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1.
Artigo em Inglês | MEDLINE | ID: mdl-31687988

RESUMO

: A zymogen-like activated factor X variant (FXa) is being developed for treating acute bleeding conditions. Activated factor V is an essential cofactor to FXa for activating prothrombin to thrombin. Thrombi/emboli formation was observed microscopically in FXa toxicity studies in animals. The objective of this research was to evaluate candidate biomarkers for FXa-induced thrombi/emboli formation to inform safety monitoring and dose-escalation decisions in FXa clinical trials. Effects of intravenous FXa administration on platelets, fibrinogen, activated partial thromboplastin time (aPTT), prothrombin time (PT), D-dimer, tissue factor pathway inhibitor, thrombin : antithrombin complex, antithrombin, and factor V, and protein C (PC) activities were evaluated in mice, rats, and monkeys. Mice had endogenous factor V activity 10× that of monkeys and were overly sensitive to FXa-induced thrombi/emboli formation. In monkeys, decreases in fibrinogen and prolongation in aPTT and PT emerged as potential biomarkers for impending FXa-induced thrombi/emboli formation, based on association of changes with microscopically observable thrombi/emboli (0-97 thrombi/emboli per monkey). PC decreases, measured by a clot-based assay, were also observed. A similar reduction in PC activity, when measured by clot-based assay, was observed in a phase 1 clinical trial. However, an in-vitro experiment with human plasma spiked with increasing concentrations of FXa indicated dose-dependent FXa-induced interference with clot-based assays and no depletion of PC or S by FXa in non-clot-based assays. Nonclinical biomarker studies identified fibrinogen, aPTT and PT as potential biomarkers for monitoring the clinical safety of FXa. Results of clot-based assays with FXa treatment should be interpreted with caution.

2.
Neuroscience ; 421: 48-58, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682826

RESUMO

Increasing studies have revealed that metabolic disorders, especially diabetes, are high risk factors for the development of Alzheimer's disease (AD) and other neurodegenerative diseases. It has been reported that patients with diabetes are prone to suffer from cognitive dysfunction (CD). Although abnormal glucose metabolism and deposition of amyloid ß (Aß) are proven to have a closely relationship with diabetes-induced CD, its exact mechanism is still undetermined. In this study, a total of 14 mice were intraperitoneally injected with streptozotocin for 5 consecutive days to mimic diabetic models, and then hierarchical cluster analysis was adopted to classify the diabetic mice into CD and Non-CD phenotypes by the results of Morris water maze test (MWMT). Furthermore, we detected Hippo signaling including mammalian sterile 20-like protein kinases1 (MST1), large tumor suppressors 1 (LATS1), Yes-associated protein (YAP) and phosphorylation of YAP (p-YAP) in brain and peripheral tissues. As compared with control mice, the levels of MST1, LATS1 and p-YAP/YAP ratio were increased in medial prefrontal cortex (mPFC), striatum and hippocampus of CD mice, while these proteins were decreased in gut tissue of CD mice. Additionally, there were significant positive correlations between escape latency and p-YAP/YAP ratio in mPFC, anterior cingulate cortex (ACC) and hippocampus, as well as the level of LATS1 in liver, kidney and gut tissues. In conclusion, alterations in Hippo signaling may contribute to CD induced by diabetes. Therefore, therapeutic interventions improving Hippo signaling might be beneficial to the treatment of diabetes-induced CD and other neurodegenerative diseases.

3.
Aging (Albany NY) ; 112019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31760385

RESUMO

It is well recognized that type 2 diabetes mellitus (T2DM) is an age-related metabolic disease, emerging gradually as a major global health burden that has gained public attention. Meanwhile, increasing attention is paid to the crucial role of gut microbiota in the pathogenesis and therapeutic mechanisms of metabolic disorders, especially T2DM. In this study, we used C57 BL/KS db/db male mice as a T2DM murine model. We found that the ß-diversity and relative abundances of gut bacteria were obviously altered in db/db mice, associated with a significant increase in Verrucomicrobia at six levels (phylum, class, order, etc.) and family S24-7 and a significant decrease in Bacteroidaceae at family, genus, and species levels, as well as Prevotellaceae at family and genus levels. Furthermore, fecal bacteria from db/db and m/m mice transplanted into pseudo-germ-free mice showed a significant change in the metabolic parameters, including the body weight, fasting blood glucose, fluid and food intake, and alterations in the composition of the gut microbiota. Taken together, these findings suggest that abnormalities in the composition of the gut microbiota might contribute to the development of T2DM and that potential therapeutic strategies improving gut microbiota might provide beneficial effects for individuals with T2DM and age-related glucose intolerance.

