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1.
Microcirculation ; : e12680, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33486837

RESUMO

OBJECTIVE: To investigate the effect of Yiqifumai injection (YQFM), a compound Chinese medicine, and its main active ingredients on lipopolysaccharide (LPS)-induced microvascular disturbance in mesentery and ileum. METHODS: Rats were infused with LPS (5 mg/kg/h) for 90 min. Thirty minutes after initiation of LPS administration, YQFM (160 mg/kg/h), Rb1 (5 mg/kg/h), Sch (2.5 mg/kg/h), or Rb1+Sch (5 mg/kg/h + 2.5 mg/kg/h) was infused until 90 min. Human umbilical vein endothelial cells (HUVECs) were incubated with LPS (100 ng/ml) for 90 min. YQFM (1 mg/ml), Rb1 (100 µM), Sch (100 µM), or Rb1+Sch (200 µM) was added 30 min after initiation of LPS stimulation. RESULTS: Yiqifumai injection and Rb1+Sch inhibited mesenteric venule hyperpermeability, suppressed microvillar erosion and submucosal edema, and protected claudin-5 from downregulation and interleukin-1ß from upregulation in ileal tissues after LPS. Study in HUVECs confirmed the effect of YQFM and Rb1+Sch on JAM-1 after LPS and revealed a similar effect on other junction proteins. Moreover, YQFM and Rb1+Sch attenuated the dysfunctional energy metabolism and the activation of TLR-4/Src/NF-κB signaling with Rb1 and Sch being partially effective. CONCLUSION: These results demonstrated the beneficial effect of post-treatment with YQFM, which is attributable to its main ingredient Rb1 and Sch, and likely mediated by targeting TLR-4/Src/NF-κB signaling pathway.

2.
Food Chem ; 339: 127985, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920305

RESUMO

There is limited research focusing on the effects of human gut microbiota on the oral bioaccessibility and intestinal absorption of pesticide residues in food. In the present study, we use a modified setup of the Simulator of the Human Intestinal Microbial Ecosystem for the determination of pesticide residue bioaccessibility in Chaenomeles speciosa, and a Caco-2 cell model of human intestinal absorption. Results showed that gut microbiota played a dual role based their effects on contaminant release and metabolism in the bioaccessibility assay, and Lactobacillus plantarum was one of key bacterial species in the gut microbiota that influenced pesticide stability significantly. The addition of L. plantarum to the system reduced the relative amounts (by 11.40-86.51%) of six pesticides. The interaction between the food matrix and human gut microbiota led to different absorption rates, and the barrier effects increased with an increase in incubation time.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Praguicidas/farmacologia , Rosaceae/química , Bactérias/metabolismo , Células CACO-2 , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/microbiologia , Lactobacillus plantarum/efeitos dos fármacos , Lactobacillus plantarum/isolamento & purificação , Neonicotinoides/metabolismo , Neonicotinoides/farmacologia , Nitrocompostos/metabolismo , Nitrocompostos/farmacologia , Compostos Organotiofosforados/metabolismo , Compostos Organotiofosforados/farmacologia , Praguicidas/química , Praguicidas/metabolismo , Rosaceae/metabolismo , Tiametoxam/metabolismo , Tiametoxam/farmacologia
3.
Math Biosci Eng ; 17(4): 4127-4146, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32987572

RESUMO

A diffusive epidemic model with two delays subjecting to Neumann boundary conditions is considered. First we obtain the existence and the stability of the positive constant steady state. Then we investigate the existence of Hopf bifurcations by analyzing the distribution of the eigenvalues. Furthermore, we derive the normal form on the center manifold near the Hopf bifurcation singularity. Finally, some numerical simulations are carried out to illustrate the theoretical results.

