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1.
Molecules ; 24(23)2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816891

RESUMO

Salvianolic acid B is one of the main water-soluble components of Salvia miltiorrhiza Bge. Many reports have shown that it has significant anti-myocardial ischemia effect. However, the underlying mechanism remains unclear. Our present study demonstrated that Sal B could alleviate myocardial ischemic injury by inhibiting the priming phase of NLRP3 inflammasome. In vivo, serum c-troponin I (cTn), lactate dehydrogenase (LDH) levels, the cardiac function and infract size were examined. We found that Sal B could notably reduce the myocardial ischemic injury caused by ligation of the left anterior descending coronary artery. In vitro, Sal B down-regulated the TLR4/NF-κB signaling cascades in lipopolysaccharide (LPS)-stimulated H9C2 cells. Furthermore, Sal B reduced the expression levels of IL-1ß and NLRP3 inflammasome in a dose-dependent manner. In short, our study provided evidence that Sal B could attenuate myocardial ischemic injury via inhibition of TLR4/NF-κB/NLRP3 signaling pathway. And in an upstream level, MD-2 may be the potential target.

2.
Med Sci Monit ; 25: 9679-9689, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31848329

RESUMO

BACKGROUND The aim of this study was to determine the association between white matter lesions (WML) and diabetes-associated cognitive decline (DACD) in rat models of type 2 diabetes (T2DM). MATERIAL AND METHODS Sixty Sprague-Dawley male rats were divided into 4 groups: control, control+metformin, T2DM, and T2DM+metformin groups. The T2DM groups were fed a diet high in fat and glucose to induce impaired glucose tolerance (IGT) and then were injected with streptozotocin to induce T2DM. The Morris water maze test was used to evaluate cognitive function. Brain diffusion tensor imaging scans were performed for WML. The expression of myelin basic protein (MBP), oligodendrocyte transcription factor 1 (OLIG1), and OLIG2 (markers of brain damage and repair) was determined using immunofluorescence. After IGT, the fractional anisotropy (FA) values of the right thalamus area were significantly lower in both T2DM groups compared with controls. RESULTS Eight weeks after streptozotocin injection, the FA values of the thalamus were lower in the T2DM (bilateral thalamus) group and T2DM+metformin (left thalamus) group than in controls, while the FA values in the left thalamus area were lower in the T2DM+metformin group than in the control and control+metformin groups. The maze escape latency was longer and the number of rats passing through the platform was smaller in the T2DM and T2DM+metformin groups than in the control group. MBP levels were lower and OLIG1 and OLIG2 levels were higher in both T2DM groups than in controls. CONCLUSIONS WML is associated with DACD and appears before the onset of T2DM and signs of DACD and plays a role in diabetes-associated cognitive decline. Metformin reduces WMLs but does not rescue cognitive dysfunction.

3.
Theranostics ; 9(24): 7403-7416, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695776

RESUMO

Bone marrow mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been widely used for treating myocardial infarction (MI). However, low retention and short-lived therapeutic effects are still significant challenges. This study aimed to determine whether incorporation of MSC-derived sEVs in alginate hydrogel increases their retention in the heart thereby improving therapeutic effects. Methods: The optimal sodium alginate hydrogel incorporating sEVs system was determined by its release ability of sEVs and rheology of hydrogel. Ex vivo fluorescence imaging was utilized to evaluate the retention of sEVs in the heart. Immunoregulation and effects of sEVs on angiogenesis were analyzed by immunofluorescence staining. Echocardiography and Masson's trichrome staining were used to estimate cardiac function and infarct size. Results: The delivery of sEVs incorporated in alginate hydrogel (sEVs-Gel) enhanced their retention in the heart. Compared with sEVs only treatment (sEVs), sEVs-Gel treatment significantly decreased cardiac cell apoptosis and promoted the polarization of macrophages at day 3 after MI. sEVs-Gel treatment also increased scar thickness and angiogenesis at four weeks post-infarction. Measurement of cardiac function and infarct size were significantly better in the sEVs-Gel group than in the group treated with sEVs only. Conclusion: Delivery of sEVs incorporated in alginate hydrogel provides a novel approach of cell-free therapy and optimizes the therapeutic effect of sEVs for MI.

