Stabilization of the Metastable α-Form of Indomethacin Induced by the Addition of 2-Hydroxypropyl-ß-Cyclodextrin, Causing Supersaturation (Spring) and Its Sustaining Deployment (Parachute).

The purpose of this study is to find that a small amount of 2-Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) can produce a parachute effect on indomethacin (INM). From the examination of dissolution curves and concentration after several days, the supersaturation of INM was observed for the mixtures containing HP-ß-CD at a molar ratio ≤ 0.5, and the sustained deployment of supersaturation was found not only in equimolar mixtures but also in mixtures with a shortage of HP-ß-CD. In the solid state, it was compared the physical properties of INM/HP-ß-CD mixtures using two different mixing methods and determined the stoichiometry of INM and HP-ß-CD. Differential scanning calorimetry (DSC) revealed that the polymorphs of INM were converted by HP-ß-CD into an amorphous state. Furthermore, X-ray powder diffraction (XRPD) and DSC-XRPD demonstrated that INM crystals from the INM/HP-ß-CD mixture prepared from an EtOH solution were metastable. In conclusion, these phenomena may be considered the "spring" and "parachute" effects of mixtures with a shortage of HP-ß-CD, as they depended on the presence of the metastable α-form of INM. The addition of 1/3 to 1/20 equivalents of HP-ß-CD to INM enhanced INM solubility.

A high-throughput and untargeted lipidomics approach reveals new mechanistic insight and the effects of salvianolic acid B on the metabolic profiles in coronary heart disease rats using ultra-performance liquid chromatography with mass spectrometry.

High-throughput lipidomics provides the possibility for the development of new therapeutic drugs. Accordingly, herein, we reveal the protective role of salvianolic acid B (Sal B) in rats with coronary heart disease (CHD) and propose a new mechanism for its action through a high-throughput and non-targeted lipidomics strategy. A CHD animal model was induced by consecutive high-fat diet feeding with vitamin D3 injection. At the end of the 8th week, the serum sample was analyzed to explore the metabolic biomarker and pathway changes using untargeted lipidomics based on ultra-performance liquid chromatography with mass spectrometry (UPLC/MS). In addition, blood and heart tissue samples were collected and processed for the detection of biochemical indicators and liver histological observation. After salvianolic acid B treatment, the levels of LDH, CK, CK-MB, MYO, CTn1, TG, TC, LDL-c, and Apo(b) were significantly lower than that in the model group, while the levels of HDL-c and Apo(a1) were significantly higher than that in the model group. Furthermore, the histological features of fibrosis and steatosis were also evidently relieved in the model group. A total of twenty-six potential biomarkers were identified to express the lipid metabolic turbulence in the CHD animal models, of which twenty-two were regulated by salvianolic acid B trending to the normal state, including TG(20:0/20:4/o-18:0), PC(20:4/18:1(9Z)), PC(18:3/20:2), PA(18:0/18:2), LysoPE(18:2/0:0), SM(d18:0/22:1), PE(22:6/0:0), LysoPE (20:4/0:0), sphinganine, Cer(d18:0/18:0), PS(14:0/14:1), PC (18:0/16:0), LysoPC(17:0), PE(22:2/20:1), PC(20:3/20:4), PE(20:4/P-16:0), PS(20:3/18:0), cholesterol sulfate, TG(15:0/22:6/18:1), prostaglandin E2, arachidonic acid and sphingosine-1-phosphate. According to the metabolite enrichment and pathway analyses, the pharmacological activity of salvianolic acid B on CHD is mainly involved in three vital metabolic pathways including glycerophospholipid metabolism, sphingolipid metabolism and arachidonic acid metabolism. Thus, based on the lipidomics-guided biochemical analysis of the lipid biomarkers and pathways, Sal B protects against CHD with good therapeutic effect by regulating glycerophospholipid metabolism, sphingolipid metabolism and arachidonic acid metabolism, inhibiting oxidative stress damage and lipid peroxidation.

