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1.
Pharmacol Rep ; 71(6): 1244-1252, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31670061

RESUMO

BACKGROUND: Coumarin and 3,4-dihydroquinolinone nuclei are two heterocyclic rings that are important and widely exploited for the development of bioactive molecules. Here, we designed and synthesized a series of 3,4-dihydroquinolinone and coumarin derivatives (Compounds 8, 9, 11, 14, 15, 18-20, 23, 24 and 28 are new compounds) and studied their antidepressant activities. METHODS: Forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mouse brain, by using ELISA. A 5-HT1A binding assay was also performed. The biological activities of the compounds were verified by molecular docking studies. The physicochemical and pharmacokinetic properties of the target compounds were predicted by Discovery Studio and ChemBioDraw Ultra. RESULTS: Of all the compounds tested, compound 7 showed the best antidepressant activity, which decreased the immobility time by 65.52 s in FST. However, in the open-field test, compound 7 did not affect spontaneous activity. The results of 5-HT concentration estimation in vivo showed that compound 7 may have an effect on the mouse brain. Molecular docking results indicated that compound 7 showed significant interactions with residues at the 5-HT1A receptor using homology modeling. The results show that compound 7 exhibits good affinity for the 5-HT1A receptor. CONCLUSION: Coumarin and 3,4-dihydroquinolinone derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.

2.
Mol Pharm ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31670970

RESUMO

Similar to glycolysis, glutaminolysis acts as a vital energy source in tumor cells, providing building blocks for the metabolic needs of tumor cells. To capture glutaminolysis in tumors, 18F-(2S,4R)4-Fluoroglutamine ([18F]FGln) and 18F-fluoroboronoglutamine ([18F]FBQ) have been successfully developed for Positron Emission Tomography (PET) imaging, but these two molecules are lack of stability, resulting in undesired yet significant bone uptake. In this study, we found that [18F]FBQ-C2 is a stable Gln PET tracer by adding two more methylene groups to the side chain of [18F]FBQ. [18F]FBQ-C2 was synthesized with a good radiochemical yield (RCY) of 35% and over 98% radiochemical purity. [18F]FBQ-C2 showed extreme stability in vitro, and no defluorination was observed after 2 hours in phosphate buffered saline at 37 °C. The competitive inhibition assay results indicated that [18F]FBQ-C2 enters cells via system ASC and N, similar to natural glutamine, and can be transported by tumor-overexpressed ASCT2. PET imaging and biodistribution results indicated that [18F]FBQ-C2 is stable in vivo with low bone uptake (0.81±0.20%ID/g) and can be cleared rapidly from most tissues. Dynamic scan and pharmacokinetic studies using BGC823-xenograft-bearing mice revealed that [18F]FBQ-C2 accumulates specifically in tumors, with a longer half-life (101.18±6.50 min) in tumor tissues than in other tissues (52.70±12.44 min in muscle). Biodistribution exhibits a high tumor-to-normal tissue ratio (4.8±1.7 for muscle, 2.5±1.0 for the stomach, 2.2±0.9 for the liver and 17.8±8.4 for the brain). In conclusion, [18F]FBQ-C2 can be used to perform high-contrast Gln imaging of tumors and can serve as a PET tracer for clinical research.