4.
Curr Pharm Des ; 26(33): 4185-4194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484767

RESUMO

BACKGROUND: The aim of the present study was to investigate the protective effects of Tanshinone IIA (Tan IIA) on hypoxia-induced injury in the medial vestibular nucleus (MVN) cells. METHODS: An in vitro hypoxia model was established using MVN cells exposed to hypoxia. The hypoxia-induced cell damage was confirmed by assessing cell viability, apoptosis and expression of apoptosis-associated proteins. Oxidative stress and related indicators were also measured following hypoxia modeling and Tan IIA treatment, and the genes potentially involved in the response were predicted using multiple GEO datasets. RESULTS: The results of the present study showed that Tan IIA significantly increased cell viability, decreased cell apoptosis and decreased the ratio of Bax/Bcl-2 in hypoxia treated cells. In addition, hypoxia treatment increased oxidative stress in MVN cells, and treatment with Tan IIA reduced the oxidative stress. The expression of SPhase Kinase Associated Protein 2 (SKP2) was upregulated in hypoxia treated cells, and Tan IIA treatment reduced the expression of SKP2. Mechanistically, SKP2 interacted with large-conductance Ca2+-activated K+ channels (BKCa), regulating its expression, and BKCa knockdown alleviated the protective effects of Tan IIA on hypoxia induced cell apoptosis. CONCLUSION: The results of the present study suggested that Tan IIA had a protective effect on hypoxia-induced cell damage through its anti-apoptotic and anti-oxidative activity via an SKP2/BKCa axis. These findings suggest that Tan IIA may be a potential therapeutic for the treatment of hypoxia-induced vertigo.

5.
Nat Commun ; 10(1): 5720, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844113

RESUMO

The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer relapse and therapy resistance. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which in turn, activates FOXO1 transcription and forms a positive regulatory loop. Disturbing the TRIB3-AKT interaction suppresses BCSCs by accelerating FOXO1 degradation and reducing SOX2 expression in mouse models of breast cancer. Our study provides insights into breast cancer development and confers a potential therapeutic strategy against TRIB3-overexpressed breast cancer.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/metabolismo , Proteína Forkhead Box O1/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Fatores de Transcrição SOXB1/genética , Animais , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Pessoa de Meia-Idade , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-akt/metabolismo , Análise Serial de Tecidos , Transcrição Genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Front Physiol ; 10: 1320, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708795

RESUMO

Objective: Lipopolysaccharide (LPS) causes microvascular dysfunction, which is a key episode in the pathogenesis of endotoxemia. This work aimed to investigate the effect of Qing-Ying-Tang (QYT), a compound Chinese medicine in cerebral microcirculation disturbance and brain damage induced by LPS. Methods: Male C57/BL6 mice were continuously transfused with LPS (7.5 mg/kg/h) through the left femoral vein for 2 h. QYT (14.3 g/kg) was given orally 2 h after LPS administration. The dynamics of cerebral microcirculation were evaluated by intravital microscopy. Brain tissue edema was assessed by brain water content and Evans Blue leakage. Cytokines in plasma and brain were evaluated by flow cytometry. Confocal microscopy and Western blot were applied to detect the expression of junction and adhesion proteins, and signaling proteins concerned in mouse brain tissue. Results: Post-treatment with QYT significantly ameliorated LPS-induced leukocyte adhesion to microvascular wall and albumin leakage from cerebral venules and brain tissue edema, attenuated the increase of MCP-1, MIP-1α, IL-1α, IL-6, and VCAM-1 in brain tissue and the activation of NF-κB and expression of MMP-9 in brain. QYT ameliorated the downregulation of claudin-5, occludin, JAM-1, ZO-1, collagen IV as well as the expression and phosphorylation of VE-cadherin in mouse brain. Conclusions: This study demonstrated that QYT protected cerebral microvascular barrier from disruption after LPS by acting on the transcellular pathway mediated by caveolae and paracellular pathway mediated by junction proteins. This result suggests QYT as a potential strategy to deal with endotoxemia.

