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1.
Anticancer Drugs ; 31(2): 123-130, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31815763

RESUMO

Cisplatin (CDDP) is the most effective chemotherapeutic drug against lung carcinoma. However, the emergence of resistant clones has severely limited its clinical application. We found that the cisplatin-resistant lung carcinoma cell line A549/CDDP had increased levels of the phosphorylated gap junction protein Cx43 and SRC tyrosine kinase, and low levels of total Cx43 protein and reduced gap junction formation. The SRC kinase inhibitor PP2 increased the expression of total Cx43 protein and enhanced cisplatin sensitivity, indicating that activated SRC kinase induces chemoresistance by decrease total Cx43 level. Furthermore, Cx43 gene silencing in the drug-resistant cell lines abrogated the sensitizing effect of PP2. Taken together, targeting SRC kinase by PP2 reverses cisplatin resistance by upregulating Cx43 protein levels, indicating a novel pathway of cisplatin resistance that may be amenable to therapeutic intervention.

2.
Rev Esp Enferm Dig ; 112(1): 12-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31599640

RESUMO

INTRODUCTION: Sixty-three patients with gastric phytobezoars were reviewed. METHODS: forty-eight (76.2%) patients received endoscopic combined with chemical therapies and 15 (23.8%) received only chemical therapy initially. Fifty-one (81.0%) patients achieved complete removal (only chemical therapy 14/15), while 12 (19.0%) received further endoscopic therapies. RESULTS: finally, 62 (98.4%) patients achieved a complete removal. Considering only patients with combined treatment as a first approach, treatment success was associated with a softer phytobezoar consistency (p = 0.023). CONCLUSION: in conclusion, most patients achieve a favorable outcome. Chemical therapy is useful in selected cases. Repeated endoscopic therapies may be needed in order to completely remove phytobezoars with a hard consistency.

3.
Sci Rep ; 9(1): 18248, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796756

RESUMO

Vascular dementia (VaD) is a complex disorder caused by reduced blood flow in the brain. However, there is no effective pharmacological treatment option available until now. Here, we reported that low-dose levamlodipine besylate could reverse the cognitive impairment in VaD mice model of right unilateral common carotid arteries occlusion (rUCCAO). Oral administration of levamlodipine besylate (0.1 mg/kg) could reduce the latency to find the hidden platform in the MWM test as compared to the vehicle group. Furthermore, vehicle-treated mice revealed reduced phospho-CaMKII (Thr286) levels in the hippocampus, which can be partially restored by levamlodipine besylate (0.1 mg/kg and 0.5 mg/kg) treatment. No significant outcome on microglia and astrocytes were observed following levamlodipine besylate treatment. This data reveal novel findings of the therapeutic potential of low-dose levamlodipine besylate that could considerably enhance the cognitive function in VaD mice.

4.
Oxid Med Cell Longev ; 2019: 1305049, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885770

RESUMO

Mesenchymal stem cells (MSCs) have shown beneficial effects in the treatment of abdominal aortic aneurysm (AAA). Nonetheless, the biological properties of adipose-derived MSCs (ASCs) from patients with AAA (AAA-ASCs) remain unclear. This study is aimed at investigating the properties of cell phenotype and function of AAA-ASCs compared with ASCs from age-matched healthy donors (H-ASCs). H-ASCs and AAA-ASCs were studied for cell phenotype, differentiation capacity, senescence, and mitochondrial and autophagic functions. Cellular senescence was examined by senescence-associated ß-galactosidase (SA-ß-gal) staining. Mitochondrial morphology was determined by MitoTracker staining. Despite the similar surface markers of AAA-ASCs and H-ASCs, AAA-ASCs exhibited altered multidifferentiation potential. Compared with H-ASCs, AAA-ASCs displayed enhanced senescence manifested by increased SA-ß-gal activity and decreased proliferation and migration ability. Furthermore, AAA-ASCs showed increased mitochondrial fusion, reactive oxygen species (ROS) production, and decreased mitochondrial membrane potential. In addition, AAA-ASCs exhibited decreased autophagy level, upregulation of IL-6 and TNF-α secretion, and downregulation of IL-10 secretion compared with H-ASCs. Nonetheless, treatment of AAA-ASCs with rapamycin (an autophagy activator) dramatically reduced secretion of IL-6 and TNF-α and enhanced secretion of IL-10. In conclusion, our study showed that AAA-ASCs exhibit senescence phenomena and decreased cell function. Understanding the specific alterations in AAA-ASCs will help explore novel strategies to restore cell function for AAA treatment.