3.
Gene ; : 144194, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31669650

RESUMO

Increasing evidence indicates that long non-coding RNA (lncRNA) may play important roles in tumorigenesis. Increased lncRNA CASC9 occurs in laryngeal carcinoma, which accounts for 20% of all head and neck cancers, but its role in this disease remains unknown. Using quantitative reverse transcriptase PCR, we found higher expression of CASC9 and GLUT-1 in laryngeal carcinoma tissues and cells, compared to adjacent tissues and cells. A correlation analysis showed a positive relationship between CASC9 and GLUT-1 expression in laryngeal carcinoma tissues. An MTT assay of TU212 and Hep-2 cells showed increased cell proliferation after transfection with overexpressed CASC9 and decreased cell proliferation after transfection with silenced CASC9. A Transwell assay showed that overexpressing CASC9 increased and silencing CASC9 decreased cell migration of TU212 and Hep-2 cells. A flow cytometry assay showed that overexpressing CASC9 reduced and silencing CASC9 increased cell apoptosis. In other words, we found that overexpressing CASC9 increased cell proliferation and cell migration and decreased apoptosis both in TU212 and Hep-2 cells, whereas silencing CASC9 had the opposite effects. Moreover, overexpression vector of GLUT-1 was used to investigate the molecular mechanism of CASC9 in laryngeal carcinoma. The results showed that transfection with an overexpressed GLUT-1vector reversed the effects of silencing CASC9 on proliferation, migration, and apoptosis in TU212 and Hep-2 cells. In conclusion, our study of laryngeal carcinoma found that CASC9 was positively correlated with GLUT-1 expression and that CASC9 may promote proliferation and metastasis of laryngeal carcinoma cells by regulating GLUT-1.

4.
Toxicol Appl Pharmacol ; : 114765, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31669777

RESUMO

BACKGROUND: The physiologically based pharmacokinetic (PBPK) model is a useful tool to predict the pharmacokinetics of various types of nanoparticles (NPs). The endocytosis mechanism plays a key role in pharmacokinetics of NPs. However, the effect of endocytosis mechanism both in the blood and tissue are seldom considered in PBPK model. OBJECTIVES: To investigate the biodistribution of intravenously injected pegylated AuNPs in mice and human using PBPK model considering the endocytosis mechanism both in the blood and tissue. METHODS: Taking polyethylene glycol-coated gold nanoparticles (AuNPs) as an example, we developed a PBPK model to explore biodistribution of different size AuNPs. In the model, we considered the role of endocytosis mechanism both in the blood and tissue. In addition, the size-dependent permeability coefficient, excretion rate constant, phagocytic capacity, uptake rate, and release rate were derived from literatures. The mice PBPK model was extrapolated to the human by changing physiology parameters and the number of phagocytic cell (PCs). RESULTS: AuNPs were primarily distributed in the blood, liver, and spleen regardless of particle size, and almost all captured by the PCs in the liver and spleen, while few was captured in the blood. There are more organ distribution and longer circulation for smaller NPs. The 24-h accumulation of AuNPs decreased with increasing size in the most organ, while the accumulation of AuNPs showed an inverted U-shaped curve in the liver and slight U-shaped curve in the blood. The human results of model-predicted displayed a similar tendency with those in mice. Size, partition coefficients, and body weight were the key factors influencing the organ distribution of AuNPs. CONCLUSIONS: The size played an important role on the distribution and accumulation of AuNPs in various tissues. Our PBPK model was well predicted the NPs distribution in mice and human. A better understanding of these mechanisms could provide effective guides for nanomedine delivery.

5.
J Anat ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31670395

RESUMO

Since embryonic heart development is a complex process and acquisition of human embryonic specimens is challenging, the mechanism by which the embryonic conduction system develops remains unclear. Herein, we attempt to gain insights into this developmental process through immunohistochemical staining and 3D reconstructions. Expression analysis of T-box transcription factor 3, cytoskeleton desmin, and nucleoskeleton lamin A protein in human embryos in Carnegie stages 11-20 showed that desmin is preferentially expressed in the myocardium of the central conduction system compared with the peripheral conduction system, and is co-expressed with T-box transcription factor 3 in the central conduction system. Further, lamin A was first expressed in the embryonic ventricular trabeculations, where the terminal ramifications of the peripheral conduction system develop, and extended progressively to all parts of the central conduction system. The uncoupled spatiotemporal distribution pattern of lamin A and desmin indicated that the association of cytoskeleton desmin and nucleoskeleton lamin A may be a late event in human embryonic heart development. Compared with model animals, our data provide a direct morphological basis for understanding the arrhythmogenesis caused by mutations in human DES and LMNA genes.