4.
Circ Res ; 123(5): 564-578, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29921652

RESUMO

RATIONALE: Autophagy can preserve cell viability under conditions of mild ischemic stress by degrading damaged organelles for ATP production, but under conditions of severe ischemia, it can promote cell death and worsen cardiac performance. Mesenchymal stem cells (MSCs) are cardioprotective when tested in animal models of myocardial infarction, but whether these benefits occur through the regulation of autophagy is unknown. OBJECTIVE: To determine whether transplanted MSCs reduce the rate of autophagic degradation (autophagic flux) in infarcted hearts and if so, to characterize the mechanisms involved. METHODS AND RESULTS: Treatment with transplanted MSCs improved cardiac function and infarct size while reducing apoptosis and measures of autophagic flux (bafilomycin A1-induced LC3-II [microtubule-associated protein 1 light chain 3] accumulation and autophagosome/autolysosome prevalence) in infarcted mouse hearts. In hypoxia and serum deprivation-cultured neonatal mouse cardiomyocytes, autophagic flux and cell death, as well as p53-Bnip3 (B-cell lymphoma 2-interacting protein 3) signaling, declined when the cells were cultured with MSCs or MSC-secreted exosomes (MSC-exo), but the changes associated with MSC-exo were largely abolished by pretreatment with the exosomal inhibitor GW4869. Furthermore, a mimic of the exosomal oligonucleotide miR-125b reduced, whereas an anti-miR-125b oligonucleotide increased, autophagic flux and cell death, via modulating p53-Bnip3 signaling in hypoxia and serum deprivation-cultured neonatal mouse cardiomyocytes. In the in vivo mouse myocardial infarction model, MSC-exo, but not the exosomes obtained from MSCs pretreated with the anti-miR-125b oligonucleotide (MSC-exoanti-miR-125b), recapitulated the same results as the in vitro experiments. Moreover, measurements of infarct size and cardiac function were significantly better in groups that were treated with MSC-exo than the MSC-exoanti-miR-125b group. CONCLUSIONS: The beneficial effects offered by MSC transplantation after myocardial infarction are at least partially because of improved autophagic flux through excreted exosome containing mainly miR-125b-5p.


Assuntos
Autofagia , Exossomos/transplante , Transplante de Células-Tronco Mesenquimais/métodos , MicroRNAs/genética , Infarto do Miocárdio/terapia , Terapêutica com RNAi/métodos , Animais , Células Cultivadas , Exossomos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo
5.
Circ Res ; 122(7): 958-969, 2018 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-29343525

RESUMO

RATIONALE: Human pluripotent stem cell-derived cardiovascular progenitor cells (hPSC-CVPCs) should be thoroughly investigated in large animal studies before testing in clinical trials. OBJECTIVE: The main of this study is to clarify whether hPSC-CVPCs can engraft for long time in the heart of primates after myocardial infarction (MI) and compare the effectiveness and safety of immunosuppression with cyclosporine alone or multiple-drug regimen (MDR) containing cyclosporine, methylprednisolone, and basiliximab in cynomolgus monkeys that had received intramyocardial injections of 1×107 EGFP (enhanced green fluorescent protein)-expressing hPSC-CVPCs after MI. A third group of animals received the immunosuppression MDR but without cell therapy after MI (MI+MDR group). METHODS AND RESULTS: Measurements of EGFP gene levels and EGFP immunofluorescence staining indicated that the hPSC-CVPC engraftment rate was greater in the MI+MDR+CVPC group than that in the MI+cyclosporine+CVPC group. However, even in the MI+MDR+CVPC group, no transplanted cells could be detected at 140 days after transplantation. Concomitantly, immunofluorescent analysis of CD3, CD4, and CD8 expression indicated that T-lymphocyte infiltration in the CVPC-transplanted hearts was less in the MDR-treated animals than in the cyclosporine-alone-treated animals. The recovery of left ventricular function on day 28 post-MI in the MI+MDR+CVPC group was better than that in the MI+MDR group. Apoptotic cardiac cells were also less common in the MI+MDR+CVPC group than in the MI+MDR group, although both immunosuppression regimens were associated with transient hepatic dysfunction. CONCLUSIONS: This is the largest study of hPSCs in nonhuman primates in cardiovascular field to date (n=32). Compared with cyclosporine alone, MDR attenuates immune rejection and improves survival of hPSC-CVPCs in primates; this is associated with less apoptosis of native cardiac cells and better recovery of left ventricular function at 28 days. However, even with MDR, transplanted hPSC-CVPCs do not engraft and do not survive at 140 days after transplantation, thereby excluding remuscularization as a mechanism for the functional effect.