5.
PeerJ ; 7: e7568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523515

RESUMO

Background & Aims: Aging is one of the risk factors of non-alcoholic fatty liver disease (NAFLD). Yet, the mechanism underlying the aging-associated NAFLD-like syndrome is not fully understood. Nicotinamide adenine dinucleotide (NAD), a ubiquitous coenzyme, has protective effects against aging. Here, we investigated the actions of NAD precursors nicotinamide riboside (NR) on the development of aging-induced NAFLD. Methods: NR supplemented food (2.5 g/kg food) was applied to aged mice for three months while normal chow to the other groups. Body weight, food intake, liver weight and fat pat mass were measured. The serum concentrations of lipid content, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and NAD were determined by biochemical assays. Pathological assessment and immunohistochemistry analysis of hepatic tissues were used to evaluate the effect of NR on NAFLD development and inflammatory infiltration. Results: NR repletion significantly reduced fat pat mass in aged mice, while not altered the body weight, food intake, and liver weight. NR repletion significantly rescued the NAD reduction in aged mice. The total cholesterol and triglyceride levels could be lowered by NR repletion in aged mice. The AST level was also significantly reduced by NR repletion in aged group, while the ALT level lowered but without significance. Notably, moderate NAFLD phenotypes, including steatosis and hepatic fibrosis could be markedly corrected by NR repletion. In addition, Kupffer cells accumulated and inflammatory infiltration could also be remarkably reversed by NR repletion in aged mice. Conclusion: Aging was associated with NAFLD-like phenotypes in mice, which could be reversed by oral NR repletion. Therefore, oral NR uptake might be a promising strategy to halt the progression of NAFLD.

6.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(7): 797-803, 2019 Jul 30.
Artigo em Chinês | MEDLINE | ID: mdl-31340912

RESUMO

OBJECTIVE: To investigate the effect of SRC kinase inhibitor PP2 on the invasion and metastasis of lung cancer A549 cells and explore its molecular mechanism. METHODS: MTT assay was used to evaluate the inhibitory effect of PP2 on the proliferation of A549 cells. Cell scratch and Transwell assays were performed to assess the invasion and metastatic capacity of A549 cells after treatment with 1, 2, 4, 8, and 16 µmol/L PP2 for 24 h. Western blotting was used to detect the expressions of connexin43 (Cx43) and MMP-2 in the cells after small interfering RNA (siRNA)-mediated silencing or overexpression of Cx43; the changes in the cell invasion and metastasis in response to PP2 treatment after Cx43 silencing or overexpression were investigated. RESULTS: MTT assay showed that treatment with PP2 at 2, 4, 8, 16, and 32 µmol/L significantly inhibited the proliferation of A549 cells in a concentration-dependent manner. Treatments with PP2 at 1, 2, 4, 8, and 16 µmol/L for 24 h also concentration-dependently lowered the invasion and metastatic abilities of the cells (P < 0.05). At 4 and 8 µmol/L, PP2 significantly increased the expression level of Cx43 protein and decreased the expression level of MMP-2 protein. Overexpression of Cx43 significantly enhanced the inhibitory effect of PP2 on the cell invasion and metastasis, and Cx43 silencing significantly attenuated the inhibitory effect of PP2 (P < 0.05). CONCLUSIONS: PP2 treatment can suppress the invasion and metastasis of A549 cells in vitro possibly by modulating the expression of Cx43.