4.
J Transl Med ; 17(1): 341, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601236

RESUMO

BACKGROUND: The role of body fat distribution in uric acid metabolism is still ambiguity. We aimed to investigate the independent contribution of visceral adipose measured by visceral adiposity index and lipid accumulation product and liver fat assessed by fatty liver index to the risk of hyperuricemia. METHODS: We conducted a cross-sectional study involving 1284 participants aged ≥ 40 years old recruited from communities in Zhonglou district, Changzhou. Each participant completed a standard questionnaire, and provided blood samples for biochemical measurements. Visceral adiposity index, fatty liver index and lipid accumulation product were calculated by simple anthropometric and functional parameters. Hyperuricemia was defined as serum uric acid ≥ 420 µmol/l for males and ≥ 360 µmol/l for females. RESULTS: The prevalence of hyperuricemia was 15.9% and gradually increased across tertiles of adiposity-based indices. The visceral adipose-based measurements (visceral adiposity index, fatty liver index, lipid accumulation product) had better power to discriminate hyperuricemia than body mass index (BMI), waist circumference and neck circumference, and visceral adiposity index exhibited the highest power, with the area under the receiver operating characteristics curve (AUROC) of 0.662 (0.636-0.688). Multivariate logistic regression found 1.49-fold, 2.21-fold and 2.12-fold increased risk of hyperuricemia with 1-unit increment of visceral adiposity index, fatty liver index, and lipid accumulation product, respectively. Compared to tertile 1, the odds ratios of hyperuricemia for the second tertile and the third tertile of visceral adiposity index were 1.57 (1.00-2.50) and 3.11 (1.96-4.94), those of fatty liver index were 1.64 (1.05-2.68) and 3.58 (1.94-6.01), and those of lipid accumulation product were 1.93 (1.19-3.15) and 3.53 (2.05-6.09), respectively. However, no significant associations of BMI, waist circumference and neck circumference with hyperuricemia were observed. CONCLUSIONS: Visceral adipose accumulation increased the risk of hyperuricemia, independently of BMI, waist circumference and neck circumference, among middle-aged and elderly Chinese adults.

5.
Stem Cell Res Ther ; 10(1): 295, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547872

RESUMO

BACKGROUND: Interleukin 33 is known to have an important influence in the process of myocardial infarction, and the immunoregulatory function of MSCs could be influenced by cell factors. In this study, we evaluated the therapeutic efficacy of IL-33-overexpressing bone marrow mesenchymal stem cells (IL33-MSCs) on myocardial infarction (MI) and detected the inflammatory level and cardiac function in rats. METHODS AND RESULTS: First, we evaluated the proliferation of T cells and polarization of macrophages that had been co-cultured with Vector-MSCs or IL33-MSCs. Co-culture experiments indicated that IL33-MSCs reduced T cell proliferation and enhanced CD206+ macrophage polarization. Second, we determined the inflammation level and cardiac function of PBS-, Vector-MSC-, and IL33-MSC-injected rats. Echocardiography indicated that left ventricular ejection fraction (LVEF) was enhanced in IL33-MSC-injected rats compared with Vector-MSC-injected rats. Postmortem analysis of rat heart tissue showed reduced fibrosis and less inflammation in IL33-MSC-injected rats. CONCLUSION: These studies indicated that the IL33-MSC injection improved heart function and reduces inflammation in rats with MI compared with PBS or Vector-MSC injections. IL-33 overexpression enhances the immunomodulatory function and therapeutic effects of MSCs on acute MI via enhancing the polarization of macrophages toward M2, enhancing the differentiation of CD4+ T cells toward CD4+IL4+Th2 cells, and finally, reducing heart inflammation and enhancing heart function.