6.
Environ Toxicol ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566301

RESUMO

Tri-ortho-cresyl phosphate (TOCP) has been widely used as plasticizers, and reported causing reproductive toxicity in mammals. However, little is known about the toxic effect on the placenta. In this study, dams were orally administered different doses of TOCP to explore the effect of TOCP on placental development. Results showed that TOCP exposure significantly reduced numbers of implanted embryo, caused atrophy and collapse of ectoplacental cone, and decreased total areas of placenta and numbers of PCNA-positive cells. Expression levels of placental development genes were prominently downregulated in the TOCP-treated groups. Moreover, TOCP administration induced placental apoptosis and autophagy by upregulating P53, Bax, Beclin-1, ratio of LC3 II/LC3 I and Atg5 and downregulating Bcl-2 protein. In addition, TOCP exposure markedly inhibited activities of catalase and superoxide dismutase and increased the production of H2 O2 and malondialdehyde. Collectively, these findings suggest that apoptosis, autophagy and oxidative stress may be involved in the TOCP-induced reproductive toxicity.

7.
Eur J Prev Cardiol ; : 2047487319880985, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604401

RESUMO

AIMS: Familial hypercholesterolemia patients are characterized by early onset of coronary artery calcification and atherosclerosis, and high incidence of cardiovascular events. Plasma proprotein convertase subtilisin/kexin type 9 was reported to be a predictor for cardiovascular risk in the general population. However, its prognostic value for predicting recurrent cardiovascular events in familial hypercholesterolemia patients remains undetermined. METHODS: A total of 249 patients with molecularly and/or clinically (Dutch Lipid Clinic Network score > 6) defined familial hypercholesterolemia who had experienced a first cardiovascular event were consecutively included and plasma proprotein convertase subtilisin/kexin type 9 concentrations were measured by enzyme-linked immunosorbent assay. Coronary artery calcification was measured using Agatston method and coronary severity was assessed by Gensini score, respectively. All patients received standard lipid-lowering therapy and were followed-up for recurrent cardiovascular events. Univariate and multivariate regression and Cox analyses was used to calculate hazard ratios with 95% confidence interval. RESULTS: Circulating proprotein convertase subtilisin/kexin type 9 concentrations were positively associated with coronary artery calcification scores and Gensini score by both univariate and multivariate analyses. During a mean follow-up of 43 ± 19 months, 29 (11.51%) recurrent cardiovascular events occurred. Kaplan-Meier analysis showed that patients with the highest proprotein convertase subtilisin/kexin type 9 levels had the lowest event-free survival time. Multivariable Cox regression analysis revealed that proprotein convertase subtilisin/kexin type 9 was independently associated with recurrent cardiovascular events (hazard ratio: 1.45, 95% confidence interval: 1.11-1.88). The combination of proprotein convertase subtilisin/kexin type 9 to Cox prediction model led to an enhanced predictive value for recurrent cardiovascular events. CONCLUSIONS: Increased level of proprotein convertase subtilisin/kexin type 9 was a significant risk factor of atherosclerosis and independently predicted future recurrent cardiovascular events in familial hypercholesterolemia patients receiving standard lipid-lowering treatment.

8.
Bioconjug Chem ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31593447

RESUMO

Boronophenylalanine (BPA) is the dominant boron delivery agent for boron neutron capture therapy (BNCT), and [18F]FBPA has been developed to assist the treatment planning for BPA-BNCT. However, the clinical application of BNCT has been limited by its inadequate tumor specificity due to the metabolic instability. In addition, the distinctive molecular structures between [18F]FBPA and BPA can be of concern as [18F]FBPA cannot quantitate boron concentration of BPA in a real-time manner. In this study, a metabolically stable boron-derived tyrosine (denoted as fluoroboronotyrosine, FBY) was developed as a theranostic agent for both boron delivery and cancer diagnosis, leading to PET imaging-guided BNCT of cancer. [18F]FBY was synthesized in high radiochemical yield (50%) and high radiochemical purity (98%). FBY showed high similarity with natural tyrosine. As shown in in vitro assays, the uptake of FBY in murine melanoma B16-F10 cells was L-type amino acid transporter (LAT-1) dependent and reached up to 128 µg/106 cells. FBY displayed high stability in PBS solution. [18F]FBY PET showed up to 6 %ID/g in B16-F10 tumor and notably low normal tissue uptake (tumor/muscle = 3.16 ± 0.48; tumor/blood = 3.13 ± 0.50; tumor/brain = 14.25 ± 1.54). Moreover, administration of [18F]FBY tracer along with a therapeutic dose of FBY showed high accumulation in B16-F10 tumor and low normal tissue uptake. Correlation between PET-image and boron biodistribution was established, indicating the possibility of estimating boron concentration via a noninvasive approach. At last, with thermal neutron irradiation, B16-F10 tumor-bearing mice injected with FBY showed significantly prolonged median survival without exhibiting obvious systemic toxicity. In conclusion, FBY holds great potential as an efficient theranostic agent for imaging-guided BNCT by offering a possible solution of measuring local boron concentration through PET imaging.

