Analysis of Key Genes and miRNA-mRNA Networks Associated with Glucocorticoids Treatment in Chronic Obstructive Pulmonary Disease.

Background: Some patients with chronic obstructive pulmonary disease (COPD) benefit from glucocorticoid (GC) treatment, but its mechanism is unclear. Objective: With the help of the Gene Expression Omnibus (GEO) database, the key genes and miRNA-mRNA related to the treatment of COPD by GCs were discussed, and the potential mechanism was explained. Methods: The miRNA microarray dataset (GSE76774) and mRNA microarray dataset (GSE36221) were downloaded, and differential expression analysis were performed. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the differentially expressed genes (DEGs). The protein interaction network of the DEGs in the regulatory network was constructed with the STRING database, and the key genes were screened through Cytoscape. Potential downstream target genes regulated by differentially expressed miRNAs (DEMs) were predicted by the miRWalk3.0 database, and miRNA-mRNA regulatory networks were constructed. Finally, some research results were validated. Results: ① Four DEMs and 83 DEGs were screened; ② GO and KEGG enrichment analysis mainly focused on the PI3K/Akt signalling pathway, ECM receptor interaction, etc.; ③ CD2, SLAMF7, etc. may be the key targets of GC in the treatment of COPD; ④ 18 intersection genes were predicted by the mirwalk 3.0 database, and 9 pairs of miRNA-mRNA regulatory networks were identified; ⑤ The expression of miR-320d-2 and TFCP2L1 were upregulated by dexamethasone in the COPD cell model, while the expression of miR-181a-2-3p and SLAMF7 were downregulated. Conclusion: In COPD, GC may mediate the expression of the PI3K/Akt signalling pathway through miR-181a-2-3p, miR-320d-2, miR-650, and miR-155-5p, targeting its downstream signal factors. The research results provide new ideas for RNA therapy strategies of COPD, and also lay a foundation for further research.

Development of Acridone Derivatives: Targeting c-MYC Transcription in Triple-Negative Breast Cancer with Inhibitory Potential.

Breast cancer, especially the aggressive triple-negative subtype, poses a serious health threat to women. Unfortunately, effective targets are lacking, leading to a grim prognosis. Research highlights the crucial role of c-MYC overexpression in this form of cancer. Current inhibitors targeting c-MYC focus on stabilizing its G-quadruplex (G4) structure in the promoter region. They can inhibit the expression of c-MYC, which is highly expressed in triple-negative breast cancer (TNBC), and then regulate the apoptosis of breast cancer cells induced by intracellular ROS. However, the clinical prospects for the application of such inhibitors are not promising. In this research, we designed and synthesized 29 acridone derivatives. These compounds were assessed for their impact on intracellular ROS levels and cell activity, followed by comprehensive QSAR analysis and molecular docking. Compound N8 stood out, significantly increasing ROS levels and demonstrating potent anti-tumor activity in the TNBC cell line, with excellent selectivity shown in the docking results. This study suggests that acridone derivatives could stabilize the c-MYC G4 structure. Among these compounds, the small molecule N8 shows promising effects and deserves further investigation.

Constructing a Protective Pillaring Layer by Incorporating Gradient Mn4+ to Stabilize the Surface/Interfacial Structure of LiNi0.815Co0.15Al0.035O2 Cathode.

Nickel-rich layered oxides are regarded as very promising materials as cathodes for lithium-ion batteries because of their environmental benignancy, low cost, and high energy density. However, insufficient cycle performance and poor thermotic characteristics induced by structural degradation at high potentials and elevated temperatures pose challenging hurdles for nickel-rich cathodes. Here, a protective pillaring layer, in which partial Ni2+ ions occupy Li slabs induced by gradient Mn4+, is integrated into the primary particle of LiNi0.815Co0.15Al0.035O2 to stabilize the surface/interfacial structure. With the stable outer surface provided by the enriched Mn4+ gradient concentration and the pillar effect of the NiO-like phase, Mn-incorporated quaternary cathodes show enhanced structural stability and improved Li+ diffusion as well as lithium-storage properties. Compared with the severe capacity fade of a pure layered structure, the cathode with gradient Mn4+ exhibits more stable cycling behavior with a capacity retention of 80.0% after 500 cycles at 5.0 C.

In Situ Grown S Nanosheets on Cu Foam: An Ultrahigh Electroactive Cathode for Room-Temperature Na-S Batteries.

