Advanced glycation end products induce chemokine/cytokine production via activation of p38 pathway and inhibit proliferation and migration of bone marrow mesenchymal stem cells

<p>Abstract</p> <p>Background</p> <p>Advanced glycation products (AGEs), as endogenous inflammatory mediator, compromise the physiological function of mesenchymal stem cells (MSCs). MSCs have a potential role in cell replacement therapy in acute myocardial infarction and ischemic cardiomyopathy. However, mechanisms of AGEs on MSCs are still not unveiled.</p> <p>Methods</p> <p>Reactive oxygen species (ROS), genes regulation, cell proliferation and migration have been detected by AGE-BSA stimulated MSCs.</p> <p>Results</p> <p>We found that <it>in vitro </it>stimulation with AGE-BSA induced generation of reactive oxygen species (ROS), and inhibited dose-dependently proliferation and migration of MSCs. Microarray and molecular biological assessment displayed an increased expression and secretion of Ccl2, Ccl3, Ccl4 and Il1b in a dose- and time-dependent manner. These chemokines/cytokines of equivalent concentration to those in conditioned medium exerted an inhibitory effect on MSC proliferation and migration after stimulation for 24 h. Transient elevation of phospho-p38 in MSCs upon AGE-BSA stimulation was blocked with p38 inhibitor.</p> <p>Conclusions</p> <p>The study indicates that AGE-BSA induces production of chemokines/cytokines in a dose- and time-dependent manner via activation of ROS-p38 mediated pathway. These chemokines/cytokines exert an inhibitory effect on MSC growth and migration, suggesting an amplified dysfunction of MSCs by AGEs.</p

Biochemistry and Molecular Biology DNA Duplex-Based Photodynamic Molecular Beacon for Targeted Killing of Retinoblastoma Cell

PURPOSES. Retinoblastoma (RB) is the most common primary intraocular malignancy of infancy. An alternative RB treatment protocol is proposed and tested. It is based on a photodynamic therapy (PDT) with a designed molecular beacon that specifically targets the murine double minute x (MDMX) high-expressed RB cells. METHODS. A MDMX mRNA triggered photodynamic molecular beacon is designed by binding a photosensitizer molecule (pyropheophorbide-a, or PPa) and a black hole quencher-3 (BHQ3) through a complementary oligonucleotide sequence. Cells with and without MDMX highexpression are incubated with the beacon and then irradiated with a laser. The fluorescence and reactive oxygen species are detected in solution to verify the specific activation of PPa by the perfectly matched DNA targets. The cell viabilities are evaluated with CCK-8 and flow cytometry assay. RESULTS. The fluorescence and photo-cytoxicity of PPa is recovered and significantly higher in the MDMX high-expressed Y79 and WERI-Rb1 cells, compared to that with the MDMX lowexpressed cells. CONCLUSIONS. The synthesized beacon exhibits high PDT efficiency toward MDMX highexpressed RB cells. The data suggest that the designed beacon may provide a potential alternative for RB therapy and secures the ground for future investigation

Effect of Atractylodes macrocephala extract on chronic heart failure in rats

Purpose: To investigate the effect of Atractylodes macrocephala extract (AME) on oxidative stress and hemodynamics in chronic congestive heart failure (CHF) rats. Methods: After Sprague Dawley (SD) rats were successfully establised into CHF, they were randomly divided into normal control group, negative control group, captopril group, as well as 1.4, 2.8 and 5.6 g/kg of AME groups, and treated with drugs for 4 weeks. Hemodynamic function, whole heart weight index, blood creatinine kinase (CK), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOS) were measured. Results: Compared with the normal control group, arterial systolic pressure (SBP)(83.12 ± 16.21 mmHg), diastolic pressure (DBP, (75.16 ± 20.18 mmHg), mean arterial pressure (MAP 76.32 ± 13.43 mmHg), heart rate (HR 353.25 ± 36.34 beats/min), left ventricular systolic peak (LVSP 101.24 ± 16.13 mmHg), and left ventricular pressure change rate (dp/dt max) significantly decreased (p &lt; 0.05), while left ventricular end diastolic pressure (LVEDP (22.13 ± 1.57 mmHg), whole heart weight index (2.74 ± 0.16 mg/g), blood CK (0.93 ± 0.14 U/mL), MDA (19.13 ± 2.26 nmol/mL), NO (34.21 ± 3.16 umol/L), and NOS (42.13 ± 3.24 U/mL) increased significantly increased in the negative control group (p &lt; 0.05). High dose AME significantly improved hemodynamic function, lowered MDA (8.75 ± 2.09 nmol/mL) and NO (22.14 ± 3.27 umol/L) levels (p &lt; 0.05), and also decreased CK (0.57 ± 0.31 U/mL) and NOS (24.24 ± 3.38 U/mL) in CHF rats (p &lt; 0.05). Conclusion: AME significantly improve adriamycin-induced chronic congestive heart failure in rats, which could be used for the therapeutic management of chronic congestive heart failure in future

Long-term glycemic variability predicts compromised development of heart failure with improved ejection fraction: a cohort study