7.
Blood Adv ; 3(21): 3406-3418, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714962

RESUMO

Thrombocytopenia is associated with life-threatening bleeding and is common in myelodysplastic syndromes (MDS). Robust molecular prognostic biomarkers need to be developed to improve clinical decision making for patients with MDS with thrombocytopenia. Wilms tumor 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) are promising immunogenic antigen candidates for immunotherapy, and their clinical effects on patients with MDS with thrombocytopenia are still not well understood. We performed a multicenter observational study of adult patients with MDS with thrombocytopenia from 7 different tertiary medical centers in China. We examined bone marrow samples collected at diagnosis for WT1 and PRAME transcript levels and then analyzed their prognostic effect for patients with MDS with thrombocytopenia. In total, we enrolled 1110 patients diagnosed with MDS with thrombocytopenia. Overexpression of WT1 and PRAME was associated with elevated blast percentage, worse cytogenetics, and higher Revised International Prognostic Scoring System (IPSS-R) risk. Further, both WT1 and PRAME overexpression were independent poor prognostic factors for acute myeloid leukemia evolution, overall survival, and progression-free survival. Together, the 2 genes overexpression identified a population of patients with MDS with substantially worse survival. On the basis of WT1 and PRAME transcript levels, patients with MDS with IPSS-R low risk were classified into 2 significantly divergent prognostic risk groups: a low-favorable group and a low-adverse group. The low-adverse group had survival similar to that of patients in the intermediate-risk group. Our study demonstrates that the evaluation of WT1/PRAME transcript analysis may improve the prognostication precision and better risk-stratify the patients.


Assuntos
Antígenos de Neoplasias/genética , Expressão Gênica , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Trombocitopenia/diagnóstico , Proteínas WT1/genética , Adulto , Idoso , Algoritmos , Biomarcadores , Transformação Celular Neoplásica/genética , Terapia Combinada , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/terapia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Trombocitopenia/etiologia , Resultado do Tratamento
8.
ACS Nano ; 13(7): 7568-7577, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31260255

RESUMO

Cellular immunotherapeutics aim to employ immune cells as anticancer agents. Ex vivo engineering of dendritic cells (DCs), the initial role of an immune response, benefits tumor elimination by boosting specific antitumor responses. However, directly activating DCs in vivo is less efficient and therefore quite challenging. Here, we designed a nanoactivator that manufactures DCs through autophagy upregulating in vivo directly, which lead to a high-efficiency antigen presention of DCs and antigen-specific T cells generation. The nanoactivator significantly enhances tumor antigen cross-presentation and subsequent T cell priming. Consequently, in vivo experiments show that the nanoactivators successfully reduce tumor growth and prolong murine survival. Taken together, these results indicate in situ DCs manipulation by autophagy induction is a promising strategy for antigen presentation enhancement and tumor elimination.


Assuntos
Autofagia/imunologia , Células Dendríticas/imunologia , Imunoterapia , Melanoma Experimental/terapia , Nanopartículas/química , Animais , Apresentação do Antígeno/imunologia , Linhagem Celular Tumoral , Feminino , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Propriedades de Superfície , Linfócitos T/imunologia
9.
Chemosphere ; 231: 538-545, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31151014

RESUMO

Problems with pesticide residues in medicinal and edible plant have received great attention. The dietary exposure risk induced by presence of pesticide residues depends on its release from the food matrix, i.e., its bioaccessibility. The bioaccessibility of pesticide residues in human food is poorly understood and thus, we used in vitro digestive method to measure the bioaccessibility of six pesticides in Chaenomelis speciosa. Results showed that the lower and upper boundary bioaccessibility values of the six pesticides in C. speciosa was 4.26 and 86.52%, and the bioaccessibility varied for the pesticide types and digestion phase. The α-amylase and pancreatin play an important role in vitro bioaccessibility. Our findings suggest that risk assessment studies should be taken into account the pesticide metabolism, and that previous studies may have underestimated pesticide bioaccessibility.


Assuntos
Resíduos de Praguicidas/metabolismo , Praguicidas/metabolismo , Rosaceae/fisiologia , Disponibilidade Biológica , Humanos , Técnicas In Vitro , Resíduos de Praguicidas/química , Resíduos de Praguicidas/toxicidade , Praguicidas/toxicidade , Medição de Risco
10.
Pharmacol Res ; 146: 104272, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31085230