Room-temperature sodium-sulfur batteries are competitive candidates for large-scale stationary energy storage because of their low price and high theoretical capacity. Herein, pure S nanosheet cathodes can be grown in situ on three-dimensional Cu foam substrate with the condensation between binary polymeric binders, serving as a model system to investigate the formation and electrochemical mechanism of unique S nanosheets on the Cu current collectors. On the basis of the confirmed conversion reactions to Na2S, The constructed cathode exhibits ultrahigh initial discharge/charge capacity of 3189/1403 mAh g-1. These results suggest that there is great potential to optimize S cathode by exploiting low-cost Cu substrates instead of conventional Al current collectors.

Applications of gray relational analysis in gastroenterology.

AIM: To introduce the basic methods of gray relational analysis (GRA) and to illustrate its applications in gastroenterology. METHODS: With the essential formulae of GRA and several typically practical examples, the procedure of GRA was introduced. Examples were drawn from the gastroenterological studies. Thus the trait of GRA could be demonstrated. RESULTS: The superiority of GRA in gastroenterological study was proved by the examples. CONCLUSION: GRA can be applied mechanically or flexibly in gastroenterology.

Time course of inflammatory response after renal artery stenting in patients with atherosclerotic renal stenosis.

BACKGROUND: Inflammatory response has been demonstrated in patients with coronary artery disease after percutaneous coronary intervention (PCI). Such response following renal artery stenting has not yet been established, however, in patients with atherosclerotic renal artery stenosis. METHODS: A total of 44 patients were enrolled in this study. Of them, 22 patients with atherosclerotic renal artery stenosis received renal angioplasty with stent (group A, mean age 51+/-8 years), and 22 patients with age- and gender-matched underwent renal angiography for diagnostic purpose as a control group (group B, age 50+/-8 years). The peripheral blood samples were taken immediately before the procedure, 1, 6 and 24 h after the procedure in both groups. The concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) were measured using ELISA. RESULTS: The result showed that there was no difference in clinical characteristics and baseline levels of CRP and IL-6 between the groups. The IL-6 increased in the first hour (before: 5.8+/-3 pg/ml; 1 h: 8.6+/-5 pg/ml, p<0.01), lasted at 6 h (12.2+/-8 pg/ml), returned to baseline at 24 h (5.4+/-3 pg/ml) in group A. The CRP did not changed at the first hour after stenting, but mean CRP increased from 0.30+/-0.09 to 0.37+/-0.15 mg/dl at 6 h (p<0.05), and peaked at 24 h (0.43+/-0.18 mg/dl, p<0.001 compared with baseline and control) after stenting in group A, while no such changes were observed in group B (p>0.05 at different time points compared with baseline and group B, respectively). CONCLUSIONS: The data indicated that renal artery stenting could trigger inflammatory response by evidence of increased plasma levels of CRP and IL-6. IL-6, however, was an early initiator of inflammatory cytokine, and CRP was a later marker of systemic inflammatory response to renal artery stenting.

beta-Adrenoceptors potentiate alpha1-adrenoceptor-mediated inotropic response in rat left atria.

AIM: To investigate whether stimulation of beta-adrenoceptor (AR) and its subtypes augment alpha1-AR-evoked positive inotropic response and inositol phosphate (InsP) accumulation in isolated rat left atria. METHODS: Inotropic response was determined by contractile function experiment in isolated electrically driven rat left atria. 3H-InsP accumulations were measured by 3H-inositol incorporation and column chromatography. RESULTS: (1) Stimulation of alpha1-AR by phenylephrine (PE) or norepinephrine (NE) in the presence of propranolol (Prop) evoked positive inotropic response and 3H-InsP accumulations, while stimulation of beta-AR by isoprenaline (ISO) or NE in the presence of phentolamine (Phen) only evoked positive inotropic response, but not 3H-InsP accumulations. (2) Simultaneous stimulation of alpha1- and beta-AR by NE or ISO plus PE significantly shifted the concentration-dependent inotropic response curves and 3H-InsP accumulation curves to the left and upward compared with individual alpha1-AR stimulation by PE or NE in the presence of Prop. (3) In the presence of ICI118551 (selective beta2-AR antagonist) or CGP12177 (selective beta1-AR antagonist), stimulation of either beta1- or beta2-AR did not change alpha1-AR-evoked inotropic response and 3H-InsP accumulations. CONCLUSION: Stimulation of beta1-AR and beta2-AR potentiates alpha1-AR-mediated positive inotropic response and InsP accumulation in isolated rat left atria.

Activation of nuclear factor-kappaB and correlation with elevated plasma c-reactive protein in patients with unstable angina.