7.
Thromb Res ; 182: 56-63, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31450009

RESUMO

INTRODUCTION: Endotoxemia often results in systemic inflammatory response syndrome (SIRS), coagulation disturbance and acute lung injury (ALI), and such a condition is associated with the activation of platelets, leukocytes and vascular endothelial cells (VECs). P-selectin glycoprotein ligand 1 (PSGL-1) is a key regulatory molecule in the activation of platelets, leukocytes and VECs. However, it still remains largely unexplored whether PSGL-1 plays an important role in SIRS, coagulation dysfunction and ALI of endotoxemia. In the present study, we aimed to study the role of PSGL-1 in above-mentioned situations using endotoxemic mice. MATERIALS AND METHODS: An endotoxemia model was established in BALB/c mice via lipopolysaccharide (LPS) administration. Moreover, the mice were simultaneously injected with PSGL-1 antibody for intervention. The survival rate, morphologic changes of lung tissues, platelet-leukocyte adhesion, tissue factor expression on leukocytes, fibrinogen deposition in lung tissues, serum levels of inflammatory factors and the activation of VECs were determined. RESULTS: The results showed that the aggregation and recruitment of platelets and leukocytes in lung tissues, the expression of tissue factor on leukocytes, the serum levels of inflammatory factors, the activation of VECs, and the fibrinogen deposition in lung tissues were increased in endotoxemic mice, which were significantly alleviated by administration of PSGL-1 antibody. Moreover, blockade of PSGL-1 markedly increased survival rate, and alleviated coagulation disturbance and lung injury in endotoxemic mice. CONCLUSIONS: Taken together, PSGL-1 played an important role in pathogenesis of SIRS and coagulation dysfunction and ALI in endotoxemic mice.

8.
J Pharmacokinet Pharmacodyn ; 46(5): 485-498, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432345

RESUMO

We developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT4 receptor agonist in healthy volunteers. Using the calibrated model, we predicted the agonist dose to normalize defecation frequency in slow transit constipation while avoiding the onset of diarrhea. Model sensitivity analysis predicted that changes in HAPC frequency and liquid secretion have the greatest impact on colonic motility. However, exclusively increasing the liquid secretion can lead to diarrhea. In contrast, increasing HAPC frequency alone can enhance bowel frequency without leading to diarrhea. The quantitative systems pharmacology approach used here demonstrates how mechanistic modeling of disease pathophysiology expands our understanding of biology and supports judicious hypothesis generation for therapeutic intervention.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31321459

RESUMO

RATIONALE: Basic and clinical studies have reported rapid and long-lasting antidepressant effects of ketamine. Although previous studies have proposed several mechanisms underlying the antidepressant effects of ketamine, these mechanisms have not been completely elucidated. OBJECTIVES: The present study evaluated the effects of systemically administered ketamine treatment in a lipopolysaccharide (LPS)-induced mouse model of depression. METHODS: Non-targeted metabolomics, western blotting, and behavioral tests (locomotion, tail suspension, and forced swimming tests) were performed. RESULT: Ketamine significantly attenuated the abnormally increased immobility time in a lipopolysaccharide (LPS)-induced mouse model of depression. Aminomalonic acid, glutaraldehyde, glycine, histidine, N-methyl-L-glutamic acid, and ribose levels in skeletal muscle were altered following ketamine administration. Furthermore, ketamine significantly decreased the LPS-induced increase in glycine receptor A1 (GlyA1) levels. However, the glycine receptor antagonist strychnine did not elicit any pharmacological effects on ketamine-induced alterations in behaviors or muscular GlyA1 levels. Exogenous glycine and L-serine significantly improved depression-like symptoms in LPS-induced mice. CONCLUSIONS: Our findings suggest that skeletal muscular glycine contributes to the antidepressant effects of ketamine in inflammation. Effective strategies for improving skeletal muscular glycine levels may be a novel approach to depression treatment.

10.
Birth Defects Res ; 111(18): 1389-1398, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31291065

RESUMO

BACKGROUND: Epidemiologic studies have consistently identified an association between spina bifida and maternal body mass index (BMI). Whether this reflects a causal relationship is unknown. If this association does reflect a causal relationship, the risk of spina bifida should change with changes in maternal BMI. We evaluated the association between spina bifida and maternal change in BMI, assessed using interpregnancy change in BMI (IPC-BMI). METHODS: We used data from the Texas Birth Defects Registry and statewide vital records for 248 spina bifida cases and 2,562 controls (2006-2012) to conduct a case-control study. We used logistic regression to estimate the association between IPC-BMI and spina bifida, with adjustment for potential confounders. RESULTS: When assessed as a continuous variable, IPC-BMI was associated with spina bifida, with a 5% increase in the odds of spina bifida per unit (approximately 6 pounds) increase in BMI (adjusted odds ratios [aOR] = 1.05, 95% CI: 1.02, 1.09). When assessed as a categorical variable, with weight stable women as the referent, the odds of spina bifida were lower in women with any BMI decrease (aOR = 0.73, 95% CI: 0.50, 1.08) and higher in women with an increase of ≥1 BMI units (aOR = 1.17, 95% CI: 0.85, 1.62). CONCLUSIONS: Our findings provide suggestive, although not conclusive, evidence that maternal prepregnancy change in BMI, assessed using IPC-BMI, is associated with spina bifida in the later pregnancy. Additional studies aimed at confirming this association and further strengthening the evidence for a causal relationship between spina bifida and maternal BMI are needed.