RESUMO

QiShenYiQi Pills (QSYQ) is a compound Chinese medicine widely used in China for treatment of cardiovascular disease. However, limited data are available regarding the anti-fibrotic role of QSYQ after ischemia/reperfusion (I/R) injury. This study aimed to investigate the effect of post-treatment with QSYQ on myocardial fibrosis after I/R-induced myocardium injury, and the role of different compounds of QSYQ, focusing especially on the involvement of chemokine ribosomal protein S19 (RP S19) dimer and monocyte migration. Male Sprague-Dawley rats were subjected to left anterior descending coronary artery occlusion for 30 min followed by reperfusion with or without administration of QSYQ (0.6, 1.2, or 1.8 g/kg) once daily by gavage for 6 days. Post-treatment with QSYQ diminished I/R-induced infarct size, alleviated myocardium injury, attenuated myocardial fibrosis after 6 days of reperfusion, and restored heart function and myocardial blood flow after I/R. In addition, the drug significantly inhibited monocyte infiltration and macrophage polarization towards M2, which was attributable to chemokine RP S19 dimer. Moreover, Western blots revealed that QSYQ blocked I/R-induced increase in TGFß1 and TGFßRⅡ and reversed its relevant gene expression, such as Smad3,4,6,7, and inhibited the increase of MMP 2,9 expression. As the major components of QSYQ, astragaloside IV (AsIV), 3,4-dihydroxy-phenyl lactic acid (DLA), and notoginsenoside R1 (R1) were assessed as to the contribution of each of them to the expression of the proteins concerned. The results showed that the effect of AsIV was similar to QSYQ, while DLA and R1 only partly simulated the effect of QSYQ. The results provide evidence for the potential role of QSYQ in treating myocardial fibrosis following I/R injury. This effect may be associated with QSYQ's inhibition effect on monocyte chemotaxis and TGFß1/Smads signaling pathway with different component targeting distinct link (s) of the signaling.


Assuntos
Cardiotônicos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Cardiotônicos/farmacologia , Linhagem Celular , Medicamentos de Ervas Chinesas/farmacologia , Fibrose , Macrófagos/efeitos dos fármacos , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , RNA Interferente Pequeno/genética , Ratos Sprague-Dawley , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
11.
Microcirculation ; 26(7): e12553, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31059171

RESUMO

OBJECTIVE: Yiqifumai injection is a compound Chinese medicine used to treat microcirculatory disturbance-related diseases clinically. Our previous study proved that Yiqifumai injection pretreatment inhibited lipopolysaccharide-induced venular albumin leakage in rat mesentery. This study aimed to investigate whether Yiqifumai injection attenuated cerebral microvascular hyperpermeability and corresponding contribution of its main ingredients. METHODS: Rats were challenged by lipopolysaccharide infusion (5 mg/kg/h) for 90 minutes. Yiqifumai injection (160 mg/kg/h), Rb1 (5 mg/kg/h), Sch (2.5 mg/kg/h), and Rb1 (5 mg/kg/h) + Sch (2.5 mg/kg/h) were infused 30 minutes before (pretreatment) or after (post-treatment) lipopolysaccharide administration. RESULTS: Both pretreatment and post-treatment with Yiqifumai injection attenuated cerebral venular albumin leakage during lipopolysaccharide infusion and cerebrovascular hyperpermeability at 72 hours after lipopolysaccharide infusion. Yiqifumai injection restrained the decreased junction protein expression, adenosine triphosphate content, and mitochondria complex I, II, IV, and V activities. Moreover, Yiqifumai injection inhibited toll-like receptor-4 expression, Src phosphorylation, and caveolin-1 expression. Its main ingredients Rb1 and Sch alone worked differently, with Rb1 being more effective for enhancing energy metabolism, while Sch attenuating toll-like receptor-4 expression and Src activation. CONCLUSION: Yiqifumai injection exerts a protective and ameliorated effect on cerebral microvascular hyperpermeability, which is more effective than any of its ingredients, possibly due to the interaction of its main ingredients through a multi-pathway mode.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Lipopolissacarídeos/toxicidade , Microcirculação/efeitos dos fármacos , Animais , Masculino , Ratos , Ratos Wistar
12.
J Colloid Interface Sci ; 539: 481-489, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611043