Assuntos
Neoplasias Pulmonares , Células A549 , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Conexina 43 , Humanos , Invasividade Neoplásica , Inibidores de Proteínas Quinases , Quinases da Família src
7.
Onco Targets Ther ; 12: 4595-4604, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354293

RESUMO

Background: Esophageal squamous-cell carcinoma (ESCC) metastasis is the major cause of death of this severe and common malignancy. Focal adhesion kinase (FAK) is one of the key components of the focal adhesion complex, which is a multi-protein structure that controls cell adhesion, migration and invasion and regulates tumor metastasis. Purpose: To identify the roles and mechanisms of FAK in the regulation of Epithelial-to-mesenchymal transition (EMT) of ESCC cells. Methods: The expression of FAK and miR-4324 in both ESCC tissues and cells were evaluated by qRT-PCR and Immunohistochemistry analysis. Dual luciferase assays were performed for the confirmation of miR-4324's specific binding to 3'UTR of FAK mRNA. Besides, the trans-well assays and wound healing assays were employed to evaluate the effects of FAK /miR-4324 axis on the EMT regulation of ESCC cells. Furthermore, the relationship between miR-4374/FAK expression and clinical pathologic parameters & patient survival were also statistically analyzed. Results: In this study, we identified the upregulation of FAK and downregulation of miR-4324 in both ESCC cells and tissues. Overexpression of miR-4324 mimic, which significantly decreased cellular FAK levels, can impair the invasion potential and migration ability of ESCC cells. Besides, co-transfection of FAK can attenuate the function of miR-4324 mimic. Further experimental results demonstrated that miR-4324 mimic remarkably downregulated epithelial-to-mesenchymal transition (EMT) phenotype, which can also be effectively prevented by overexpressing FAK in ESCC cells. What's more, low miR-4324 and high FAK tissue levels have significant association with poor cell differentiation, tumor size and invasion depth as well as overall number of metastatic lymph nodes. Patients with high miR-4324 and low FAK levels in tumoral tissues lived longer than their counterparts, respectively. Conclusions: In conclusion, miR-4324/FAK axis could be a promising therapeutic target and potential prognostic biomarker for ESCC, which deserves further investigation in the clinic.

8.
Oxid Med Cell Longev ; 2019: 4915149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31178962

RESUMO

Mesenchymal stem cell- (MSC-) based therapy is a novel strategy in regenerative medicine. The functional and regenerative capacities of MSCs decline with senescence. Nonetheless, the potential mechanisms that underlie their senescence are not fully understood. This study was aimed at exploring the potential mechanisms of fibroblast growth factor 21 (FGF21) in the regulation of MSC senescence. The senescence of MSCs was determined by senescence-associated ß-galactosidase (SA-ß-gal) staining. The morphology and the level of mitochondrial reactive oxygen species (ROS) of MSCs were assessed by MitoTracker and Mito-Sox staining, respectively. The expression of FGF21 and mitochondrial dynamics-related proteins was detected by Western blotting. As MSCs were expanded in vitro, the expression of FGF21 decreased. Depletion of FGF21 enhanced production of mitochondrial reactive oxidative species (ROS) and increased the senescence of early-passage MSCs whereas inhibition of ROS abolished these effects. The senescent MSCs exhibited increased mitochondrial fusion and decreased mitochondrial fission. Treatment of early-passage MSCs with FGF21 siRNA enhanced mitochondrial fusion and reduced mitochondrial fission. Moreover, treatment of mitofusin2- (Mfn2-) siRNA inhibited depletion of FGF21-induced MSC senescence. Furthermore, we demonstrated that depletion of FGF21-induced mitochondrial fusion was regulated by the AMPK signaling pathway. Treatment with an AMPK activator, AICAR, abrogated the depletion of FGF21-induced senescence of MSCs by inhibiting mitochondrial fusion. Compared with MSCs isolated from young donors, those derived from aged donors showed a lower level of FGF21 and a higher level of senescent activity. Furthermore, overexpression of FGF21 in aged MSCs inhibited senescence. Our study shows that FGF21, via the AMPK signaling pathway, regulates the senescence of MSCs by mediating mitochondrial dynamics. Targeting FGF21 might represent a novel strategy to improve the quality and quantity of MSCs.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Dinâmica Mitocondrial/fisiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Senescência Celular/fisiologia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Transfecção , Adulto Jovem
9.
Polymers (Basel) ; 11(5)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052528