11.
Biomed Res Int ; 2019: 1283717, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355247

RESUMO

To investigate whether angiogenesis changes in early menopausal osteoporosis treated with estrogen replacement therapy, 120 rats were randomly divided into five groups: sham operation group (SHAM), ovariectomy group (OVX), and ovariectomy plus three different estrogen doses replacement therapy groups (OVX + E2). We detected the bone microarchitecture and measured the expression levels of estrogen receptor beta (ERß), vascular endothelial growth factor (VEGF), osteoprotegerin (OPG), and receptor activator of NF-κB ligand (RANKL). CD31 immunofluorescence and silica gel perfusion imaging were used to analyze the vascular distribution. We confirmed that the femur BMD of ovariectomized rats was significantly lower than SHAM group and OVX+E2 groups. After estrogen therapy, the local microvascular formation increased after estrogen treatment in a dose dependent manner. ERß was downregulated and VEGF was upregulated, positively correlated with estrogen dosage. We successfully constructed an osteoporosis model of ovariectomized rats with estrogen replacement therapy. We also found angiogenesis changed in early menopausal osteoporosis treated with estrogen replacement therapy. We indicated that estrogen replacement therapy increased angiogenesis through VEGF upregulation. However, we observed that, at the highest doses of estrogen studied, increased angiogenesis was associated with a decrease in BMD, the underlying mechanisms of which remain unclear.

12.
Int J Nanomedicine ; 14: 3875-3892, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213807

RESUMO

Multipotent mesenchymal stem cells have shown great promise for application in regenerative medicine owing to their particular therapeutic effects, such as significant self-renewability, low immunogenicity, and ability to differentiate into a variety of specialized cells. However, there remain certain complicated and unavoidable problems that limit their further development and application. One of the challenges is to noninvasively monitor the delivery and biodistribution of transplanted stem cells during treatment without relying on behavioral endpoints or tissue histology, and it is important to explore the potential mechanisms to clarify how stem cells work in vivo. To solve these problems, various nanoparticles (NPs) and their corresponding imaging methods have been developed recently and have made great progress. In this review, we mainly discuss NPs used to label stem cells and their toxic effects on the latter, the imaging techniques to detect such NPs, and the current existing challenges in this field.


Assuntos
Células-Tronco Mesenquimais/citologia , Nanopartículas/toxicidade , Medicina Regenerativa , Morte Celular/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Imagem Molecular , Imagem Multimodal
13.
Inflammation ; 42(4): 1504-1510, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102123

RESUMO

In the present study, we aimed to investigate the effects of puerarin on the hyperpermeability of vascular endothelial cells induced by lipopolysaccharide (LPS) and its underlying mechanisms. Human umbilical vein endothelial cells (HUVECs) were pre-incubated with puerarin (25, 50, and 100 µM) for 1 h, and then exposed to LPS (1 µg/mL). The monolayer permeability of endothelial cells was assessed by measuring the paracellular flux of FITC-dextran 40,000 (FD40). The expression of vascular endothelial cadherin (VE-cadherin) in HUVECs was examined by Western blotting analysis. A total of 18 mice were randomly assigned into three groups as follows: control group, LPS group, and puerarin group. The pulmonary W/D ratio (wet-to-dry weight ratios) was calculated, and the lung morphology was examined. The levels of TNF-α and IL-1ß in cell supernatant and mouse serum were determined by ELISA. Compared with the control group, LPS obviously increased the flux of FD40 and the monolayer permeability, raised the levels of TNF-α and IL-1ß in cell supernatant, and reduced the VE-cadherin expression in HUVECs. However, puerarin (25, 50, and 100 µM) was able to relieve such LPS-induced increase in flux of FD40 and then reduce the hyperpermeability. Puerarin decreased the levels of TNF-α and IL-1ß in cell supernatant and increased the VE-cadherin expression in HUVECs (P < 0.05). Moreover, LPS obviously increased the levels of TNF-α and IL-1ß in mouse serum and elevated the pulmonary W/D ratios, resulting in lung injury. However, all of above-mentioned LPS-induced changes were improved by puerarin pre-treatment. Puerarin could alleviate LPS-induced hyperpermeability in endothelial cells via preventing downregulation of endothelial cadherin.