RESUMO

In this investigation, a new polymer with low surface energy was synthesized by grafting a triazole group onto polyepichlorohydrin (PECH) rubber that contained no halogens. The chlorine on PECH was first replaced by an azide group, and this attached azide was then converted to a triazole group with alkyl chains using the azide-alkyne Huisgen cycloaddition reaction. Analyses confirmed the structure of final product, PECH-triazole polymer. The grafting reactions increased the surface roughness. The static contact angles of water or CH2I2 droplets on the PECH-azole film were 101.7° and 71.3°, respectively. The advancing and receding contact angles for water on PECH-azide were 119.8° and 13.7°, respectively. The PECH-triazole polymer has omniphobic properties with rose petal characteristics. The PECH-triazole has low dispersive surface energy (21 mN/m) and negligible non-dispersive surface energy, giving a wetting envelope that is similar to the one of PTFE polymer. X-ray photoelectron spectroscopy and transmission infrared spectroscopy suggested that the interactions of the N atoms on the triazole ring and the O atoms on the PECH backbone constrained the orientation of CH2 groups and reduced the surface energy of the thin film.

13.
Cell Biol Int ; 43(4): 384-393, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30599080

RESUMO

Non-small-cell carcinoma (NSCLC) is the most common cancer along with high mortality rate worldwide. In the present study, our data showed that lncRNA MAF BZIP Transcription Factor G Antisense RNA 1 (MAFG-AS1) was over-expressed in NSCLC tissues and cell lines. Overexpression of MAFG-AS1 promoted the migration, invasion and enhanced epithelial-mesenchymal transition (EMT) of NSCLC cell. In addition, miR-339-5p was predicted to be a target of MAFG-AS1 and the level of miR-339-5p was down-regulated in NSCLC. Over-expression of MAFG-AS1 significantly decreased the level of miR-339-5p in NSCLC cell. Moreover, the matrix metalloproteinase 15 (MMP15) was identified to be a target of miR-339-5p. The level of MMP15 was negatively regulated by miR-339-5p whereas positively controlled by MAFG-AS1. In addition, up-regulation of miR-339-5p neutralized the promoting impact of MAFG-AS1 on the migration, invasion and EMT of NSCLC cell. Finally, the xenograft model suggested that MAFG-AS1 promoted the metastasis of NSCLC cell in vivo. Altogether, we proved that MAFG-AS1-miR-339-5p-MMP15 axis might be a promising therapeutic target for the treatment of patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Metaloproteinase 15 da Matriz/metabolismo , MicroRNAs/metabolismo , RNA Antissenso/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fator de Transcrição MafG/genética , Fator de Transcrição MafG/metabolismo , Metaloproteinase 15 da Matriz/genética , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Invasividade Neoplásica , RNA Antissenso/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
14.
Food Funct ; 10(1): 289-295, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30566153

RESUMO

Humans are frequently exposed to the residues of various neonicotinoids, highlighting the need to understand human exposure through oral ingestion of contaminated foods. In this study, the effects of different food matrices (tomato, cucumber, and carrot) and their interaction with dietary component additives, including proteins and dietary fiber, was investigated. The results showed that the presence of a food matrix had a significant effect on the bioaccessibility of neonicotinoids (imidacloprid, thiamethoxam, acetamiprid, and thiacloprid) in both the gastric and intestinal environments. Neonicotinoids in tomato presented relatively low bioaccessibility, indicating that the daily intake of the tomato can be regarded as being relatively safer. Moreover, the addition of protein or dietary fiber to fruit and vegetables had a marked influence on neonicotinoid bioaccessibility and the effects varied between the different matrices. In particular, the addition of 2.0% dietary fiber significantly reduced the bioaccessibility (18.38-67.91%). Therefore, we recommend that consuming an increased intake of dietary fiber could improve the safety of fruit and vegetables in daily life. The present results can support the identification of suitable food intake conditions for the significant reduction of pesticide residue levels.