BACKGROUND: Unstable coronary syndromes are currently believed to be caused by rupture of an atherosclerotic plaque due to local events, which may be of general inflammatory etiology. There is increasing evidence that nuclear factor-kappaB (NF-kappaB) is a key transcription factor in controlling gene expression concerning inflammatory response, and that plasma concentrations of C-reactive protein (CRP) is a sensitive marker of inflammation in unstable coronary syndromes. However, whether NF-kappaB activation is associated with coronary heart disease (CHD) activity as well as plasma CRP level has been less well investigated. The aim of this study was to explore whether NF-kappaB activation was associated with CHD activity and plasma CRP elevation in patients with unstable angina (UA). METHODS: NF-kappaB activity derived from white blood cells circulating in 33 patients with CHD was determined by electrophoretic mobility shift assay. Of these, 16 had UA and were within 24h of the last episode of chest pain. The remaining 17 were being evaluated for stable angina (SA). The CRP was also evaluated in both groups using a high-sensitivity ELISA. RESULTS: There was marked NF-kappaB activation and elevated levels of CRP in UA group compared with SA group (4.02+/-0.71 AU versus 1.24+/-0.23 AU and 5.0+/-0.7mg/l versus 1.4+/-0.4mg/l, respectively, P<0.01), no NF-kappaB signal was observed in normal subjects (n=10). The NF-kappaB activation had a positive correlation with levels of CRP in patients with UA (n=11, gamma=0.771, P<0.01), but had no relationship between other clinical characteristics and the status of NF-kappaB activation. CONCLUSIONS: Our data suggest that inflammation is an important feature of unstable coronary artery disease, and both NF-kappaB and CRP are useful markers for the detection of UA or vulnerable plaques.

[Effect of benidipine on plasma level of calcitonin gene-related peptide in essential hypertension].

OBJECTIVE: To explore the effect of benidipine, a calcium channel blocker on the plasma levels of calcitonin gene-related peptide (CGRP) in patients with essential hypertension. METHODS: 58 outpatients with essential hypertension were treated with benidipine 4-8 mg/day for 8 weeks. 38 matched healthy people were taken as controls. The plasma levels of CGRP were measured in all patients before and after treatment and in controls. RESULTS: The plasma levels of CGRP in hypertensive patients were significantly lower than those in controls (minimal value: 1.28 vs 39.95 ng/L; maximal value: 43.72 vs 155.59 ng/L; P <0.001). In hypertensive patients, treatment with benidipine for 2 weeks markedly decreased systolic pressure and diastolic pressure and its depressor effect was maintained during the study (P <0.05). At 8 week after treatment, the plasma levels of CGRP in hypertensive patients were significantly increased compared with those before treatment (minimal value: 2.84 vs 1.28 ng/L; maximal value: 123.99 vs 43.72 ng/L; P <0.001). CONCLUSION: Benidipine, a calcium channel blocker significantly decreases blood pressure concomitantly with an increase in the plasma levels of CGRP in the patients with essential hypertension.

Intramuscular injection of naked plasmid DNA encoding human preproinsulin gene in streptozotocin-diabetes mice results in a significant reduction of blood glucose level.

The insulin complement with gene therapy has been used as an experimental treatment for insulin dependent diabetes (IDDM). In the present study, we constructed naked plasmid DNA vector encoding recombinant human preproinsulin gene (pCMV-IN), and injected the plasmids (100 microg/mouse) intramuscularly combined with electroporation, to achieve the in vivo transfer of insulin gene in streptozotocin (STZ)-induced diabetic C57 mice. The expression of vector-derived insulin mRNA was detected with RT-PCR in transfected local skeletal muscles. The plasma insulin was elevated significantly in pCMV-IN injected diabetic C57 mice, which was complemented to the level similar to the intact normal control. The protein expression lasted for at least 35 days after the plasmid injection. Gene therapy with pCMV-IN plasmids considerably decreased the blood glucose level in STZ-induced diabetic mice from d 7 to d 35 by about 6 mmol/L. The gene therapy also reduced the mortality of severe diabetic mice significantly from 100% to 37% at the 6th week. Our results indicate that the direct intramuscular injection of naked plasmids encoding human preproinsulin gene achieves the effective expression of insulin. The restoration of insulin decreases blood glucose and increases the survival in severe diabetic mice. The gene therapy might be provided as a practical therapeutic approach to IDDM.

A pedigree analysis of familial hypercholesterolemia in monozygote twin brothers.

