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1.
J Cell Physiol ; 236(5): 3641-3659, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33044023

RESUMO

Random-pattern skin flaps are widely applied to rebuild and restore soft-tissue damage in reconstructive surgery; however, ischemia and subsequent ischemia-reperfusion injury lead to flap necrosis and are major complications. Exenatide, a glucagon-like peptide-1 analog, exerts therapeutic benefits for diabetic wounds, cardiac injury, and nonalcoholic fatty liver disease. Furthermore, Exenatide is a known activator of autophagy, which is a complex process of subcellular degradation that may enhance the viability of random skin flaps. In this study, we explored whether exenatide can improve skin flap survival. Our results showed that exenatide augments autophagy, increases flap viability, enhances angiogenesis, reduces oxidative stress, and alleviates pyroptosis. Coadministration of exenatide with 3-methyladenine and chloroquine, potent inhibitors of autophagy, reversed the beneficial effects, suggesting that the therapeutic benefits of exenatide for skin flaps are due largely to autophagy activation. Mechanistically, we identified that exenatide enhanced activation and nuclear translocation of TFE3, which leads to autophagy activation. Furthermore, we found that exenatide activates the AMPK-SKP2-CARM1 and AMPK-mTOR signaling pathways, which likely lead to exenatide's effects on activating TFE3. Overall, our findings suggest that exenatide may be a potent therapy to prevent flap necrosis, and we also reveal novel mechanistic insight into exenatide's effect on flap survival.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Exenatida/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Pele , Pele/irrigação sanguínea , Adenina/análogos & derivados , Adenina/farmacologia , Adenilato Quinase/metabolismo , Animais , Autofagia/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Regulação para Baixo/efeitos dos fármacos , Edema/patologia , Masculino , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/metabolismo , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
J Cell Physiol ; 236(3): 1939-1949, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32730652

RESUMO

Osteoarthritis (OA) is a degenerative joint disease characterized by destruction of articular cartilage. The inflammatory response is the most important factor affecting the disease process. As interleukin-1ß (IL-1ß) stimulates several key mediators in the inflammatory response, it plays a major role in the pathogenesis of OA. Maslinic acid (MA) is a natural compound distributed in olive fruit. Previous studies have found that maslinic acid has an inhibitory effect on inflammation, but its specific role in the progression of OA disease has not been studied so far. In this study, we aim to assess the protective effect of MA on OA progression by in vitro and in vivo experiments. Our results indicate that, in IL-1ß-induced inflammatory response, MA is effective in attenuating some major inflammatory mediators such as nitric oxide (NO) and prostaglandin E2, and inhibits the expression of IL-6, inducible nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-α (TNF-α) in a concentration-dependent manner. Also, MA downregulated the expression levels of thrombospondin motif 5 (ADAMTS5) and matrix metalloproteinase 13 in chondrocytes, resulting in reduced degradation of its extracellular matrix. Mechanistically, MA exhibits an anti-inflammatory effect by inactivating the PI3K/AKT/NF-κB pathway. In vivo, the protective effect of MA on OA development can be detected in a surgically induced mouse OA model. In summary, these findings suggest that MA can be used as a safe and effective potential OA therapeutic strategy.


Assuntos
Inflamação/prevenção & controle , NF-kappa B/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Triterpenos/uso terapêutico , Idoso , Animais , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Humanos , Inflamação/complicações , Interleucina-1beta/efeitos adversos , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Inibidor de NF-kappaB alfa/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Transporte Proteico/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Triterpenos/química , Triterpenos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
3.
J Orthop Surg Res ; 16(1): 41, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430913

RESUMO

BACKGROUND: Anterior-posterior compression (APC) type II pelvis fracture is caused by the destruction of pelvic ligaments. This study aims to explore ligaments injury in APC type II pelvic injury. METHOD: Fourteen human cadaveric pelvis samples with sacrospinous ligament (SPL), sacrotuberous ligament (SBL), anterior sacroiliac ligament (ASL), and partial bone retaining unilaterally were acquired for this study. They were randomly divided into hemipelvis restricted and unrestricted groups. We recorded the separation distance of the pubic symphysis and anterior sacroiliac joint, external rotation angle, and force when ASL ruptured. We observed the external rotation damage to the pelvic bone and ligaments. RESULT: When ASL failed, there was no significant difference in pubic symphysis separation (28.6 ± 8.4 mm to 23.6 ± 8.2 mm, P = 0.11) and anterior sacroiliac joint separation (11.4 ± 3.8 mm to 9.7 ± 3.9 mm, P = 0.30) between restricted and unrestricted groups. The external rotation angle (33.9 ± 5.5° to 48.9 ± 5.2°, P < 0.01) and force (553.9 ± 82.6 N to 756.6 ± 41.4 N, P < 0.01) were significantly different. Pubic symphysis separation between two groups ranged from 14 to 40 mm. In the restricted group, both SBL and SPL were injured. SPL ruptured first, and then SBL and the interosseous sacroiliac ligament were damaged while the posterior ligament remained unharmed. In the unrestricted group, interosseous sacroiliac ligament and posterior sacroiliac ligaments were damaged, while SBL and SPL were not. When the ASL, SBL, and SPL all failed, pubic symphysis and anterior sacroiliac joint separation between two groups increased significantly (from 28.6 ± 8.4 to 42.0 ± 7.6 mm, 11.4 ± 3.8 to 16.7 ± 4.2 mm respectively, all P < 0.05). CONCLUSION: Pelvic external rotation injury is either hemipelvic restricted or unrestricted, which can result in different outcomes. When the ASL ruptures, the unrestricted group needs greater external rotation angle and force, without SBL or SPL injury, while both SBL and SPL were injured in another group. When ASL fails in two groups, pubic symphysis separation fluctuates considerably. Finally, when the ASL ruptures, SBL and SPL may be undamaged.


