A theoretical investigation on the synergetic effect of hydrogen-bonding interactions and thermodynamic property in the 1: 2 (azacyclopentane-2-one: N-methylolacetamide) ternary complex.

CONTEXT: Using chemical penetration enhancers to improve the penetration effect is one kind of important strategies in transdermal drug delivery system. Azone is a widely used transdermal absorption enhancer for transdermal drug delivery. To shed light on the permeation-promoting mechanism of azone, we selected ternary systems formed by azacyclopentane-2-one and N-methylolacetamide (1: 2) and explored the synergetic effect of hydrogen-bonding interactions among them and their thermodynamic properties. The findings indicate that the synergetic effects can enhance the ability of azone to change the original conformation of ceramides and even break the original hydrogen bonds, which is more beneficial for azone to destroy the 3D network structure of ceramides. When azone interacts with ceramide, the order of action tends to interact with one molecule of ceramide first and then with another molecule of ceramide. METHODS: The synergetic effects of hydrogen-bonding interactions in ternary systems were computed at the B3LYP/6-311 + + G** and MP2(full)/6-311 + + G** levels. Thermodynamic parameters for two ternary-complex routes were worked out at the B3LYP/aug-cc-pVDZ level. The shift of the electron density occurring simultaneously with trimer formation was analyzed at the MP2(full)/6-311 + + G** level. The above calculations were carried out using the Gaussian 03 program packages. Atoms in molecules (AIM) method and the AIMPAC program showed the topological charge density at the MP2(full)/6-311 + + G** level. The synergetic effects of hydrogen-bonding interactions and thermodynamic property in the 1: 2 (azacyclopentane-2-one: N-methylolacetamide) ternary systems were investigated using the B3LYP and MP2(full) methods.

Plasma Level of Elabela in Patients with Coronary Heart Disease and Its Correlation with the Disease Classification.

This study aimed to evaluate the concentration of plasma elabela (ELA) in patients with coronary heart disease (CHD) and its correlation with the disease classification.We enrolled 238 patients diagnosed by coronary angiography as CHD and 86 controls. The CHD group was divided into three subgroups: stable angina (SA), unstable angina (UAP), and acute myocardial infarction (AMI). The plasma levels of ELA were measured in all participants and compared among different groups. The relationship between ELA and CHD classification was analyzed.ELA levels were markedly higher by 10.71% in patients with CHD than in controls (P < 0.05). The concentration of ELA in UAP and AMI subgroups were higher than in controls and SA subgroup. The former difference was significant (P < 0.05), but the latter was not. In addition, the ELA concentration was not correlated with SYNTAX score, left ventricular ejection fraction, and other biochemical variables.The newfound hormone, ELA, significantly increased in patients with UAP and AMI. There is a tendency that ELA levels might be correlated with CHD classification, but not with lesion severity. ELA may play a role in acute coronary syndrome.

Discovery and identification of antithrombotic chemical markers in Gardenia Fructus by herbal metabolomics and zebrafish model.

ETHNOPHARMACOLOGICAL RELEVANCE: Gardenia Fructus (GF), a traditional Chinese medicine for clearing heat and purging fire, has been reported to use to treat thrombotic related diseases, but the antithrombotic components are not clear. AIM OF THE STUDY: To develop efficient research methods for discovering some representative antithrombotic compounds of GF. MATERIALS AND METHODS: AB line zebrafish induced by arachidonic acid (AA) was used as a fast and trace-sample-required valuation model for antithrombptic effect of GF samples. Among nine samples of GF from different production areas, two samples with the largest difference in bioactivity were selected for downstream analysis. High-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF/MS) was applied to detect compounds in the GF samples. And herbal metabolomics and grey correlation analysis (GCA) were used to identify crucial compounds with potential antithrombotic activity. Then the bioactivity of those important compounds was verified on the zebrafish model. Network pharmacology was used to explore the protein targets and signaling pathways of these compounds. RESULTS: Among the GF samples, S1 (Huoshan City, Anhui Province), and S6 (Jichun City, Hubei Province), significantly differed in thrombus inhibiting bioactivity. HPLC-Q-TOF/MS identified a total of 614 compounds in each GF sample. 19 compounds were selected as important potential variables from metabolomics data by orthogonal partial least squares discriminant analysis (OPLS-DA). And 10 compounds among them were further found to be positively correlated with the antithrombotic bioactivity of GF by GCA. Finally, 3 compounds in them, geniposide, citric acid, and quinic acid, were confirmed as representative antithrombotic chemical markers of GF. Using network pharmacology analysis, some key protein targets, such as proto-oncogene tyrosine-protein kinase Src (SRC) and cyclin-dependent kinase 2 (CDK2), and some signaling pathways were found to supply powerful evidence about antithrombotic mechanisms of three compounds and GF. CONCLUSIONS: This research have succeeded to discover and identify three representative antithrombotic compounds of GF using an efficient integrated research strategy we established, an Omics Discriminant-Grey Correlation-Biological Activity strategy. The antithrombotic chemical makers we found could also contribute to provided more accurate index components for comprehensive quality control of GF.