14.
Aging (Albany NY) ; 11(10): 3262-3279, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123221

RESUMO

Both diabetes and Alzheimer's disease are age-related disorders, and numerous studies have demonstrated that patients with diabetes are at an increased risk of cognitive dysfunction (CD) and Alzheimer's disease, suggesting shared or interacting pathomechanisms. The present study investigated the role of abnormal gut microbiota in diabetes-induced CD and the potential underlying mechanisms. An intraperitoneal injection of streptozotocin administered for 5 consecutive days was used for establishing a diabetic animal model. Hierarchical cluster analysis of Morris water maze (MWM) performance indices (escape latency and target quadrant crossing) was adopted to classify the diabetic model mice into CD and Non-CD phenotypes. Both ß-diversity and relative abundance of several gut bacteria significantly differed between the CD and Non-CD groups. Further, fecal bacteria transplantation from Non-CD mice, but not from CD mice, into the gut of pseudo-germ-free mice significantly improved host MWM performance, an effect associated with alterations in ß-diversity and relative abundance of host gut bacteria. Collectively, these findings suggest that abnormal gut microbiota composition contributes to the onset of diabetes-induced CD and that improving gut microbiota composition is a potential therapeutic strategy for diabetes and related comorbidities.

16.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 48-52, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078152

RESUMO

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. Compound K, an active metabolite of ginsenosides, is reported to exhibit anti-cancer property in various types of human malignancies. The present study investigated the role of compound K on glucose metabolism in NSCLC cells and its underlying mechanism. Our study found that compound K dose-dependently inhibited the cell viability of NSCLC cells. Moreover, administration with compound K decreased glucose uptake and lactate secretion under normoxic and hypoxic conditions. Consistently, the expression of key enzymes (HK II, PDK1 and LDHA) involved in glucose metabolism were inhibited in compound K-treated tumor cells. In addition, compound K inhibited the expression of HIF-1α and its downstream gene GLUT1. On the contrary, overexpression of HIF-1α elevated metabolic reactions and partly attenuated the inhibitory role of compound K on NSCLC cell growth. These results demonstrate that compound K suppresses NSCLC cell growth via HIF-1α mediated metabolic alteration, contributing to novel anticancer therapy by targeting glucose metabolism.


Assuntos
Ginsenosídeos/farmacologia , Glucose/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética
17.
Am J Med Genet B Neuropsychiatr Genet ; 180(5): 291-304, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31016859

RESUMO

Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. It is commonly diagnosed at 3 or 4 years of age. We explored whether there was an association of any analytes measured by newborn screening tests with a later diagnosis of ASD. A database was compiled of 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Two controls (without any ASD diagnosis) were matched to each case by infant sex and birth year/month. All study subjects were linked to their 2007-2009 birth and newborn screening laboratory records, including values for 36 analytes or analyte ratios. We examined the association of analytes/ratios with a later diagnosis of ASD. Among 3,258 cases and 6,838 controls, seven analytes (e.g., 17-hydroxyprogesterone, acylcarnitines) were associated with a later ASD diagnosis. In this exploratory study, an ASD diagnosis was associated with 7 of 36 newborn screening analytes/ratios. These findings should be replicated in other population-based datasets.

18.
BMC Pregnancy Childbirth ; 19(1): 119, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953457

RESUMO

BACKGROUND: Maternal prepregnancy body mass index (BMI) is associated with several infant outcomes, but it is unclear whether these associations reflect causal relationships. We conducted a study of interpregnancy change in BMI (IPC-BMI) to improve understanding of the associations between BMI and large for gestational age (LGA), small for gestational age (SGA), and preterm birth (PTB). METHODS: Birth certificate data from 2481 linked sibling pairs (Texas, 2005-2012) were used to estimate IPC-BMI and evaluate its association with LGA, SGA, and PTB in the younger sibling of the pair. Multivariable logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) using data from the full sample and within strata defined by prepregnancy BMI for the older sibling. RESULTS: On average, women gained 1.1 BMI units between pregnancies. In the full sample, interpregnancy BMI decreases were associated with reduced odds of LGA and increased odds of SGA and PTB (IPC-BMI < -1 versus 0 to < 1: LGA aOR 0.7, 95% CI 0.4, 1.1; SGA aOR 1.6, 95% CI 1.0, 2.7; PTB aOR 1.9, 95% CI 1.3, 2.8). In stratified analyses, similar associations were observed in some, but not all, strata. Findings for interpregnancy BMI increases were less consistent, with little evidence for associations between these outcomes and the most extreme IPC-BMI increases. CONCLUSIONS: There is growing evidence that interpregnancy BMI decreases are associated with LGA, SGA, and PTB. However, taken as a whole, the literature provides insufficient evidence to establish causal links between maternal BMI and these outcomes.