Assuntos
Frutas/química , Resíduos de Praguicidas/química , Verduras/química , Cucumis sativus/química , Cucumis sativus/metabolismo , Daucus carota/química , Daucus carota/metabolismo , Digestão , Contaminação de Alimentos/análise , Frutas/metabolismo , Humanos , Lycopersicon esculentum/química , Lycopersicon esculentum/metabolismo , Neonicotinoides/metabolismo , Resíduos de Praguicidas/metabolismo , Verduras/metabolismo
15.
Shock ; 51(6): 745-756, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29863652

RESUMO

Sirtuin1 (Sirt1) and Sirtuin3 (Sirt3) are known to participate in regulating mitochondrial function. However, whether Total Salvianolic Acid Injection (TSI) protects against myocardial ischemia/reperfusion (I/R) injury through regulating Sirt1, Sirt3, and mitochondrial respiratory chain complexes is unclear. The aim of this study was to explore the effects of TSI on I/R-induced myocardial injury and the underlying mechanism. Male Sprague-Dawley rats were subjected to 30 min occlusion of the left anterior descending coronary artery followed by 90 min reperfusion with or without TSI treatment (8 mg/kg/h). The results demonstrated that TSI attenuated I/R-induced myocardial injury by the reduced infarct size, recovery of myocardial blood flow, and decreased cardiac apoptosis. Moreover, TSI protected heart from oxidative insults, such as elevation of myeloperoxidase, malondialdehyde, hydrogen peroxide, ROS, as well as attenuated I/R-elicited downregulation of Sirt1, Sirt3, NADH dehydrogenase [ubiquinone] 1 alpha subcomplex 10 (NDUFA10), succinate dehydrogenase complex, subunit A, flavoprotein variant (SDHA), and restoring mitochondrial respiratory chain complexes activity. The in vitro study in H9c2 cells using siRNA transfection further confirmed the critical role of Sirt1 and Sirt3 in the effect of TSI on the expression of NDUFA10 and SDHA. These results demonstrated that TSI attenuated I/R-induced myocardial injury via inhibition of oxidative stress, which was related to the activation of NDUFA10 and SDHA through the upregulation of Sirt1 and Sirt3.


Assuntos
Antioxidantes/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Lactatos/farmacologia , Proteínas Mitocondriais/biossíntese , Traumatismo por Reperfusão Miocárdica , Sirtuína 1/biossíntese , Sirtuínas/biossíntese , Regulação para Cima/efeitos dos fármacos , Animais , Transporte de Elétrons/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/patologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Ratos , Ratos Sprague-Dawley
16.
Stroke ; 49(9): 2211-2219, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30354988

RESUMO

Background and Purpose- tPA (tissue-type plasminogen activator) is the only recommended intravenous thrombolytic agent for ischemic stroke. However, its application is limited because of increased risk of hemorrhagic transformation beyond the time window. T541 is a Chinese compound medicine with potential to attenuate ischemia and reperfusion injury. This study was to explore whether T541-benefited subjects underwent tPA thrombolysis extending the time window. Methods- Male C57BL/6 N mice were subjected to carotid artery thrombosis by stimulation with 10% FeCl3 followed by 10 mg/kg tPA with/without 20 mg/kg T541 intervention at 4.5 hours. Thrombolysis and cerebral blood flow were observed dynamically until 24 hours after drug treatment. Neurological deficit scores, brain edema and hemorrhage, cerebral microvascular junctions and basement membrane proteins, and energy metabolism in cortex were assessed then. An in vitro hypoxia/reoxygenation model using human cerebral microvascular endothelial cells was used to evaluate effect of T541 on tight junctions and F-actin in the presence of tPA. Results- tPA administered at 4.5 hours after carotid thrombosis resulted in a decrease in thrombus area and survival rate, whereas no benefit on cerebral blood flow. Study at 24 hours after tPA administration revealed a significant angioedema and hemorrhage in the ischemia hemisphere, a decreased expression of junction proteins claudin-5, zonula occludens-1, occludin, junctional adhesion molecule-1 and vascular endothelial cadherin, and collagen IV and laminin. Meanwhile, ADP/ATP, AMP/ATP, and ATP5D (ATP synthase subunit) expression and activities of mitochondria complex I, II, and IV declined, whereas malondialdehyde and 8-Oxo-2'-deoxyguanosine increased and F-actin arrangement disordered. All the insults after tPA treatment were attenuated by addition of T541 dose dependently. Conclusions- The results suggest T541 as a potential remedy to attenuate delayed tPA-related angioedema and hemorrhage and extend time window for tPA treatment. The potential of T541 to upregulate energy metabolism and protect blood-brain barrier is likely attributable to its effects observed.