Association of Circulating Neuregulin-4 with Presence and Severity of Coronary Artery Disease.

Neuregulin-4 (Nrg4) is a newly discovered adipokine that is synthesized in many tissues and plays an important role in modulating systemic energy metabolism and in the development of metabolic disorders. However, little is known about the relationship between Nrg4 and coronary artery disease (CAD). In this study, we investigated the association between Nrg4 and the presence and severity of CAD.We enrolled 73 patients diagnosed by coronary angiography (CAG) as having CAD and 32 controls. The CAD group was divided into two subgroups according to their SYNTAX score. Plasma levels of Nrg4 were measured in all participants and compared among different groups. The relationship between Nrg4 and CAD was analyzed. Receiver operating characteristic (ROC) analysis was conducted to evaluate the usefulness Nrg4 in assessing the presence and severity of CAD.Nrg4 levels were negatively associated with the SYNTAX score (r = -0.401, P = 0.000). The patients with a higher SYNTAX score had significantly lower Nrg4 levels as compared with the low SYNTAX score subgroup and the controls (P < 0.05). The Nrg4 levels of the low SYNTAX score subgroup were much lower than controls (P < 0.05). Furthermore, an association between Nrg4 and CAD (odds ratio, 0.279; 95% confidence interval, 0.088-0.882) was observed. Nrg4 had 43.8% sensitivity and 96.9% specificity for identifying CAD, and 73.1% sensitivity and 87.3% specificity for identifying patients who had severe coronary artery lesions.Nrg4 levels were found to be inversely associated with the presence and severity of CAD.

Tenacissoside H exerts an anti-inflammatory effect by regulating the nf-κb and p38 pathways in zebrafish.

Marsdenia tenacissima exhibits biological activity with heat-clearing and detoxifying properties, relieving coughs and asthma and exerting anticancer and anti-HIV effects. Tenacissioside H (TH) is a Chinese medicine monomer extracted from the dried stem of Marsdenia tenacissima. We investigated the in vivo anti-inflammatory activity of TH using three different zebrafish inflammation models: local inflammation induced by tail cutting, acute inflammation induced by CuSO4, and systemic inflammation induced by lipopolysaccharide (LPS). Real time-polymerase chain reaction (RT-PCR) was used to elucidate the mechanism of TH action against LPS-induced inflammatory responses. Our results showed TH significantly reduced the number of macrophages in the injured zebrafish tail, inhibited CuSO4-induced migration of macrophages toward the neural mound, and decreased the distribution of macrophages in tail fin compared to LPS-treated group. Furthermore, TH inhibits LPS-induced inflammation responses in zebrafish by modulating the nuclear factor κB (nf-κb) and p38 pathways to regulate inflammatory cytokines, such as tumor necrosis factor-α (tnf-α), cyclooxygenase (cox-2), interleukin-1b (il-1b), interleukin-8 (il-8), interleukin-10 (il-10), nitric oxide synthase (nos2b) and prostaglandin E synthase (ptges). In conclusion, TH possesses anti-inflammation activity via the regulation of the nf-κb and p38 pathways. This finding provides a reference for the clinical application of Xiaoaiping (the trade name of Marsdenia tenacissima extract).