RESUMO

In melt blowing, microfibrous nonwoven material is manufactured by using high-speed air to attenuate polymer melt. The melt-blown air jet determines the process of polymer attenuation and fiber formation. In this work, the importance of lateral velocity on the fiber was first theoretical verified. The lateral diffused characteristic of the air flow field in slot-die melt blowing was researched by measuring the velocity direction using a dual-wire probe hot-wire anemometer. Meanwhile, the fiber path was captured by high-speed photography. Results showed that there existed a critical boundary of the lateral diffusion, however, air jets in the x-z plane are a completely diffused field. This work indicates that the lateral velocity in the y-z plane is one of the crucial factors for initiating fiber whipping and fiber distribution.

10.
Polymers (Basel) ; 11(4)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30960601

RESUMO

The surfaces of polymer and interfaces between polymer and inorganic particles are of particular importance for the properties of polymers and composites. However, the determination of the properties of surfaces and interfaces poses many challenges due to their extremely small dimensions. Herein, polystyrene and polymethyl methacrylate thin film on silicon wafer was used as a model system for the measurement of the properties of the polymer near free surface and at the polymer-solid interface. Two different methods, i.e., nanoindentation using atomic force microscopy (AFM) and the gold nanoparticle embedding technique, were used for these measurements. The results showed the elastic modulus of PS near the free surface determined by nanoindentation was lower than the bulk value. Based on contact mechanics analysis, nanoparticle embedding also revealed the existence of a lower-modulus, non-glassy layer near the free surface at temperatures below the bulk glass transition temperature (Tg). However, near the polymer-solid interface, the AFM nanoindentation method is not applicable due to the geometry confinement effect. On the other hand, the nanoparticle embedding technique can still correctly reflect the interactions between the polymer and the substrate when compared to the ellipsometry results.

11.
Biochem Biophys Res Commun ; 508(2): 339-347, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30473216

RESUMO

DNA mismatch repair-proficient colon cancer is the most common type of colon cancer, but its initiation and progression are still unknown. Our previous study has revealed that a long noncoding RNA (lncRNA) ENST00000455974 was significantly associated with TNM stage and distant metastasis in patients with DNA mismatch repair-proficient (pMMR) colon cancer (CC). Here, firstly, we observed that ENST00000455974 was gradual increased across colon normal-adenoma-carcinoma-metastasis sequence by quantitative real-time PCR. Secondly, ENST00000455974 showed a better sensitivity and specificity than CEA and CA19-9 in the diagnosis of pMMR CC by drawing the receiver operating characteristic (ROC) curve. Thirdly, a higher level of ENST00000455974 was associated with a poorer patient survival. Furthermore, Knockdown of ENST00000455974 led to reduced proliferation and migration of colon cancer cells. Mechanistically, ENST00000455974 was mainly located in the nucleus of colon cancer cells and it promoted the growth and metastasis of pMMR CC cells through up-regulating JAG2.


Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Reparo de Erro de Pareamento de DNA/genética , Proteína Jagged-2/genética , Proteína Jagged-2/metabolismo , RNA Longo não Codificante/genética , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Células CACO-2 , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias do Colo/patologia , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Oncogenes , Prognóstico , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , Regulação para Cima
12.
FASEB J ; 33(3): 4559-4570, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30566395