9.
Soc Sci Med ; : 112575, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31606188

RESUMO

Although the association between childhood socioeconomic status (SES) and late-life cognition is well-established, the mechanisms underlying this association are less clear. One important potential mediator seldom examined is adolescent cognitive ability. To address this gap, we examined 5,880 respondents from the Wisconsin Longitudinal Study, which follows a random sample of high school students who graduated from Wisconsin high schools in 1957. Structural equation models were used to examine the direct and indirect effects of childhood SES on cognition in late midlife through adolescent cognitive ability, educational attainment, midlife economic condition, and midlife health. Cognitive function was measured as a latent variable composed of scores from 6 cognitive assessments including immediate and delayed recall, digit ordering, letter and category fluency, and a subset of the Wechsler Adult Intelligence Scale similarities test. We found that childhood SES predicts cognition in late midlife, and this association is largely mediated by adolescent cognitive ability and educational attainment and to a lesser extent by midlife economic condition and health. The findings underscore the long-arm of childhood SES in cognitive function in later life and highlight the complex life-course pathways underlying the association between childhood SES and cognition.

10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1633-1640, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607325

RESUMO

OBJECTIVE: To investigate the effects of cytomegalovirus (CMV) DNA load on immune reconstitution and clinical outcomes of patients after unrelated cord blood transplantation (UCBT). METHODS: Eight-color flow cytometry was used to dynamically monitor the changes of peripheral blood lymphocyte subsets of 41 patients at one year after UCBT, and 10 healthy volunteers were enroled as controls. Patients were divided into two groups according to the DNA load of CMV (DNA copies <1000/ml and DNA copies ≥1000/ml). Comparative analyse of the effect of CMV DNA load on lymphocyte subsets and transplantation outcomes were carried out after transplantation. RESULTS: The high CMV DNA load group showed a faster and expanded T cell reconstitution, and the differences between the two groups were statistically significant at one and nine months after transplantation (0.38×109 /L vs 0.25×109 /L, P=0.015 and 2.53×109 /L vs 1.36×109 /L, P=0.006, respectively). Further analysis of T cell subsets suggested that CD8+ T cells presented a higher and faster recovery in the high DNA load group, and the differences between the two groups were statistically significant at one and nine months after transplantation (0.20×109 /L vs 0.10×109 /L, P=0.038 and 1.62×109 /L vs 0.68×109 /L, P=0.003, respectively). In addition, there were no significant differences in levels of B cells, regulatory B cells and NK cells between the two groups. Outcomes after one- and a-half-year transplantation showed that there were no significant difference in relapse, non-relapse mortality and overall survival between the high and the low DNA load groups (7.7% vs 7.5%) (P=0.900) (15.4% vs 21.4%) (P=0.686) and (76.9% vs 78.6%) (P=0.889) respectively. CONCLUSION: The high CMV DNA load induces a faster and long-lasting expansion of T cells, mainly as the expansion of CD8+ T cells after UCBT. Besides, under the current pre-emptive treatment of CMV, the high CMV DNA load does not affect the early survival of patients with acute myeloid leukemia after UCBT.