Assuntos
Intervalo entre Nascimentos/estatística & dados numéricos , Peso ao Nascer , Índice de Massa Corporal , Complicações na Gravidez/etiologia , Ganho de Peso , Adulto , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Modelos Logísticos , Análise Multivariada , Obesidade/complicações , Razão de Chances , Gravidez , Nascimento Prematuro/etiologia , Fatores de Risco , Texas
19.
J Cell Physiol ; 234(10): 17775-17785, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30864145

RESUMO

Circular RNAs have been found to be aberrantly expressed in tumors and their significance in tumorigenesis has been focused on. The role of circDYNC1H1 in hepatocellular carcinoma (HCC) pathogenesis and its relationship with miR-140-5p were explored. The expression of circDYNC1H1, miR-140-5p, and SULT2B1 in HCC tissues and cells was measured, and Pearson's analysis was used to analyze their expression correlation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays were performed to determine cell proliferation and migration. Binding between circDYNC1H1 and miR-140-5p was evaluated with RNA pull-down assay. A luciferase reporter assay was conducted to assess the interaction between circDYNC1H1 and miR-140-5p and between miR-140-5p and SULT2B1. circDYNC1H1 was highly expressed in HCC tissues (n = 20), and it was negatively associated with the expression of miR-140-5p but positively correlated with SULT2B1 messenger RNA expression. circDYNC1H1 was upregulated in cell lines of HCC. Interference of circDYNC1H1 suppressed cell proliferation and migration of HCC. circDYNC1H1 acted as a sponge of miR-140-5p. miR-140-5p controlled SULT2B1 expression by targeting its 3'-untranslated region. circDYNC1H1 enhanced SULT2B1 expression via sponging miR-140-5p. Downregulation of circDYNC1H1 disturbed cell proliferation and migration of HCC through miR-140-5p/SULT2B1 pathway. Silencing of circDYNC1H1 delayed tumor growth in HCC mouse model. Acting like a sponge of miR-140-5p, silenced circDYNC1H1 downregulated SULT2B1 to restrain HCC cell proliferation and migration, which is adverse to HCC growth and progression.

20.
J Biochem Mol Toxicol ; 33(4): e22279, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30537341

RESUMO

Platelet activation contributes to organs failure in inflammation and plays an important role in endotoxemia. Clopidogrel inhibits platelet aggregation and activation. However, the role of clopidogrel in modulating inflammatory progression of endotoxemia remains largely unexplored. Therefore, we investigated the role of clopidogrel on the activation of platelet and leukocytes in lipopolysaccharide (LPS)-induced inflammation in mice. Animals were treated with clopidogrel or vehicle before LPS induction. The expression of neutrophil-platelet aggregates and platelet activation and tissue factor was determined. Immunofluorescence was used to analyze platelet-leukocyte interactions and tissue factor (TF) expression on leukocytes. Clopidogrel pretreatment markedly decreased lung damage, inhibited platelet-neutrophil aggregates and TF expression. In addition, clopidogrel reduced thrombocytopenia and affected the number of circulating white blood cell in endotoxemia mice. Moreover, clopidogrel also reduced platelet shedding of CD40L and CD62P in endotoxemic mice. Taken together, clopidogrel played an important role through reducing platelet activation and inflammatory process in endotoxemia.


Assuntos
Plaquetas/efeitos dos fármacos , Clopidogrel/farmacologia , Endotoxemia/induzido quimicamente , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Neutrófilos/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Animais , Plaquetas/citologia , Plaquetas/metabolismo , Ligante de CD40/metabolismo , Inflamação/induzido quimicamente , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Camundongos Endogâmicos BALB C , Modelos Animais , Neutrófilos/citologia , Neutrófilos/metabolismo , Selectina-P/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/prevenção & controle , Tromboplastina/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo
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