RESUMO

The age-related functional exhaustion limits potential efficacy of mesenchymal stem cells (MSC) in treating cardiovascular disease. Therefore, rejuvenation of aged MSC in the elderly population is of great interest. We have previously reported that Erb-B2 receptor tyrosine kinase 4 ( ERBB4) plays a critical role in regulating MSC survival under hypoxia. The aim of this study was to investigate whether ERBB4 rejuvenates aged MSC and how ERBB4 enhances therapeutic efficacy of aged MSC in treating myocardial infarction (MI). Compared with vector aged MSC (aged-MSC), ERBB4-engineered aged MSC (ER4-aged-MSC) conferred resistance to oxidative stress-induced cell death and ameliorated the senescent phenotype in vitro. Four weeks after MI, the ER4-aged-MSC group exhibited enhanced blood vessel density, reduced cardiac remodeling and apoptosis with improved heart function compared with the aged-MSC group. Overexpression of ERBB4 caused an increase in phosphorylated v-akt murine thymoma viral oncogene homolog 1 (AKT), and phosphorylated ERK expression under hypoxia. ER4-aged-MSC secreted higher levels of angiopoietin, epithelial neutrophil activating peptide 78, VEGF, and fibroblast growth factor 2, and enhanced tube formation in HUVEC. The impact of ERBB4 on protein expression, proangiogenesis, cell behavior, and cytokine secretion was abolished by inhibiting PI3K/AKT and MAPK/ERK signaling pathway.-Liang, X., Ding, Y., Lin, F., Zhang, Y., Zhou, X., Meng, Q., Lu, X., Jiang, G., Zhu, H., Chen, Y., Lian, Q., Fan, H., Liu, Z. Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways.

13.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 49(5): 700-705, 2018 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-30378329

RESUMO

OBJECTIVE: To investigate the role of SRC kinase inhibitor PP2 in drug resistance to adriamycin (ADM) in breast cancer cells and invasion, metastasis of cells. METHODS: MTT assay was used to detect the inhibitory effect of ADM on MCF-7 and MCF-7/ADM cells. The 50% inhibitory concentration (IC50) and resistance index (RI) of cells were calculated. The expression of MDR1, connexin 43 (Cx43) and SRC proteins in breast cancer cells were detected by Western blot assay. Transwell experiment and cell scratch test were used to determine the invasion and migration of cells respectively [MCF-7, MCF-7/ADM, PP2 (1, 2, 4 µmol/L)]. Standard colony formation assay was used to detect the cytotoxicity effect of 4 µmol/L PP2 pretreatment on ADM. RESULTS: ADM inhibited the proliferation of MCF-7 more than MCF-7/ADM cells (P<0.01). The IC50 of MCF-7/ADM cells was 24.55 µmol/L, the IC50 of MCF-7/ADM cells was 770.57 µmol/L, the RI was 31. Compared with MCF-7 cells, expressions of the multidrug resistance proteins MDR1 and SRC were significantly increased (P<0.01). The invasion and migration ability of the MCF-7/ADM cells was stronger than that of the sensitive cells (P<0.01). When MCF-7/ADM was exposed to SRC inhibitor PP2, the invasion and metastasis ability of cells were inhibited (P<0.01) and the rate of colony formation was decreased, that is, more sensitivity to ADM (P<0.01). CONCLUSION: The resistance of MCF-7 to ADM is accompanied by increased expression of SRC. SRC inhibitor PP2 can reduce the cell resistance, ability of invasion and metastasis.


Assuntos
Neoplasias da Mama/enzimologia , Doxorrubicina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Pirimidinas/farmacologia , Quinases da Família src/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Conexina 43/metabolismo , Humanos , Células MCF-7 , Invasividade Neoplásica , Metástase Neoplásica
14.
Gene ; 661: 68-77, 2018 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-29605603