11.
Acta Pharmacol Sin ; 2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31607752

RESUMO

T cell metabolic activation plays a crucial role in inflammation of atherosclerosis. Shikonin (SKN), a natural naphthoquinone with anti-inflammatory activity, has shown to exert cardioprotective effects, but the effect of SKN on atherosclerosis is unclear. In addition, SKN was found to inhibit glycolysis via targeting pyruvate kinase muscle isozyme 2 (PKM2). In the present study, we investigated the effects of SKN on hyperhomocysteinemia (HHcy)-accelerated atherosclerosis and T cell inflammatory activation in ApoE-/- mice and the metabolic mechanisms in this process. Drinking water supplemented with Hcy (1.8 g/L) was administered to ApoE-/- mice for 2 weeks and the mice were injected with SKN (1.2 mg/kg, i.p.) or vehicle every 3 days. We showed that SKN treatment markedly attenuated HHcy-accelerated atherosclerosis in ApoE-/- mice and significantly decreased inflammatory activated CD4+ T cells and proinflammatory macrophages in plaques. In splenic CD4+ T cells isolated from HHcy-ApoE-/- mice, SKN treatment significantly inhibited HHcy-stimulated PKM2 activity, interferon-γ secretion and the capacity of these T cells to promote macrophage proinflammatory polarization. SKN treatment significantly inhibited HHcy-stimulated CD4+ T cell glycolysis and oxidative phosphorylation. Metabolic profiling analysis of CD4+ T cells revealed that Hcy administration significantly increased various glucose metabolites as well as lipids and acetyl-CoA carboxylase 1, which were reversed by SKN treatment. In conclusion, our results suggest that SKN is effective to ameliorate atherosclerosis in HHcy-ApoE-/- mice and this is at least partly associated with the inhibition of SKN on CD4+ T cell inflammatory activation via PKM2-dependent metabolic suppression.

12.
J Sci Med Sport ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31623958

RESUMO

OBJECTIVES: The aim of the present study was to determine the effects of altering both hamstring flexibility and strength on hamstring optimal lengths. DESIGN: Controlled laboratory study. METHODS: A total of 20 male and 20 female college students (aged 18-24 years) participated in this study and were randomly assigned to either a flexibility intervention group or a strength intervention group. Passive straight leg raise and isokinetic strength test were performed before and after interventions. Paired T-tests were performed to determine hamstring flexibility or strength intervention effects on hamstring optimal lengths. RESULTS: Male participants in the flexibility intervention group significantly increased range of hip joint flexion (P=0.001) and optimal lengths of semimembranosus and biceps long head (P≤0.026). Male participants in the strength intervention group significantly increased hamstring strength (P=0.001), the range of hip joint flexion (P=0.037), and optimal lengths of all three bi-articulated hamstring muscles (P≤0.041). However, female participants did not significantly increase their hamstring optimal lengths in either intervention groups (P≥0.097) although both groups significantly increased the range of hip joint flexion and strength (P≤0.009). CONCLUSION: Hamstring optimal lengths can be modified through flexibility intervention as well as strength intervention for male participants, but not for female participants in this study. Hamstring optimal lengths should be considered as hamstring flexibility measures in future prospective studies to identify potentially modifiable risk factors for hamstring injury.

13.
Pharmacogenomics J ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624334

RESUMO

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer deaths. Afatinib is the first-line anti-cancer agent for treatment of NSCLC. However, unexpected resistance has been a major obstacle for its clinical efficacy. In this study, we dissected afatinib resistance from the perspective of N6-Methyladenosine (m6A) modification. First, we depicted the m6A modification profiles for the afatinib resistant and sensitive NSCLC cell lines (H1299 and A549). We found that the sum enrichment scores of the resistant cell line (H1299) was much higher than that of the sensitive cell line (A549). Next, we identified the functionally m6A-modified genes, which were the intersection of the differentially m6A methylated genes and the differentially expressed genes between H1299 and A549, as well as negative correlation between m6A modification levels and gene expression levels. In addition, functional enrichment analysis of the functionally m6A-modified genes indicated that m6A methylation might modify cell cycle to affect afatinib response. Furthermore, the functionally m6A-modified genes were over-represented in the putative drug resistance-associated genes and the FDA-approved drug targets, and had significantly higher average degree and clustering coefficient than other genes in protein-protein interaction (PPI) network. We also identified five network modules, which were all related to drug resistance functions. Finally, survival analysis demonstrated that m6A modification could affect prognosis of NSCLC patients. In conclusion, we conducted a first attempt to dissect m6A methylation affection on afatinib resistance in NSCLC, and brought inspiration for the study of epigenetic roles in drug resistance.