Theoretical investigations into the intermolecular hydrogen-bonding interactions of N-(hydroxymethyl)acetamide dimers.

The structures of the N-(hydroxymethyl)acetamide (model molecule of ceramide) dimers have been fully optimized at B3LYP/6-311++G** level. The intermolecular hydrogen bonding interaction energies have been calculated using the B3LYP/6-311++G**, B3LYP/6-311++G(2df,2p), MP2(full)/6-311++G** and MP2(full)/6-311++G(2df,2p) methods, respectively. The results show that the O-H···O, N-H···O, O-H···N, and C-H···O hydrogen bonding interactions could exist in N-(hydroxymethyl)acetamide dimers, and the O-H···O, N-H···O, and O-H···N hydrogen bonding interactions could be stronger than C-H···O. The three-dimensional network structure formed by ceramide molecules through intermolecular hydrogen bonding interactions may be the main reason why the stratum corneum of skin could prevent foreign substances from entering our body, as is in accordance with the experimental results. The stability of hydrogen-bonding interactions follow the order of (a) > (b) ≈ (c) > (d) > (e) ≈ (f) > (g) > (h). The analyses of the energy decomposition, frequency, atoms in molecules (AIM), natural bond orbital (NBO), and electron density shift are used to further reveal the nature of the complex formation. In the range of 263.0-328.0 K, the complex is formed via an exothermic reaction, and the solvent with lower temperature and dielectric constant is favorable to this process. Graphical abstract The structures and the O-H···O=C, N-H···O=C and C-H···O=C H-bonding interactions in the N-(hydroxymethyl)acetamide (model molecule of ceramide) dimers were investigated using the B3LYP and MP2(full) methods.

A theoretical investigation into the cooperativity effect between the H∙∙∙O and H∙∙∙F⁻ interactions and electrostatic potential upon 1:2 (F⁻:N-(Hydroxymethyl)acetamide) ternary-system formation.

The cooperativity effects between the O/N-H∙∙∙F(-) anionic hydrogen-bonding and O/N-H∙∙∙O hydrogen-bonding interactions and electrostatic potentials in the 1:2 (F(-):N-(Hydroxymethyl)acetamide (signed as "ha")) ternary systems are investigated at the B3LYP/6-311++G** and MP2/6-311++G** levels. A comparison of the cooperativity effect in the "F(-)∙∙∙ha∙∙∙ha" and "FH∙∙∙ha(-)∙∙∙ha" systems is also carried out. The result shows that the increase of the H∙∙∙O interaction energy in the O-H∙∙∙O-H, N-H∙∙∙O-H or N-H∙∙∙O = C link is more notable than that in the O-H∙∙∙O = C contact upon ternary-system formation. The cooperativity effect is found in the complex formed by the O/N-H∙∙∙F(-) and O/N-H∙∙∙O interactions, while the anti-cooperativity effect is present in the system with only the O/N-H∙∙∙F(-) H-bond or the "FH∙∙∙ha(-)∙∙∙ha" complex by the N(-)∙∙∙H-F contact. Atoms in molecules (AIM) analysis and shift of electron density confirm the existence of cooperativity. The most negative surface electrostatic potential (V(S,min)) correlates well with the interaction energy E' int.(ha∙∙∙F-) and synergetic energy E(syn.), respectively. The relationship between the change of V(S,min) (i.e., ΔV(S,min)) and E(syn.) is also found.

[Aspirin response and related factors in aged patients].