Assuntos
Alcenos/farmacologia , Edema Encefálico , Trombose das Artérias Carótidas , Circulação Cerebrovascular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Hemorragias Intracranianas , Polifenóis/farmacologia , Traumatismo por Reperfusão , Saponinas/farmacologia , Animais , Antígenos CD/efeitos dos fármacos , Antígenos CD/metabolismo , Astrágalo (Planta) , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Caderinas/efeitos dos fármacos , Caderinas/metabolismo , Moléculas de Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Claudina-5/efeitos dos fármacos , Claudina-5/metabolismo , Colágeno Tipo IV/efeitos dos fármacos , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Combinação de Medicamentos , Complexo I de Transporte de Elétrons , Complexo II de Transporte de Elétrons , Complexo IV da Cadeia de Transporte de Elétrons , Laminina/efeitos dos fármacos , Laminina/metabolismo , Masculino , Camundongos , Ocludina/efeitos dos fármacos , Ocludina/metabolismo , Panax notoginseng , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Ativador de Plasminogênio Tecidual/farmacologia , Proteína da Zônula de Oclusão-1/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo
17.
Free Radic Biol Med ; 129: 202-214, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30218773

RESUMO

The transplanted liver inevitably suffers from ischemia reperfusion (I/R) injury, which represents a key issue in clinical transplantation determining early outcome and long-term graft survival. A solution is needed to deal with this insult. This study was undertaken to explore the effect of Caffeic acid (CA), a naturally occurring antioxidant, on I/R injury of grafted liver and the mechanisms involved. Male Sprague-Dawley rats underwent orthotopic liver transplantation (LT) in the absence or presence of CA administration. In vitro, HL7702 cells were subjected to hypoxia/reoxygenation. LT led to apparent hepatic I/R injury, manifested by deteriorated liver function, microcirculatory disturbance and increased apoptosis, along with increased PDIA3 expression and nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase activity, and membrane translocation of NADPH oxidase subunits. Treatment with CA attenuated the above alterations. siRNA/shRNA-mediated knockdown of PDIA3 in HL7702 cells and rats played the same role as CA not only in inhibiting ROS production and NADPH oxidase activity, but also in alleviating hepatocytes injury. CA protects transplanted livers from injury, which is likely attributed to its protection of oxidative damage by interfering in PDIA3-dependent activation of NADPH oxidase.


Assuntos
Antioxidantes/farmacologia , Ácidos Cafeicos/farmacologia , Transplante de Fígado , NADPH Oxidases/genética , Isomerases de Dissulfetos de Proteínas/genética , Traumatismo por Reperfusão/prevenção & controle , Animais , Antioxidantes/isolamento & purificação , Apoptose/efeitos dos fármacos , Ácidos Cafeicos/isolamento & purificação , Hipóxia Celular/genética , Linhagem Celular , Regulação da Expressão Gênica , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , NADPH Oxidases/metabolismo , Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Isomerases de Dissulfetos de Proteínas/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Salvia miltiorrhiza/química , Transdução de Sinais , Transplante Homólogo
18.
Front Physiol ; 9: 1104, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30177885

RESUMO

Objective: Acute lung injury is a severe clinic condition with limited therapeutic approaches. This study evaluated whether schisandrin (Sch), an ingredient of Schisandra chinensis, has preventive effects on endothelium and epithelium injury induced by lipopolysaccharide (LPS) and the underlying mechanisms. Methods: Male Wistar rats were continuously infused with LPS (5 mg/kg/h) via the left jugular vein for 90 min. In some rats, Sch (2.5 mg/kg/h) was administrated through the left jugular vein 30 min before LPS infusion. Leukocyte recruitment, levels of inflammatory cytokines, lung histology and edema, vascular and alveolar barrier disruption and related proteins were evaluated at indicated time point after LPS challenge. Results: LPS infusion for 90 min resulted in an increased leukocyte adhesion to pulmonary venules and overproduction of cytokine and chemokine in both serum and lung homogenate. At 8 h after termination of LPS infusion, obvious Evans blue extravasation and lung edema were observed, along with an increased apoptosis, a decreased expression of tight junction and adherent junction proteins, and a reduction in von Willebrand factor (vWF) and keratin, all of which were attenuated by Sch treatment. Meanwhile, the LPS-elicited activation of TLR-4/NF-κB/MAPK and FoxO1 signaling was inhibited by Sch. Conclusion: The present study revealed that pretreatment with Sch alleviated lung endothelium and epithelium injury after LPS stimulation, which is attributable to inhibition of cell injury and activation of cell regeneration via regulation of TLR-4/NF-κB/MAPK and Akt/FoxO1 signaling pathway.