RESUMO

PIN1 is a peptidyl-prolyl cis/trans isomerase (PPIase) that controls cell fate by regulating multiple signal transduction pathways and is found to be overexpressed in a variety of malignant tumors. Herein, we found the expression of PIN1 is up-regulated while miRNA-370 (miR-370) down-regulated in both esophageal squamous-cell carcinoma (ESCC) tissues and cells. Transfection of miR-370 can significantly decrease PIN1 expression in targeting ESCC cells. Overexpression of miR-370 can induce decreased cell proliferation and cell cycle arrest, as well as increased apoptosis in ESCC cells, while this function can be significantly prevented by co-transfection of PIN1. Further experimental results demonstrated that ß-catenin, cyclin D1, and caspase activation might be involved in miR-370/PIN1 induced growth inhibition and apoptosis. Besides, low miR-370 and high PIN1 expression significantly correlated with tumor diameter, poor differentiation, tumor invasion and lymph node metastasis in patients diagnosed with ESCC. In conclusion, downregulation of miR-370 in ESCC is associated with cancer progression and promotes cancer cell proliferation via upregulating PIN1, which might be a potential therapeutic target and adverse prognostic factor in the clinic.


Assuntos
Carcinoma de Células Escamosas/genética , Proliferação de Células/genética , Neoplasias Esofágicas/genética , MicroRNAs/genética , Peptidilprolil Isomerase de Interação com NIMA/genética , Adulto , Idoso , Animais , Carcinoma de Células Escamosas/patologia , Células Cultivadas , Progressão da Doença , Regulação para Baixo/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Regulação para Cima/genética
15.
Neurosci Lett ; 662: 219-226, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29061394

RESUMO

Cerebral ischemia and reperfusion is a common pathophysiologic process, which is involved in stroke and brain trauma. Recent studies revealed that activating epidermal growth factor receptor (EGFR) ameliorates cerebral ischemia/reperfusion (I/R) injury, however, the precise mechanisms remain to be illuminated. In this study, the neurological behavior was evaluated by Longa score. The infarct volume was performed by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining and the expression of p-EGFR, p-STAT3, connexin (Cx43), Bax and Bcl-2 were detected by Western blot. The neurological behavior and infarct volume were increased in rats with cerebral I/R injury. Epidermal growth factor (EGF) pretreatment significantly decreased neurological deficit and infarct volume. However, the antagonist of EGFR, AG1478 attenuated the EGF-induced reduction of neurological deficit and infarct volume. Moreover, the inhibitor of JAK2/STAT3, AG490 undermined the protective effects stimulated by activating EGFR in rats with I/R injury. In addition, EGF pretreatment increased the expression of Bcl-2 and reduced the expression of Bax and Cx43, and the effects were abolished after using AG1478 and AG490. These findings implicate that JAK2/STAT3 pathway plays the vital role in I/R injury protection from activating EGFR. And the neuroprotective effects may associate with inhibiting the Cx43 expression and the inhibition of apoptosis.


Assuntos
Isquemia Encefálica/metabolismo , Receptores ErbB/administração & dosagem , Receptores ErbB/metabolismo , Janus Quinase 2/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/metabolismo , Traumatismo por Reperfusão/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose , Comportamento Animal , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Conexina 43/metabolismo , Regulação para Baixo , Masculino , Fosforilação , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Transdução de Sinais
16.
Mol Med Rep ; 16(6): 8691-8698, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28990070

RESUMO

Wound healing impairment is increasingly recognized to be a consequence of hyperglycemia­induced dysfunction of endothelial precursor cells (EPCs) in type 2 diabetes mellitus (T2DM). Metformin exhibits potential for the improvement of endothelial function and the wound healing process. However, the underlying mechanisms for the observed beneficial effects of metformin application remain to be completely understood. The present study assessed whether metformin, a widely used therapeutic drug for T2DM, may accelerate wound closure in T2DM db/db mice. Genetically hyperglycemic db/db mice were used as the T2DM model. Metformin (250 mg/kg/day; intragastric) was administered for two weeks prior to EPC collection and wound model creation in db/db mice. Wound healing was evaluated by alterations in the wound area and the number of platelet endothelial cell adhesion molecule­positive cells. The function of the isolated bone marrow­derived EPCs (BM­EPCs) was assessed by a tube formation assay. The number of circulating EPCs, and the levels of intracellular nitric oxide (NO) and superoxide (O2­) were detected by flow cytometry. Thrombospondin­1 (TSP­1) expression was determined by western blot analysis. It was observed that treatment with metformin accelerated wound healing, improved angiogenesis and increased the circulating EPC number in db/db mice. In vitro, treatment with metformin reversed the impaired BM­EPC function reflected by tube formation, and significantly increased NO production while decreasing O2­ levels in BM­EPCs from db/db mice. In addition, TSP­1 expression was markedly attenuated by treatment with metformin in cultured BM­EPCs. Metformin contributed to wound healing and improved angiogenesis in T2DM mice, which was, in part, associated with stimulation of NO, and inhibition of O2­ and TSP­1 in EPCs from db/db mice.