OBJECTIVE: To explore clinical and laboratory factors associated aspirin response, and the association between gastrointestinal bleeding and aspirin response in aged patients. METHODS: A total of 136 patients aged 60 and over [mean age (74.9 ± 7.0) years] with ischemic heart disease and at high risk for ischemic heart disease were included. Arachidonic acid induced platelet aggregation (AA-Ag) was measured before and at 7(th) day after taking aspirin (100 mg/d). Patients were followed for 6 months and incidence of gastrointestinal bleeding was obtained. RESULTS: Post-treatment AA-Ag was significantly reduced compared to baseline (13.29% ± 5.52% vs. 73.20% ± 7.32%, P < 0.05). A heterogeneous distributed post-treatment AA-Ag was observed (range 0.42% to 30.50%). Post-treatment AA-Ag was positively correlated with baseline AA-Ag (r = 0.493, P < 0.01). The level of post-treatment AA-Ag was significantly higher in the fourth quartile group at baseline than in the others quartile groups at baseline. Patients aged 80 years and over had significantly lower post-treatment AA-Ag (10.25% ± 4.68%) compared with patients of 60 - 69 years (13.96% ± 5.20%) and of 70 - 79 years (13.73% ± 5.48%, all P < 0.01). The incidence of patients in the lowest quartile of post-treatment AA-Ag was significantly higher in patients ≥ 80 years (38.24%) than in patients of 60 - 69 years (11.1%) and of 70 - 79 years (24.0%). Multiple variable analysis revealed post-treatment AA-Ag was significantly influenced by baseline AA-Ag, ≥ 80 years old, diabetes mellitus and acute coronary syndrome. We observed 4 (2.9%) mild gastrointestinal bleeding during follow up. Post-treatment AA-Ag was in the lowest quartile in 3 patients with mild gastrointestinal bleeding. CONCLUSIONS: Increased baseline platelet reactivity as well as diabetes mellitus and acute coronary syndrome are associated with low aspirin response in the aged patients. Aspirin response is significantly higher in very old patients.

[Relationship between plasma cortistatin and coronary heart disease].

OBJECTIVE: To analyze the relationship between plasma level of cortistatin(CST) and coronary heart disease(CHD) and the factors that influence the level of CST. METHODS: Plasma levels of CST were measured using ELISA method. The clinical data and the levels of CST of 40 healthy subjects and 39 CHD patients before and 1 d after percutaneous coronary intervention (PCI) were compared. And the factors that influenced the CST level were analyzed. RESULTS: The CST levels of CHD group before or 1 d after PCI were significantly higher than those of the control group (1.97+/-1.12 and 2.01+/-0.77 vs 1.21+/-0.27, P<0.01);The procedure of PCI didn't influence the CST levels(1.97+/-1.12 vs 2.01+/-0.77, P>0.05);There was no correlation between CST levels and fasting blood glucose(FBG), high sensitivity C-reactive protein (hsCRP), left ventricular ejection fraction(LVEF), severity of lesions of coronary arteries or history of hypertension; The levels of triglyceride(TG) and total cholesterol(TCHOL) negatively correlated with CST levels(beta=-2.594, P<0.05;and beta=-0.650, P<0.01), but history of diabetes mellitus(DM) or myocardial infarction(MI) positively correlated with CST levels(beta=4.149 and 6.430, P<0.05).The CST level of subgroup of CHD with DM or MI was higher than that of CHD without DM or MI, but the difference was not significant(2.07+/-10.7 vs 1.85+/-1.20; 2.20+/-1.53 vs 1.79+/-0.66, P<0.05). CONCLUSION: Patients with CHD have higher plasma levels of CST. CST may play an important role in the procedure of CHD.

[Application of genetic algorithm in formulation optimization of microemulsion for transdermal delivery].

Using naproxen as model drug, the formulation of microemulsion vehicle for transdermal delivery was optimized by genetic algorithm. The ranges of microemulsion composed of Tween 80, IPM, alcohol and water, were defined through construction of the pseudo-ternary phase diagrams. Systematic model microemulsions containing naproxen 1.12% were prepared by a three-factor, three-level center design method, and their diffusion studies via excised rabbit skin were performed. Using the quadratic regression model of steady-state permeation rate (Js) of naproxen as objective function, the consequence of center design experiment was optimized by genetic algorithm, and the formulation of microemulsion with highest permeation rate for naproxen was screened. The optimum formulation was composed of 21.41% Tween 80, 15.17% alcohol, 4.14% IPM, and 59.28% water, and the anticipated Js was 183.57 microg x cm(-2) x h(-1). The results of back substitution test showed the steady-state permeation rate of naproxen microemulsion prepared according to optimum formulation was 189.43 microg x cm(-2) x h(-1), which was higher than anticipated value. This result demonstrated optimizing formulation of microemulsion for transdermal delivery by genetic algorithm is feasible, reliable and reasonable.