14.
Pediatr Infect Dis J ; 38(11): 1100-1103, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31626044

RESUMO

BACKGROUND: Tuberculous pleural effusion (TPE) is often misdiagnosed as severe Mycoplasma pneumoniae pneumonic effusion (SMPPE) in children at early stage. The aim of this study was to develop a predictive model based on clinical and laboratory indices to make accurate differential diagnosis. METHODS: Patients included in this study were 167 children (83 patients with TPE and 84 with SMPPE), containing 117 patients for predictive model development and 50 patients for external validation. Multivariate logistic regression analysis was conducted to select potentially useful characteristics for discrimination of TPEs. External validation was performed for model evaluation. RESULTS: Multivariate analysis revealed that blood neutrophils and serum lactate dehydrogenase were significant independent factors to discriminate between TPEs and SMPPEs. The results indicated that blood neutrophils ≤69.6% and concentration of serum lactate dehydrogenase ≤297 U/L were the extremely important discrimination factors of TPEs. The area under the receiver operating characteristic curve of the model was 0.9839. The accuracy rate, sensitivity and specificity of the model were 94.02%, 98.28% and 89.83%, respectively. Meanwhile, the accuracy rate of the external validation from the 50 patients was 94.0%. CONCLUSIONS: Applying a predictive model with clinical and laboratory indices can facilitate the differential diagnosis of TPE from SMPPE in children, which seems helpful when a microbiologic or histologic diagnosis of pleural tuberculosis could not be established.

15.
J Food Biochem ; : e13086, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646664

RESUMO

Rutin is a bioflavonoid found in many plants and derived foods, accordingly, rutin likely interacts with α-amino acids such as Lys, Ile, His or Glu to give Maillard reaction products (MRPs). The heated rutin-Lys system exhibited highest brown intensity and in vitro antioxidant activities. The 30-50 kDa rutin-Lys fraction had higher in vitro antioxidant activities than the other fractions, and at a dose of 0.4 mg/ml preserved over 90% cell viability for HepG2 cells exposed to H2 O2 . The dose-dependent protective effects against H2 O2 -induced oxidative stress of the rutin-Lys MRPs may involve the inhibition of reactive oxygen species generation, enhancement of the superoxide dismutase and catalase activities, along with the activation of the Nrf2-dependent pathway and upregulation of phase II antioxidant genes (including NQO1, HO-1, GCLG, and GCLM). PRACTICAL APPLICATIONS: Rutin is widely distributed in vegetables and grains. The Maillard reaction is a common reaction occurring during food processing, and produces Maillard reaction products (MRPs) with distinct processing and biological properties. This study shows that a 30-min thermal treatment at 120°C generates antioxidative MRPs in the rutin-Lys, rutin-His, rutin-Ile and rutin-Glu model systems, which can directly inhibit reactive oxygen species generation and enhance SOD and CAT activities while activating the Nrf2-dependent pathway and upregulating the expression of phase II detoxifying antioxidant genes. Therefore, for food systems containing phenolic antioxidants and proteins (such as rutin and Lys), one may enhance the antioxidant properties of these food systems through a 30-min thermal treatment at 120°C. Also, the resultant rutin-Lys MRPs may be isolated and used as commercial preparations of natural antioxidants.