Assuntos
Fraturas por Compressão/etiologia , Fraturas por Compressão/fisiopatologia , Ligamentos/lesões , Ossos Pélvicos/lesões , Adulto , Fenômenos Biomecânicos , Cadáver , Feminino , Humanos , Ligamentos/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ruptura
4.
Cell Death Dis ; 10(12): 872, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31740658

RESUMO

Random-pattern skin flap is commonly used for surgical tissue reconstruction due to its ease and lack of axial vascular limitation. However, ischemic necrosis is a common complication, especially in distal parts of skin flaps. Previous studies have shown that FGF21 can promote angiogenesis and protect against ischemic cardiovascular disease, but little is known about the effect of FGF21 on flap survival. In this study, using a rat model of random skin flaps, we found that the expression of FGF21 is significantly increased after establishment skin flaps, suggesting that FGF21 may exert a pivotal effect on flap survival. We conducted experiments to elucidate the role of FGF21 in this model. Our results showed that FGF21 directly increased the survival area of skin flaps, blood flow intensity, and mean blood vessel density through enhancing angiogenesis, inhibiting apoptosis, and reducing oxidative stress. Our studies also revealed that FGF21 administration leads to an upregulation of autophagy, and the beneficial effects of FGF21 were reversed by 3-methyladenine (3MA), which is a well-known inhibitor of autophagy, suggesting that autophagy plays a central role in FGF21's therapeutic benefit on skin flap survival. In our mechanistic investigation, we found that FGF21-induced autophagy enhancement is mediated by the dephosphorylation and nuclear translocation of TFEB; this effect was due to activation of AMPK-FoxO3a-SPK2-CARM1 and AMPK-mTOR signaling pathways. Together, our data provides novel evidence that FGF21 is a potent modulator of autophagy capable of significantly increasing random skin flap viability, and thus may serve as a promising therapy for clinical use.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Transplante de Pele/métodos , Sobrevivência de Tecidos/fisiologia , Animais , Autofagia , Masculino , Ratos , Ratos Sprague-Dawley
5.
Cell Death Dis ; 10(7): 483, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31522191

RESUMO

Random-pattern skin flaps are commonly used and valuable tools in reconstructive surgery, however, post-operative random skin flap necrosis remains a major and common complication. Previous studies have suggested that activating autophagy, a major pathway for degradation of intracellular waste, may improve flap survival. In this study, we investigated whether trehalose, a novel and potent autophagy activator, improves random skin flap viability. Our results demonstrated that trehalose significantly improves viability, augments blood flow, and decreases tissue edema. Furthermore, we found that trehalose leads to increased angiogenesis, decreased apoptosis, and reduced oxidative stress. Using immunohistochestry and western blot, we demonstrated that trehalose augments autophagy, and that inhibition of autophagy augmentation using 3MA significantly blunted the aforementioned benefits of trehalose therapy. Mechanistically, we showed that trehalose's autophagy augmentation is mediated by activation and nuclear translocation of TFEB, which may be due to inhibition of Akt and activation of the AMPK-SKP2-CARM1 signaling pathway. Altogether, our results established that trehalose is a potent agent capable for significantly increasing random-pattern skin flap survival by augmenting autophagy and subsequently promoting angiogenesis, reducing oxidative stress, and inhibiting cell death.