[The predictive value of the ambulatory blood pressure monitoring parameters on left ventricular hypertrophy and carotid artery intima-media thickness in hypertensives].

OBJECTIVE: To investigate the predictive value of the ambulatory blood pressure monitoring parameters on left ventricular hypertrophy (LVH) and carotid artery intima-media thickness (IMT) in the hypertensives. METHODS: We evaluated 147 hypertensive patients who were never treated regularly before. All patients underwent ultrasound examinations of the heart and the IMT of carotid arteries. We classified them as LVH group (n = 45) or no LVH group (n = 102), and as IMT increased group (n = 52) or no IMT increased group (n = 95). The record of medical history, physical examination and 24 h ambulatory blood pressure monitoring (ABPM) were performed in all the patients. The biochemical parameters such as blood lipids, glucose and so on were tested. Then the data comparison was made. RESULTS: (1) There were no significant differences in clinical manifestations and biochemical parameters between the LVH and no LVH groups (P > 0.05). Age (68.3 +/- 6.2) year vs (65.6 +/- 5.8) year, male 75.6% vs 66.7%, body mass index (24.1 +/- 4.1) vs (23.8 +/- 4.7) (kg/m(2)), diabetes mellitus and(or) impaired glucose tolerance 40.0% vs 38.2%, angina pectoris 42.3% vs 38.9%, cerebral vascular diseases 19.2% vs 15.7%, total cholesterol (5.40 +/- 1.42) vs (5.28 +/- 1.46) mmol/L, triglycerides (1.80 +/- 1.02) vs (1.74 +/- 1.08) mmol/L, low-density lipoprotein cholesterol (4.03 +/- 1.43) vs (4.06 +/- 1.48) mmol/L, high-density lipoprotein cholesterol (1.00 +/- 0.30) vs (0.99 +/- 0.26) mmol/L. (2) The parameters of ABPM in LVH group were higher than those in no LVH group. There were significant differences (P < 0.05) in 24 h mean systolic blood pressure (140.7 +/- 14.1) vs (128.3 +/- 12.3) mm Hg, 24 h mean diastolic blood pressure (86.4 +/- 8.9) vs (81.6 +/- 9.3) mm Hg, daytime mean systolic blood pressure (142.8 +/- 13.9) vs (130.9 +/- 11.1) mm Hg, daytime mean diastolic blood pressure (86.9 +/- 8.8) vs (83.4 +/- 9.0) mm Hg, nighttime mean systolic blood pressure (129.0 +/- 13.2) vs (114.6 +/- 11.4) mm Hg, nighttime mean diastolic blood pressure (77.2 +/- 9.4) vs (67.5 +/- 8.1) mm Hg, 24 h pulse pressure (54.2 +/- 10.2) vs (46.9 +/- 9.6) mm Hg, daytime pulse pressure (55.9 +/- 10.5) vs (47.5 +/- 9.1) mm Hg, nighttime pulse pressure (51.8 +/- 10.7) vs (47.1 +/- 8.7) mm Hg, 24 h systolic blood pressure variance (8.4 +/- 2.0) vs (7.2 +/- 1.9), 24 h diastolic blood pressure variance (9.5 +/- 2.2) vs (8.0 +/- 2.1), the non-dipper rhythm of ambulatory blood pressure 55.6% vs 25.5%. (3) There were also no significant differences in clinical manifestations between the IMT increased and no IMT increased group (P > 0.05). While there were significant differences between the IMT increased and no IMT increased group in those parameters of ABPM (P < 0.05). CONCLUSION: There were more LVH or IMT increased persons in the hypertensives whose ABPM parameters were abnormal.