Assuntos
Metformina/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Biomarcadores , Glicemia , Complicações do Diabetes , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Masculino , Camundongos , Neovascularização Fisiológica/efeitos dos fármacos , Óxido Nítrico/metabolismo , Trombospondina 1/metabolismo
17.
Cell Physiol Biochem ; 42(6): 2255-2266, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28817808

RESUMO

BACKGROUND: Impaired wound healing is a common complication of diabetes and is the leading cause of lower extremity amputation. Treatment with fenofibrate, a peroxisome proliferators-activated receptor α (PPARα) agonist, was associated with a lower risk of amputations, particularly minor amputations without known large-vessel diseases, probably through non-lipid mechanisms. The current study aimed to test our hypothesis that fenofibrate stimulates angiogenesis and restores endothelial precursor cell (EPC) function via inhibiting Nod-like receptor protein 3 (NLRP3) inflammasome in streptozotocin (STZ)-induced diabetic mice. METHODS: Male C57BL/6 mice were randomly divided into three groups: control, STZ-induced diabetic mice and fenofibrate treated diabetic group. Wound closure was assessed by wound area and CD31 positive capillaries. Both the migration and tube formation capacities of EPCs were measured. Intracellular nitric oxide (NO) and superoxide (O2-) levels were determined. Activity of NLRP3 inflammasome in EPCs was assessed by measuring thioredoxin-interacting protein (TXNIP), NLRP3, and caspase-1 expression. RESULTS: Compared with the untreated diabetic mice, wound closure and capillary densities were significantly increased in fenofibrate treated group. Fenofibrate treatment restored EPC function, increased NO production, and decreased O2- level in EPCs of diabetic mice. Furthermore, fenofibrate deregulated the activity of NLRP3 inflammasome by reducing TXNIP, NLRP3 and caspase-1 expression in EPCs of diabetic mice. In vitro, fenofibrate prevented high glucose induced EPC dysfunction, deregulated NLRP3 inflammasome activity. In addition, fenofibrate inhibited IL-1ß expression caused by combination use of high glucose and lipopolysaccharide. CONCLUSION: Fenofibrate can accelerate wound healing in diabetic mice, which at least in part was mediated by improving the impaired EPC function via a NLRP3 inflammasome pathway, suggesting the significance of PPARα agonists in the treatment of diabetes.


Assuntos
Fenofibrato/farmacologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , PPAR alfa/agonistas , Transdução de Sinais/efeitos dos fármacos , Animais , Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Movimento Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Glucose/toxicidade , Interleucina-1beta/análise , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/análise , PPAR alfa/metabolismo , Superóxidos/análise , Tiorredoxinas/metabolismo
18.
Mater Sci Eng C Mater Biol Appl ; 79: 687-696, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28629069

