema/tratamento farmacológico , Edema/genética , Edema/metabolismo , Edema/patologia , Ativação Enzimática/efeitos dos fármacos , Fibroblastos/metabolismo , Técnicas de Inativação de Genes , Humanos , Quinase I-kappa B/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Leucotrieno B4/metabolismo , Inibidores de Lipoxigenase/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/genética
19.
Artigo em Inglês | MEDLINE | ID: mdl-24191169

RESUMO

The rhizome of Davallia formosana is commonly used to treat bone disease including bone fracture, arthritis, and osteoporosis in Chinese herbal medicine. Here, we report the effects of WL1101, the ethanol extracts of fresh rhizomes of Davallia formosana on ovariectomy-induced osteoporosis. In addition, excess activated bone-resorbing osteoclasts play crucial roles in inflammation-induced bone loss diseases, including rheumatoid arthritis and osteoporosis. In this study, we examined the effects of WL1101 on receptor activator of nuclear factor- κ B ligand (RANKL)-induced osteoclastogenesis. Treatment with WL1101 significantly inhibited RANKL-stimulated osteoclastogenesis. Two isolated active compounds, ((-)-epicatechin) or WL14 (4-hydroxy-3-aminobenzoic acid) could also inhibit RANKL-induced osteoclastogenesis. WL1101 suppressed the RANKL-induced nuclear factor- κ B (NF- κ B) activation and nuclear translocation, which is the key process during osteoclastogenesis, by inhibiting the activation of I κ B kinase (IKK) and I κ B α . In animal model, oral administration of WL1101 (50 or 200 mg/kg/day) effectively decreased the excess bone resorption and significantly antagonized the trabecular bone loss in ovariectomized rats. Our results demonstrate that the ethanol extracts of fresh rhizomes of Davallia formosana inhibit osteoclast differentiation via the inhibition of NF- κ B activation and effectively ameliorate ovariectomy-induced osteoporosis. WL1101 may thus have therapeutic potential for the treatment of diseases associated with excessive osteoclastic activity.

20.
Taiwan J Obstet Gynecol ; 52(2): 264-6, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23915862

RESUMO

OBJECTIVE: Fetal intracranial hemorrhage (ICH) in utero is a rare complication of pregnancy associated with subsequent neurological sequelae or fetal death. CASE REPORT: A 34-year-old woman with Crohn's disease presented at 36 weeks' gestation due to decreased fetal movement. Fetal heart-rate tracing indicated poor beat-to-beat variability. In addition, a Doppler ultrasonography suggested a prenatal stroke with evidences of ICH, reverse-end diastolic velocity of the middle cerebral artery, and a persistent distended bladder. A nonaggressive treatment option was chosen after counseling about the unfavorable prognosis. However, 22 hours after her admission, intrauterine fetal death occurred. CONCLUSION: Fetal ICH in utero might be a rare yet lethal complication of Crohn's disease in pregnancy.


Assuntos
Morte Fetal , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/patologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologia , Adulto , Doença de Crohn , Evolução Fatal , Feminino , Humanos , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/patologia , Imageamento por Ressonância Magnética , Gravidez , Complicações na Gravidez/diagnóstico por imagem , Complicações na Gravidez/patologia , Ultrassonografia Pré-Natal
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