Assuntos
Células-Tronco Embrionárias Humanas/citologia , Desenvolvimento Muscular , Mioblastos Cardíacos/transplante , Infarto do Miocárdio/terapia , Transplante de Células-Tronco/métodos , Animais , Linhagem Celular , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Humanos , Imunossupressão/efeitos adversos , Imunossupressão/métodos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Macaca fascicularis , Masculino , Mioblastos Cardíacos/citologia , Transplante de Células-Tronco/efeitos adversos
6.
Endocr J ; 64(8): 787-796, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28674284

RESUMO

C1qTNF-related protein 1 (CTRP1) is independently associated with type 2 diabetes. However, the relationship between CTRP1 and insulin resistance is still not established. This study aimed to explore the role of CTRP1 under the situation of insulin resistance in adipose tissue. Plasma CTRP1 level was investigated in type 2 diabetic subjects (n = 35) and non-diabetic subjects (n = 35). The relationship between CTRP1 and phosphorylation of multi insulin receptor substrate 1 (IRS-1) serine (Ser) sites was further explored. Our data showed that Plasma CTRP1 was higher and negative correlation with insulin resistance in diabetic subjects (r = -0.283, p = 0.018). Glucose utilisation test revealed that the glucose utilisation rate of mature adipocytes was improved by CTRP1 in the presence of insulin. CTRP1 was not only related to IRS-1 protein, but also negatively correlated with IRS-1 Ser1101 phosphorylation (r = -0.398, p = 0.031). Furthermore, Phosphorylation levels of IRS-1 Ser1101 were significantly lower after incubation with 40 ng/mL CTRP1 in mature adipocytes than those with no intervention (p < 0.05). There was no significant correlation between CTRP1 and other IRS-1 serine sites (Ser302, Ser307, Ser612, Ser636/639, and Ser789). Collectively, our results suggested that CTRP1 might improve insulin resistance by reducing the phosphorylation of IRS-1 Ser1101, induced in the situation of insulin resistance as a feedback adipokine.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina/fisiologia , Proteínas/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adulto , Idoso , Feminino , Humanos , Insulina/farmacologia , Masculino , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Proteínas/farmacologia , Transdução de Sinais/efeitos dos fármacos
7.
Stem Cells Transl Med ; 6(1): 209-222, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28170197