Analysis of single-nucleotide polymorphism of Sonic hedgehog signaling pathway in non-syndromic cleft lip and/or palate in the Chinese population / 北京大学学报(医学版)

OBJECTIVE@#To study the relationship between Sonic hedgehog (Shh) associated single-nucleotide polymorphism (SNP) and non-syndromic cleft lip and/or palate (NSCL/P), and to explore the risk factors of cleft lip and/or palate. Many studies suggest that the pathogenesis of NSCL/P could be related to genes that control early development, in which the Shh signaling pathway plays an important role.@*METHODS@#Peripheral blood was collected from 197 individuals (100 patients with NSCL/P and 97 healthy controls). Haploview software was used for haplotype analysis and Tag SNP were selected, based on the population data of Han Chinese in Beijing of the international human genome haplotype mapping project. A total of 27 SNP were selected for the 4 candidate genes of SHH, PTCH1, SMO and GLI2 in the Shh signaling pathway. The genotypes of 27 SNP were detected and analyzed by Sequenom mass spectrometry. The data were analyzed by chi-squared test and an unconditional Logistic regression model.@*RESULTS@#The selected SNP basically covered the potential functional SNP of the target genes, and its minimum allele frequency (MAF) was >0.05: GLI2 73.5%, PTCH1 91.0%, SMO 100.0%, and SHH 75.0%. It was found that the genotype frequency of SNP (rs12674259) located in SMO gene and SNP (rs2066836) located in PTCH1 gene were significantly different between the NSCL/P group and the control group. Linkage disequilibrium was also found on 3 chromosomes (chromosomes 2, 7 and 9) where the 4 candidate genes were located. However, in the analysis of linkage imbalance haplotype, there was no significant difference between the disease group and the control group.@*CONCLUSION@#In China, NSCL/P is the most common congenital disease in orofacial region. However, as it is a multigenic disease and could be affected by multiple factors, such as the external environment, the etiology of NSCL/P has not been clearly defined. This study indicates that Shh signaling pathway is involved in the occurrence of NSCL/P, and some special SNP of key genes in this pathway are related to cleft lip and/or palate, which provides a new direction for the etiology research of NSCL/P and may provide help for the early screening and risk prediction of NSCL/P.

Incidence and clinical characteristics of pulmonary hypertension in patients with idiopathic pulmonary fibrosis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Pulmonary hypertension (PH) frequently complicates the course of idiopathic pulmonary fibrosis (IPF) patients and is associated with significantly worse outcomes. The aim of the present study was to investigate the incidence of PH in IPF patients and evaluate the correlation between clinical parameters and systolic pulmonary artery pressure (sPAP).</p><p><b>METHODS</b>Hospitalized patients with IPF, who were evaluated for sPAP by Doppler echocardiography from January 2004 to December 2011, were enrolled in our study. Patients were defined as PH by an estimated sPAP > 50 mmHg and graded as PH likely, PH possible and PH unlikely, based on the 2009 European Society of Cardiology/European Respiratory Society PH Guidelines. The correlations between clinical parameters and sPAP were analyzed by multiple linear regression.</p><p><b>RESULTS</b>Totally, 119 IPF patients were enrolled in our study and 28 (23.5%), 20 (16.8%) and 71 (59.7%) patients were PH likely, PH possible and PH unlikely, respectively. Borg dyspnea score was positively correlated with sPAP, r = 0.467, P < 0.001. Oxygen saturation was negatively correlated with sPAP, r = -0.416, P < 0.001. Diffusing capacity of the lung for carbon monoxide percentage predicted was negatively correlated with sPAP, r = -0.424, P = 0.003. N-terminal fragment of pro-brain natriuretic peptide and pulmonary artery width was positively correlated with sPAP, r = 0.452, P = 0.011 and r = 0.513, P < 0.001, respectively.</p><p><b>CONCLUSIONS</b>The incidence of PH in IPF patients was 23.5% in a single center of China. PH may worsen the dyspnea, right heart dysfunction and decrease the life quality of the patients with IPF.</p>

Smoothened gene alterations in keratocystic odontogenic tumors.

BACKGROUND: It has been widely demonstrated that the hedgehog pathway is strongly associated with basal cell carcinoma of the skin (NBCCS). To assess potential DNA alterations related to keratocystic odontogenic tumors (KCOTs), we sequenced smoothened (SMO) genes in 12 sporadic KCOTs. METHODS: Polymerase chain reaction (PCR), capillary electrophoresis and dideoxy chain-termination sequencing were used to examine potential DNA alterations in sporadic KCOTs. RESULTS: Five alterations in SMO genes were detected. Four of these mutations consisted of two synonymous and three missense mutations; two of which have not been reported to date (c.T776A, c.T1281G). CONCLUSIONS: SMO genes may play an important role in the sonic hedgehog (SHH) pathway and could also be responsible for generating KCOTs and NBCCS. However, their influence on SHH signaling remains to be elucidated.