16.
Ann Epidemiol ; 38: 28-34.e2, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31591027

RESUMO

PURPOSE: We provide population-based longitudinal evidence of marital status differences in the risk of cognitive impairment and dementia in the United States. METHODS: Data were from the longitudinal National Health and Aging Trends Study, 2011-2018. The sample included 7508 respondents aged 65 years and older who contributed 25,897 person-year records. We estimated discrete-time hazard models to predict the risk of dementia and cognitive impairment, not dementia (CIND), as well as impairment in three major cognitive domains: memory, orientation, and executive function. RESULTS: Relative to their married counterparts, divorced and widowed elders had higher odds of dementia and CIND, as well as higher odds of impairment in each of the cognitive domains. Never-married elders had higher odds of impairment in memory and orientation than their married counterparts but did not differ significantly in the odds of impaired executive function, dementia, or CIND. Cohabiting elders did not differ significantly from married respondents on any measure of cognitive impairment. We found no gender differences in the associations between marital status and the measures of cognitive impairment. CONCLUSIONS: Marital status is a potentially important but overlooked social risk/protective factor for cognitive impairment. Divorced and widowed older adults are particularly vulnerable to cognitive impairment.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31615194

RESUMO

BACKGROUND: Functional electrical stimulation (FES) plus body weight-supported treadmill training (BWSTT) provide effective gait training for poststroke patients with abnormal gait. These features promote a successful active motor relearning of ambulation in stroke survivors. AIM: This is a retrospective study to assess the effect of FES plus BWSTT for gait rehabilitation in patients poststroke. DESIGN: A retrospective case-matched study. SETTING: Participants were recruited from a rehabilitation department in an acute university-affiliated hospital. POPULATION: Ninety patients poststroke from Yue Bei People's Hospital underwent BWSTT (A: control group) were compared to an equal number of cross-matched patients who received FES plus BWSTT (B: FES plus BWSTT group). METHODS: While B group received FES for 45 minutes plus BSWTT for 30 minutes in the program, group A received time-matched BWSTT alone. The walking speed, step length, step cadence, Fugl-Meyer lower-limb scale (LL-FMA), composite spasticity scale (CSS), 10-Meter Walk Test (10MWT), Tinetti Balance Test (TBT) and nerve physiology testing were collected before and after intervention. RESULTS: One hundred and eighty patients with poststroke abnormal gait were chosen. There were significant differences in walking speed, step length, step cadence, LL-FMA, CSS, TBT, and 10MWT between baseline and post-intervention (P<0.05). There were significant differences in walking speed, step length, step cadence, LL-FMA, CSS, TBT, and 10MWT between two groups at the end of the eighth week (P<0.05), but not at baseline (P>0.05). In comparison with group A, the peak of somatosensory evoked potential (SEP) and motor evoked potential (MEP) amplitude increased, the latency was shortened, and the conduction velocity of sensory nerve (SCV) and motor nerve (MCV) was significantly increased in the group B (P < 0.05). No adverse events occurred during the study. CONCLUSIONS: This study suggests that FES plus BWSTT could be more effective than BWSTT alone in the improvement of gait, balance, spasticity, and function of the lower limb in patients poststroke. CLINICAL REHABILITATION IMPACT: Introduce effective rehabilitation strategies for poststroke patients with abnormal gait.

18.
Theranostics ; 9(22): 6396-6411, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588225

RESUMO

Effective therapeutic targets against post-myocardial infarction (MI) arrhythmias remain to be discovered. We aimed to investigate the role of macrophages in post-MI arrhythmias. Methods: Mononuclear cell accumulation, macrophage polarization from M0 to M1 subset, and gap junction formation were analyzed in MI patients and MI mice by flow cytometry, immunofluorescence and patch clamping. Differentially expressed genes were identified by RNA sequencing. Macrophages and cardiomyocytes were cocultured in vitro, and the effects of gap junction and KCa3.1 on electrophysiological properties were assessed by patch clamping. The effects of KCa3.1 inhibition on post-MI arrhythmias were assessed by intracardiac stimulation and ambulatory electrocardiograms in vivo. Results: Percentage of pro-inflammatory mononuclear cells were significantly elevated in patients with post-MI arrhythmias compared with MI patients without arrhythmias and healthy controls (p<0.001). Macrophages formed gap junction with cardiomyocytes in MI border zones of MI patient and mice, and pro-inflammatory macrophages were significantly increased 3 days post-MI (p<0.001). RNA sequencing identified Kcnn4 as the most differentially expressed gene encoding ion channel, and the upregulation is mainly attributed to macrophage accumulation and polarization into pro-inflammatory subset. In vitro coculture experiments demonstrated that connection with M0 macrophages via gap junction slightly shortened the action potential durations (APDs) of cardiomyocytes. However, the APD90 of cardiomyocytes connected with M1 macrophages were significantly prolonged (p<0.001), which were effectively attenuated by gap junction inhibition (p=0.002), KCa3.1 inhibition (p=0.008), KCa3.1 silencing (p<0.001) and store-operated Ca2+ channel inhibition (p=0.005). In vivo results demonstrated that KCa3.1 inhibition significantly decreased the QTc durations (p=0.031), intracardiac stimulation-induced ventricular arrhythmia durations (p=0.050) and incidence of premature ventricular contractions (p=0.030) in MI mice. Conclusion: Macrophage polarization leads to APD heterogeneity and post-MI arrhythmias via gap junction and KCa3.1 activation. The results provide evidences of a novel mechanism of post-MI heterogeneous repolarization and arrhythmias, rendering macrophages and KCa3.1 to be potential therapeutic targets.