RESUMO

Our group recently reported positive therapeutic benefit of human endometrium-derived mesenchymal stem cells (EnMSCs) delivered to infarcted rat myocardium, an effect that correlated with enhanced secretion of protective cytokines and growth factors compared with parallel cultures of human bone marrow MSCs (BMMSCs). To define more precisely the molecular mechanisms of EnMSC therapy, in the present study, we assessed in parallel the paracrine and therapeutic properties of MSCs derived from endometrium, bone marrow, and adipose tissues in a rat model of myocardial infarction (MI). EnMSCs, BMMSCs, and adipose-derived MSCs (AdMSCs) were characterized by fluorescence-activated cell sorting (FACS). Paracrine and cytoprotective actions were assessed in vitro by coculture with neonatal cardiomyocytes and human umbilical vein endothelial cells. A rat MI model was used to compare cell therapy by intramyocardial injection of BMMSCs, AdMSCs, and EnMSCs. We found that EnMSCs conferred superior cardioprotection relative to BMMSCs or AdMSCs and supported enhanced microvessel density. Inhibitor studies indicated that the enhanced paracrine actions of EnMSCs were mediated by secreted exosomes. Analyses of exosomal microRNAs (miRs) by miR array and quantitative polymerase chain reaction revealed that miR-21 expression was selectively enhanced in exosomes derived from EnMSCs. Selective antagonism of miR-21 by anti-miR treatment abolished the antiapoptotic and angiogenic effects of EnMSCs with parallel effects on phosphatase and tensin homolog (PTEN), a miR-21 target and downstream Akt. The results of the present study confirm the superior cardioprotection by EnMSCs relative to BMMSCs or AdMSCs and implicates miR-21 as a potential mediator of EnMSC therapy by enhancing cell survival through the PTEN/Akt pathway. The endometrium might be a preferential source of MSCs for cardiovascular cell therapy. Stem Cells Translational Medicine 2017;6:209-222.


Assuntos
Cardiotônicos/metabolismo , Endométrio/citologia , Exossomos/metabolismo , Células-Tronco Mesenquimais/citologia , MicroRNAs/metabolismo , Tecido Adiposo/citologia , Animais , Células da Medula Óssea/citologia , Endocitose , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , MicroRNAs/genética , Modelos Biológicos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Miócitos Cardíacos/metabolismo , Comunicação Parácrina , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
8.
Circ Res ; 118(6): 970-83, 2016 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-26838793

RESUMO

RATIONALE: The effectiveness of transplanted bone marrow mesenchymal stem cells (MSCs) for cardiac repair has been limited; thus, strategies for optimizing stem-cell-based myocardial therapy are needed. OBJECTIVE: The present study was designed to test our central hypothesis that hypoxia-preconditioned MSCs (HP-MSCs) are more effective than MSCs cultured under ambient oxygen levels for the treatment of myocardial injury in a large-scale (N=49), long-term (9 months), nonhuman primate (Cynomolgous monkeys) investigation. METHODS AND RESULTS: MSCs were engineered to express green fluorescent protein, cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then tested in the infarcted hearts of Cynomolgus monkeys (1×10(7) cells per heart). Hypoxia preconditioning increased the expression of several prosurvival/proangiogenic factors in cultured MSCs, and measurements of infarct size and left-ventricular function at day 90 after myocardial infarction were significantly more improved in monkeys treated with HP-MSCs than in monkeys treated with the control vehicle; functional improvements in normal cultured bone marrow mesenchymal stem cells-treated monkeys were not significant. HP-MSCs transplantation was also associated with increases in cardiomyocyte proliferation, vascular density, myocardial glucose uptake, and engraftment of the transplanted cells and with declines in endogenous cell apoptosis, but did not increase the occurrence of arrhythmogenic complications. CONCLUSIONS: Hypoxia preconditioning improved the effectiveness of MSCs transplantation for the treatment of myocardial infarction in nonhuman primates without increasing the occurrence of arrhythmogenic complications, which suggests that future clinical trials of HP-MSCs transplantation are warranted.


Assuntos
Precondicionamento Isquêmico Miocárdico/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Infarto do Miocárdio/terapia , Revascularização Miocárdica , Comunicação Parácrina/fisiologia , Animais , Hipóxia Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Macaca fascicularis , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Primatas , Transplante Homólogo/métodos
9.
Endocr J ; 61(9): 841-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24965225