RESUMO

To engineer bone tissue, it is crucial to design scaffolds with micro- and nano-sized architecture imitating approximate hierarchical structure of native bone, and afford desirable biological properties by introducing biocompatible polymers and bioceramics into the scaffolds. Here, a novel scaffold consisting of poly-3-hydroxybutyrate-co-3-hydroxyvalerate (PHBV)/polyaspartic acid (PAA) was fabricated by electrospinning and nano-hydroxyapatite (nHA) was deposited by calcium-phosphate dipping process for bone tissue regeneration. Characterization of the prepared nanofibers revealed the formation of definite nHA crystal, porous structure of membranes, improved wettability with nHA deposition and satisfied mechanical properties. Human fetal osteoblasts were cultured on nanofibers and experienced in vitro evaluations of cell proliferation, adhesion and mineralization confirming the non-cytotoxicity and biocompatibility of scaffolds. Cells proliferation rate and ALP expression on PHBV/PAA-nHA were 36.40% and 40.14% higher than on PHBV/PAA, respectively. The utmost significance of this study is introducing bioactive PAA-nHA on polymeric nanofibers to regulate and improve specific cells adhesion, proliferation and mineralization of osteoblasts. All results indicate PHBV/PAA-nHA nanofibrous scaffolds can be applied as biomimetic platform for bone tissue repairation with appropriate physico-chemical properties, osteoinductivity and osteoconductivity.


Assuntos
Osteoblastos , Biomimética , Proliferação de Células , Durapatita , Humanos , Hidroxibutiratos , Poliésteres , Engenharia Tecidual , Tecidos Suporte
19.
PeerJ ; 5: e3155, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28439456

RESUMO

BACKGROUND & AIMS: Metformin is currently the most widely used first-line hypoglycemic agent for diabetes mellitus. Besides glucose-lowering action, there is increasingly interest in the potential anti-inflammatory action of this drug. In the present study, we investigated the actions of metformin on experimental insulitis using STZ-induced diabetic mice. METHODS: Mice with acute diabetes induced by STZ were administered metformin by gavage. Changes of blood glucose and body weight, and the daily amount of food and water intake were measured. Pancreatic tissues were collected for histologic analyses. Pathological assessment and immunohistochemistry analysis were used to determine the effect of metformin on insulitis. Inflammatory cytokines in the pancreas and insulin levels were measured through ELISA analysis. RESULTS: Metformin significantly reduced blood glucose levels and improved aberrant water intake behavior in experimental diabetic mice. No significant differences were observed in terms of body weight and food intake behavior in metformin-treated animals. In the STZ-induced model of diabetes, we found the appearance of pronounced insulitis. However, metformin administration reduced the severity of insulitis assessed by blind pathological scoring. In addition, metformin treatment improved insulin levels in experimental diabetic mice. ELISA assay revealed decreased levels of inflammatory response marker IL-1ß and TNF-α in the pancreatic tissues following metformin treatment. CONCLUSION: Metformin attenuated insulitis in the STZ-induced mice model of diabetes. This islet-protective effect might be partly correlated with the anti-inflammatory action of metformin.

20.
Oxid Med Cell Longev ; 2017: 7809581, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28373902

RESUMO

Refractory wound is a dreaded complication of diabetes and is highly correlated with EPC dysfunction caused by hyperglycemia. Acarbose is a widely used oral glucose-lowering drug exclusively for T2DM. Previous studies have suggested the beneficial effect of acarbose on improving endothelial dysfunction in patients with T2DM. However, no data have been reported on the beneficial efficacy of acarbose in wound healing impairment caused by diabetes. We herein investigated whether acarbose could improve wound healing in T2DM db/db mice and the possible mechanisms involved. Acarbose hastened wound healing and enhanced angiogenesis, accompanied by increased circulating EPC number in db/db mice. In vitro, a reversed BM-EPC dysfunction was observed after the administration of acarbose in db/db mice, as reflected by tube formation assay. In addition, a significantly increased NO production was also witnessed in BM-EPCs from acarbose treated db/db mice, with decreased O2 levels. Akt inhibitor could abolish the beneficial effect of acarbose on high glucose induced EPC dysfunction in vitro, accompanied by reduced eNOS activation. Acarbose displayed potential effect in promoting wound healing and improving angiogenesis in T2DM mice, which was possibly related to the Akt/eNOS signaling pathway.


Assuntos
Acarbose/farmacologia , Acarbose/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Western Blotting , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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