The current study was designed to investigate the features of a family with familial hypercholesterolemia (FH). Twenty members of 3 generations in a family with hypercholesterolemia were enrolled in the study. The data collected were from clinical observation and subjected to pedigree analysis. The proband was a 41-year-old male who suffered from angina pectoris with multi-vessel stenosis of coronary arteries at the age of 40. Among 20 members, 8 individuals had FH in this family with a total incidence of 40% (54.5% [6/11] in male and 22.2% [2/9] in female). The serum total cholesterol level was increased in childhood from 7.1 to 10.8 mmol/L and tended to increase with increasing age. In addition, the level of total cholesterol was increased in monozygote twin brothers and their offspring in the family. This pedigree analysis showed that FH appears to be a hereditary disease of autosomal dominance, and attention should be paid, especially in the only son or daughter society of China.

Rapid effects of simvastatin on lipid profile and C-reactive protein in patients with hypercholesterolemia.

BACKGROUND: Rapid lowering of low-density lipoprotein (LDL) cholesterol levels as well as C-reactive protein (CRP) by administration of drugs may produce early benefit to the coronary endothelium in patients with coronary heart disease and reduce angina and coronary events after revascularization. Limited information has been available in evaluating a potentially effective first 2-week therapeutic approach for the treatment of patients with hypercholesterolemia using a statin. HYPOTHESIS: The study was undertaken to investigate whether a rapid LDL cholesterol and CRP reduction can be achieved by 2-week simvastatin therapy using a common lipid-lowering protocol in patients with hypercholesterolemia. METHODS: Forty-two patients were randomly assigned to 20 or 40 mg/day of simvastatin. Blood samples were drawn at Day 0 and at Day 14 for measuring lipid profile, CRP levels, and hepatic enzymes in all patients. RESULTS: The results showed that both doses of simvastatin (20 and 40 mg) induced significant reductions in total cholesterol (TC, 25 and 38%) and LDL cholesterol (31 and 46%) compared with baseline. However, the highest dose of simvastatin (40 mg) resulted in significantly greater reductions in TC and LDL cholesterol (p = 0.04, p = 0.02, respectively) compared with the group receiving 20 mg (p < 0.04, p < 0.02, respectively). A less significant reduction was observed in mean triglycerides (TG) level (16 and 25%) compared with TC and LDL cholesterol. There was no significant difference in mean high-density lipoprotein (HDL) cholesterol levels compared with baseline in either group. In addition, both doses of simvastatin induced significant reductions in mean CRP levels on Day 14 (22.3 and 23.1%) in a non dose-dependent manner (p < 0.001, respectively. CONCLUSIONS: Our data suggest that a common daily dose of simvastatin, especially 40 mg, is an effective 2-week therapy for patients with hypercholesterolemia, and benefit to the vascular endothelium can be derived quickly by reduction of CRP levels.

Functional alpha1-adrenergic receptor subtypes in human right gastroepiploic artery.

AIM: To study the functional alpha1-adrenergic receptor (alpha1-AR) subtypes in human right gastroepiploic artery (RGA). METHODS: The effects of alpha2-AR, alpha1-AR, and alpha1-AR subtype selective antagonists on norepinephrine (NE)-induced vasoconstriction in isolated human RGA were observed by contractile function experiment. RESULTS: Cumulative concentration-response curves for NE were competitively antagonized in RGA by alpha2-AR selective antagonist yohimbine (pA2 6.82+/-0.28, slope 1.12+/-0.40),alpha1-AR selective antagonist prazosin (pA2 9.77+/-0.22, slope 0.90+/-0.22),alpha1A-AR selective antagonists RS17053 (pA2 8.42+/-0.20, slope 0.93+/-0.20) and 5-MU (pA2 8.42+/-0.22, slope 0.88+/-0.18),alpha1D-AR selective antagonist BMY7378 (pA2 6.84+/-0.32, slope 1.05+/-0.17), and alpha1A-,alpha1B-AR selective antagonist WB4101 (pA2 8.88+/-0.20, slope 1.15+/-0.16). The correlation coefficients between these pA2 values of alpha1-AR selective antagonists with pKi values of which obtained from alpha1A-, alpha1B- and alpha1D-AR cloned cells are 0.95, 0.82, and 0.42. After the vessels were pretreated by chlorethylclonidine (CEC), an alpha1B- and alpha1D-AR irreversible alkylating agent, the pD2 values were changed from 5.9+/-0.5 to 5.6+/-0.6 and the maximal contraction was changed from (8.9+/-3.2) g to (8.0+/-3.2) g, respectively. The difference was not significant. CONCLUSION: In human RGA, the contraction response is mainly mediated by alpha1-AR, of which alpha1A-AR plays an important role, whereas alpha1B- and alpha1D-AR are not involved in the contraction response.