RESUMO

Complement C1q tumor necrosis factor-related protein 1 (CTRP1), an adipose tissue-derived adipokine has been shown to decrease blood glucose levels and to improve metabolism of glucose in mice. In addition, CTRP1 has exhibited significant association with BMI, adiponectin and TNF-α in diabetic animal models. However, there are no published studies addressing CTRP1 levels in type 2 diabetic patients. Therefore, it was of interest to evaluate plasma CTRP1 levels and associated clinical parameters and biomarkers in patients with type 2 diabetes. 135 subjects were recruited to this study, including 62 type 2 diabetic patients (DM group) and 73 healthy subjects (control group). We measured biochemical parameters, CTRP1, TNF-α and adiponectin using enzyme-linked immunosorbent assay (ELISA). Plasma CTRP1 levels showed a significant difference between the DM group and the control group (646.3 ± 154.4 ng/mL vs. 442.6 ± 165.4 ng/mL, p < 0.01). In addition, CTRP1 was strongly positively associated with BMI, glucose levels, HbA1c, HOMA-IR and TNF-α in diabetic patients. CTRP1 showed negative correlation with adiponectin. In Multivariate regression analysis, CTRP1 was strongly independently associated with diabetes when CTRP1 levels were analyzed by both as a continuous variable and quartile (OR: 1.009, 95% CI: 1.004-1.015, p < 0.05; OR: 2.443, 95% CI: 1.379-4.182, p < 0.01, respectively). Increased plasma CTRP1 was independently associated with type 2 diabetes. Profiling of plasma adipokines such as CTRP1 is particularly important to obtain a greater understanding of their contribution to the type 2 diabetic state.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Proteínas/metabolismo , Adipocinas , Adiponectina/sangue , Adulto , Idoso , Biomarcadores/sangue , Glicemia , Índice de Massa Corporal , Feminino , Hemoglobina A Glicada/metabolismo , Homeostase , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fator de Necrose Tumoral alfa/sangue
10.
Gynecol Oncol ; 105(3): 722-6, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17408728

RESUMO

OBJECTIVE: This work was set out to investigate the effect of saphenous vein preservation during inguinal lymphadenectomy for patients with vulval malignancies. METHODS: 64 patients with vulval malignancies were allocated into two groups depending on their clinical stages, with one of them (31 patients included) being subjected to sparing of saphenous vein and the other to saphenous vein ligated surgery while treated with inguinal lymphadenectomy. The operative time, blood loss, 5-year survival rate, short- and long-term postoperative complications, 5-year survival rate and groin recurrence were selected as the monitored parameters, through which the above two groups were compared with each other using t test, chi2 and life table analysis. RESULTS: (1) The median operative time for bilateral inguinal lymphadenectomy was 155 min (130-170 min) in the sparing group, compared to 140 min (120-170 min) in the excision group (P>0.05). The median intraoperative blood loss was 295 mL (100-450 mL) in the sparing group, and 270 mL (150-390 mL) in the excision group (P>0.05). (2) Short-term lower extremity lymphedema occurred with 27 patients (43.5%) in the sparing group and 44 patients (66.7%) in the excision group (P<0.01). Still, short-term lower extremity phlebitis was observed with 7 patients (11.3%) in the sparing group while 17 developed phlebitis (25.8%) in the excision group (P<0.05). However, there was no statistical difference in postoperative fever, acute cellulites, seroma, or lymphocyst formation. (3) Long-term complication occurrence rate decreased by about 50% in patients subjected to saphenous vein sparing surgery compared with those to ligated surgery, while there was no remarkable difference between two groups in the occurrence rates of phlebitis and deep venous thrombosis (P>0.05). (4) The overall 5-year survival rate was 67.3%, with 66.7% and 68.0% for the excision group and the sparing group, respectively (P>0.05). CONCLUSION: The application of saphenous vein preservation technique during inguinal lymphadenectomy for patients with vulval malignancies could significantly decrease the occurrence rate of postoperative complications without compromising outcomes and should be widely put into clinical practice.


Assuntos
Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Veia Safena/cirurgia , Neoplasias Vulvares/cirurgia , Adulto , Idoso , Perda Sanguínea Cirúrgica , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Vulvares/patologia
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