19.
Clin Exp Hypertens ; : 1-8, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610701

RESUMO

The antidiabetic effect of liraglutide in patients with type 2 diabetes mellitus has been explored in several trials. We performed this meta-analysis determining the effects of liraglutide on blood pressure in these patients. Three electronic databases (Pubmed, Web of Science, and Cochrane Central) were searched for all published articles evaluating the effects of liraglutide on blood pressure in subjects with type 2 diabetes mellitus. Total 968 patients were included in 10 randomized, double-blind, placebo-controlled trials with a follow-up of 16 ± 9 weeks. Liraglutide 1.8 mg/day reduced systolic blood pressure (weighted mean differences -5.39 (95% confidence interval, -7.26, -3.51) mm Hg, p < .001) and body weight (weighted mean differences -2.07 (95% confidence interval, -2.62, -1.51) kg, p < .001) in patients with type 2 diabetes mellitus. There was no significant difference for changes of diastolic blood pressure between liraglutide 1.8 mg/day and placebo in these patients (weighted mean differences -0.53 (95% confidence interval, -1.96, 0.89) mm Hg, p > .05). The increases of heart rate were greater than placebo in patients treated with liraglutide 1.8 mg/day (weighted mean differences 6.03 (95% confidence interval, 4.78, 7.29) kg, p < .001). There was no significant correlation between reduction of systolic blood pressure and weight loss in patients treated with liraglutide 1.8 mg/day (p = .24). In conclusion, liraglutide reduces systolic blood pressure and body weight in patients with type 2 diabetes mellitus. These data suggest the beneficial effects of liraglutide on cardiovascular protection and may improve prognosis in these patients.

20.
J Clin Lab Anal ; : e23057, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31663630

RESUMO

BACKGROUND: Renal failure is a severe complication of symptomatic myeloma, related to higher mortality. Recovery from dialysis dependence can lead to enormous survival benefits. We investigated the effect factors for probability of dialysis independence. METHODS: Retrospective data on 45 newly diagnosed MM (NDMM) patients with serious renal impairment and requiring hemodialysis were analyzed. The statistical methods including logistic regression analysis, Kaplan-Meier survival curves, the log-rank test and the Cox proportional hazards model for survival analysis were used in our study. RESULTS: Twenty-two of the 45 patients, who were on hemodialysis at diagnosis, became dialysis independence. In the logistic regression analysis, serum level of ß2-microglobulin, kidney disease history, involved free light chain, and achieving at least VGPR were significantly associated with reversibility from dialysis dependence. In addition, achieving hemodialysis discontinuation was related to better survival. The multivariate analyses demonstrated that reversibility from dialysis dependence, proteinuria < 3.5 g/24 h, and achieving at least VGPR were significantly associated with OS among NDMM patients requiring hemodialysis. CONCLUSION: Lower serum level of ß2-microglobulin and lower level of free light chain at diagnosis, achieving at least VGPR, and shorter kidney disease history are related to a high probability of dialysis independence in NDMM patients with serious renal failure requiring dialysis.

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