BackgroundA substantial portion of heart failure (HF) patients adherent to guideline-directed medical therapies have experienced improved ejection fraction (EF), termed HFimpEF. Glycemic variability (GV) has emerged as a critical cardiometabolic factor. However, the relation between long-term GV and the incidence of HFimpEF is still unclear.MethodsA total of 591 hospitalized HF patients with reduced EF (HFrEF, EF≤ 40%) admitted from January 2013 to December 2020 were consecutively enrolled. Repeat echocardiograms were performed at baseline and after around 12 months. The incidence of HFimpEF, defined as (1) an absolute EF improvement ≥10% and (2) a second EF &gt; 40% and its association with long-term fasting plasma glucose (FPG) variability were analyzed.ResultsDuring a mean follow-up of 12.2 ± 0.6 months, 218 (42.0%) patients developed HFimpEF. Multivariate analysis showed FPG variability was independently associated with the incidence of HFimpEF after adjustment for baseline HbA1c, mean FPG during follow-up and other traditional risk factors (odds ratio [OR] for highest vs. lowest quartile of CV of FPG: 0.487 [95% CI 0.257~0.910]). Evaluation of GV by alternative measures yielded similar results. Subgroup analysis revealed that long-term GV was associated with HFimpEF irrespective of glycemic levels and diabetic conditions.ConclusionsThis study reveals that greater FPG variability is associated with compromised development of HFimpEF. A more stable control of glycemic levels might provide favorable effects on myocardial functional recovery in HF patients even without diabetes

Development of a prognostic model to identify the metastatic nasopharyngeal carcinoma patients who may benefit from chemotherapy combination PD-1 inhibitor

BackgroundWe aimed to establish a prognostic model to identify suitable candidates for chemotherapy combination PD-1 inhibitor in metastatic nasopharyngeal carcinoma (NPC) patients.Patients and methodsIn this retrospective study, we included 524 patients (192 patients treated with chemotherapy combination PD-1 inhibitor and 332 received chemotherapy alone as first-line regimen) with metastatic NPC between January 2015 and March 2021. We developed a prognostic model to predict progression-free survival (PFS). A model-based trees approach was applied to estimate stratified treatment effects using prognostic scores and two well-matched risk groups (low-risk and high-risk) were created using propensity score matching.ResultsA prognostic nomogram was established with good accuracy for predicting PFS (c-index values of 0.71; 95% confidence interval, 0.66-0.73). The survival curves were significantly different between low-risk and high-risk groups (median PFS: 9.8 vs. 22.8 months, P &lt; 0.001, respectively). After propensity matching analysis, chemotherapy combination PD-1 inhibitor was significantly associated with superior PFS as compared with chemotherapy alone (median PFS, 10.6 versus 9.3 months, P = 0.016) in the high-risk group. However, no significant difference between chemotherapy combination PD-1 inhibitor and chemotherapy was observed (P = 0.840) in the low-risk groups.ConclusionsOur novel prognostic model was able to stratify patients with metastatic NPC into low-risk or high-risk groups and identify candidates for PD-1 inhibitor therapy. These results are expected to be confirmed by a prospective clinical trial

The Role of Monocyte to High-Density Lipoprotein Cholesterol Ratio in Prediction of Carotid Intima-Media Thickness in Patients With Type 2 Diabetes

Background: Chronic inflammatory disorders and dyslipidemia in type 2 diabetes mellitus (T2DM) are essential contributors to the development of atherosclerotic cardiovascular disease. Monocyte to high-density lipoprotein cholesterol (HDL-C) ratio (MHR) is a novel and simple measure associated positively with the body inflammatory and oxidative stress status. However, little is known regarding the role of MHR in evaluating carotid intima-media thickness (CIMT), a surrogate predictor of subsequent vascular events, especially in diabetic patients.Methods: A total of 494 patients with T2DM and 1,848 non-diabetic subjects were consecutively enrolled in study 1. Correlation between MHR and CIMT was compared between diabetic and non-diabetic subjects. In study 2, a total of 110 T2DM patients from study 1 with normal basal CIMT and a follow-up ultrasonography at 12 months were enrolled. The predictive role of MHR on CIMT progression in diabetic patients was analyzed.Results: In study 1, MHR was higher in patients with T2DM than non-diabetic subjects (p &lt; 0.001). After adjustment for confounding risk factors, MHR remained correlated significantly with CIMT in diabetic (r = 0.172, p = 0.001) but not non-diabetic (r = 0.006, p = 0.813) subjects. Logistic regression analyses demonstrated that MHR is superior to traditional lipid parameters in association with elevated CIMT in diabetic patients. In study 2, MHR at baseline was positively correlated with change in CIMT (r = 0.313, p = 0.001). Basal MHR was independently associated with change in CIMT [β = 0.059, (95% CI: 0.012–0.105), p = 0.014] in multivariate linear regression analysis.Conclusions: Our study suggests that MHR is a convenient and effective measure in prediction of the presence and progression of subclinical carotid atherosclerosis in patients with T2DM