Assuntos
Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Retalhos Cirúrgicos/fisiologia , Trealose/uso terapêutico , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Western Blotting , Imuno-Histoquímica , Fluxometria por Laser-Doppler , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Front Pharmacol ; 10: 1017, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572190

RESUMO

Random-pattern skin flap replantation is commonly used to repair skin defects during plastic and reconstructive surgery. However, flap necrosis due to ischemia and ischemia-reperfusion injury limits clinical applications. Betulinic acid, a plant-derived pentacyclic triterpene, may facilitate flap survival. In the present study, the effects of betulinic acid on flap survival and the underlying mechanisms were assessed. Fifty-four mice with a dorsal random flap model were randomly divided into the control, betulinic acid group, and the betulinic acid + 3-methyladenine group. These groups were treated with dimethyl sulfoxide, betulinic acid, and betulinic acid plus 3-methyladenine, respectively. Flap tissues were acquired on postoperative day 7 to assess angiogenesis, apoptosis, oxidative stress, and autophagy. Betulinic acid promoted survival of the skin flap area, reduced tissue edema, and enhanced the number of microvessels. It also enhanced angiogenesis, attenuated apoptosis, alleviated oxidative stress, and activated autophagy. However, its effects on flap viability and angiogenesis, apoptosis, and oxidative stress were reversed by the autophagy inhibitor 3-methyladenine. Our findings reveal that betulinic acid improves survival of random-pattern skin flaps by promoting angiogenesis, dampening apoptosis, and alleviating oxidative stress, which mediates activation of autophagy.

7.
Biosci Biotechnol Biochem ; 72(12): 3206-10, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19060414

RESUMO

Redox factor-1 (Ref-1) is a multifunctional protein involved in DNA base excision repair (BER) and transcription factor modification. By the use of retrovirus-delivered shRNA, we effectively suppressed endogenous Ref-1 expression in human embryonic kidney (HEK) 293 cells. Our results showed that downregulation of Ref-1 rendered cells more sensitive to H(2)O(2)-induced apoptosis. In this process, the absence of Ref-1 decreased the ratio of Bcl-2/Bax protein expression, which resulted in cytochrome c release and caspase-3 activation. These data indicate that constitutive Ref-1 is required for cellular defense and that this protective function is dependent on its role in the regulation of Bcl-2 family proteins.


Assuntos
Apoptose/efeitos dos fármacos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Inativação Gênica , Peróxido de Hidrogênio/toxicidade , RNA Interferente Pequeno/metabolismo , Retroviridae/genética , Apoptose/genética , Sequência de Bases , Caspase 3/metabolismo , Linhagem Celular , Citocromos c/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Ativação Enzimática , Humanos , Estresse Oxidativo/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Interferente Pequeno/genética , Proteína X Associada a bcl-2/genética
8.
Huan Jing Ke Xue ; 35(8): 3002-6, 2014 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-25338372

RESUMO

The corrosion behavior of stainless steel 201, 304 and 316L which would be used as sewer in-situ rehabilitation materials was studied in the simulated sewage pipes reactor. The corrosion potential and corrosion rate of these three materials were studied by potentiodynamic method on the 7th, 14th, 21st, 56th day under two different conditions which were full immersion condition or batch immersion condition with a 2-day cycle. The electrode process was studied by Electrochemical Impedance Spectroscopy (EIS) on the 56th day. The microstructure and composition of the corrosion pitting were analyzed by Scanning Electron Microscope (SEM) and Energy Dispersive Spectrometer (EDS) on the 56th day. The results showed that 304 and 316L had much better corrosion resistance than 201 under both conditions. 304 and 316L had much smaller corrosion rate than 201 under both conditions. The corrosion resistance of all three kinds of stainless steel under the batch immersion condition was much better than those under the full immersion condition. The corrosion rate of all three kinds of stainless steel under the batch immersion condition was much smaller than those under the full immersion condition. Point pitting corrosion was formed on the surfaces of 304 and 316L. In comparison, a large area of corrosion was formed in the surface of 201.


Assuntos
Teste de Materiais , Esgotos , Aço Inoxidável/química , Corrosão
9.
BMB Rep ; 41(11): 765-70, 2008 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-19017487

RESUMO

Undesirable hyperpigmentation that can arise from increased melanocyte activity may be alleviated by targeting active melanocytes for apoptosis. The role of Stathmin 1 as an important regulator of microtubule dynamics is well documented. The current study examined the potential of Stathmin 1-targeting strategies in eliminating active melanocytes. A vector to overexpress Stathmin 1 and vectors to express three distinct small hairpin RNAs to knockdown Stathmin 1 expression in normal melanocytes were produced and in cell cultures acted accordingly. Both overexpression and knockdown of Stathmin 1 led to a marked increase in melanocyte apoptosis, as indicated by the accumulation of apoptotic cells and increased levels of cleaved caspase-3. Both up- and down-regulation of Stathmin 1 expression inhibited the activity of differentiated melanocytes, as indicated by decreases in both melanin production and tyrosinase activity. Taken together, these results indicate that hyperactive melanocytes can be inhibited by altering Stathmin 1 expression.


Assuntos
Apoptose/genética , Melanócitos/fisiologia , Estatmina/fisiologia , Diferenciação Celular/genética , Proliferação de Células , Células Cultivadas , Expressão Gênica/fisiologia , Humanos , Melaninas/metabolismo , Melanócitos/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Estatmina/genética , Estatmina/metabolismo , Transfecção
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