19.
Front Physiol ; 9: 527, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867568

RESUMO

Type 2 Diabetes mellitus (T2DM) is closely correlated with cognitive impairment and neurodegenerative disease. Bushen Huoxue (BSHX) is a compound Chinese medicine used clinically to treat diabetes-induced cognitive impairment. However, its underlying mechanisms remain unclear. In the present study, KKAy mice, a genetic model of type 2 diabetes with obesity and insulin resistant hyperglycemia, received a daily administration of BSHX for 12 weeks. Blood glucose was measured every 4 weeks. After 12 weeks, BSHX treatment significantly ameliorated the T2DM related insults, including the increased blood glucose, the impaired spatial memory, decreased cerebral blood flow (CBF), occurrence of albumin leakage, leukocyte adhesion and opening capillary rarefaction. Meanwhile, the downregulation of the tight junction proteins (TJ) claudin-5, occludin, zonula occluden-1 (ZO-1) and JAM-1 between endothelial cells, amyloid-ß (Aß) accumulation in hippocampus, increased AGEs and RAGE, and expression of RhoA/ROCK/moesin signaling pathway and phosphorylation of Src kinase in KKAy mice were significantly protected by BSHX treatment. These results indicate that the protective effect of BSHX on T2DM-induced cognitive impairment involves regulation of RhoA/ROCK1/moesin signaling pathway and phosphorylation of Src kinase.

20.
Front Physiol ; 9: 658, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29910744

RESUMO

The purpose of the study was to explore the effect and the underlying mechanism of YangXue QingNao Wan (YXQNW) and Silibinin Capsules (SC), the two Chinese medicines, on cognitive impairment in older people with familial hyperlipidaemia. Fourteen month-old female LDLR (+/-) golden Syrian hamsters were used with their wild type as control. YXQNW (0.5 g/kg/day), SC (0.1 g/kg/day), or YXQNW (0.5 g/kg/day) + SC (0.1 g/kg/day) were administrated orally for 30 days. To assess the effects of the two drugs on plasma lipid content and cognitive ability, plasma TC, TG, LDL-C, and HDL-C were measured, and Y maze task was carried out both before and after administration. After administering of the drugs for 30 days, to evaluate the effect of the two drugs on disturbed blood flow caused by hyperlipidemia, the cerebral blood flow (CBF) was measured. To assess blood-brain barrier integrity, albumin leakage in middle cerebral artery (MCA) area was determined. To evaluate the effect of the drugs on impaired microvessels, the number and morphology of microvessels were assessed in hippocampus area. To further evaluate the ultrastructure of microvessels in hippocampus, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) were carried out. To assess the profiles of claudin-5 and occludin in hippocampus, we performed immunofluorescence. Finally, to assess the expression of claudin-5, JAM-1, occludin and ZO-1 in hippocampus, western blot was carried out. The results showed that YXQNW, SC, and YXQNW + SC improved cognitive impairment of aged LDLR (+/-) golden Syrian hamsters without lowering plasma TC and LDL-C. YXQNW, SC, and YXQNW + SC attenuated albumin leakage in MCA area and neuronal damage in hippocampus, concomitant with an increase in CBF, a decrease of perivascular edema and an up-regulated expression of claudin-5, occludin and ZO-1. In conclusion, YXQNW, SC, and YXQNW + SC are able to improve cognitive ability in aged LDLR (+/-) golden Syrian hamsters via mechanisms involving maintaining blood-brain barrier integrity. These findings provide evidence suggesting YXQNW or SC as a potential regime to counteract the cognitive impairment caused by familial hypercholesterolemia.

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