Metabolomic investigate into the serum of pulmonary hypertension Beagle dogs and the effect of sGC003 / 药学学报

Based on dehydrogenation of monocrotaline-induced Beagle dog model of pulmonary hypertension (PH), GC-TOF-MS metabolomics technique was used to identify potential biomarkers and biologically significant changes in the serum. Pattern recognition method was used for processing metabolomics data to compare PH Beagle dogs (n=11) versus healthy controls (n=8). The results show that 514 compounds were detected in the serum. The profiles of PH models and healthy controls can be distinguished clearly, indicating that there are significant differences in the metabolic profiles. Data analysis revealed 15 types of potential biomarkers, including amino acids glycine and 3-cyanoalanine, glucose, fructose, 1-monopalmitic acid glycerin, and malic acid. Diversified metabolites and their metabolic pathways have been analyzed. We found that different degrees of turbulence and disorganization occurred in glyoxylate and dicarboxylate metabolism, TCA cycle, starch and sucrose metabolism pathways in the Beagle dogs. A soluble guanylate cyclase activator, 4,6-diamino-2-[1-(3-fluorothiophen-2-yl)methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl-N-methyl methyl carbamate (sGC003), was administered (n=15) for comparison with the model and the control. We found that three groups were clearly clustered, indicating that there were differences in the three groups of metabolites. ANOVA statistical analysis results suggested that sGC003 exhibited pharmacodynamic effect, and at the same time, it also changed the endogenous metabolites to some extent. This study laid a foundation for the application of metabolomics in early diagnosis of pulmonary hypertension and provided experimental evidence for the application of sGC003 compound. In this study, the program of animal testing had been approved by Committee on the management of experimental animal in the Beijing Rixin Technology Co. Ltd.

The expression and clinical significance of lncRNA-uc003jsd.1 in congenital microtia / 中华整形外科杂志

Objective@#To investigate the expression of long non-coding RNA(lncRNA) uc003jsd.1 in congenital microtia and its clinical significance.@*Methods@#Real-time quantitative polymerase chain reaction (Real-time PCR) was used to detect the expression of lncRNA-NR_028308 in the residual ear cartilage and normal ear cartilage of 8 patients with microtia.@*Results@#The expression of uc003jsd.1 was significantly higher in the residual ear cartilage (P=0.015) than paired normal tissues.@*Conclusions@#LncRNA-uc003jsd.1 is up-regulated in the cartilage of the congenital microtia, suggesting a certain relationship with the development of congenital microtia.

Effect of novel agonist of soluble guanylate cyclase sGC 003 on endothelin-1-induced cardiomyocyte hypertrophy / 中国药理学与毒理学杂志

OBJECTIVE To investigate the protective effect of sGC003,a novel agonist of soluble guanylate cyclase,on endothelin-1(ET-1)-induced cardiomyocyte hypertrophy. METHODS Cardiomy?ocytes were isolated from neonatal Sprague-Dawley rats using serial enzymatic digestion and then incubated with ET-1 10 nmol·L-1 in the absence or presence of sGC003 0.01,0.1 and 1.0μmol·L-1. Hyper?trophic responses including the cardiomyocyte area(Image-Pro Plus 6.0),the expression of atrial natri?uretic peptide gene(ANP)mRNA(RT-PCR method)and total protein content(BCA method)were detect?ed. RESULTS After 48 h stimulation with ET-1 10 nmol·L-1,the cardiomyocyte area increased by 80%(P<0.01),the total protein content increased by 120%(P<0.01) and the expression of ANP mRNA up-regulated by 140%(P<0.01). sGC003 0.01,0.1 and 1.0μmol · L-1 elicited antihypertrophic actions, including inhibition of ET-1-mediated increase in the cardiomyocyte area(P<0.01),raised total protein content(P<0.05)and upregulation of ANP mRNA(P<0.05). CONCLUSION sGC003 has protective,car?diomyocyte-selective antihypertrophic effects in vitro.

Impact of a Meditation Program on Pulse-Wave Velocity, C-reactive Protein and Quality of life / Impacto de un programa de meditación sobre la velocidad de onda de pulso, la proteína C-reactiva y la calidad de vida

background: Although various studies refer to the effect of meditation on blood pressure (BP), its impact on other cardiovascular clinical variables is unknown. Objective: The aim of this study was to evaluate the effects of a meditation program on pulse wave velocity (PWV), quality of life and ultrasensitive C-reactive protein (us-CRP) in patients with ischemic heart disease or chronic heart failure. Methods: This was a randomized study with two groups of patients: a meditation group (M) and an active control group (AC) with cardiovascular health education, evaluating the difference between initial and final values at 12 weeks of B P, PWV, quality of life (assessed by the SF-36 questionnaire) and us-CRP. results: Thirty-five patients were included in the M group and 35 in the AC group; mean age was 61 years and 80% were men. Both groups had similar baseline characteristics, except for higher number of smokers and triglyceride levels in the M group. At 12 weeks, no significant differences were found for ∆PWV: +0.51 (±1.40) in AC and +0.19 (±1.53) in M (p=0.37). Conversely, ∆SF-36 was +0.79 (±7.58) in AC vs. +5.40 (±9.69) (p=0.03) in M, and ∆us-PCR was +1.17 (±2.9) in AC vs. -0.69 (±0.89) in M (p=0.02). Conclusions: A meditation program did not significantly modify PWV at 12 weeks. However, patients allocated to this intervention improved their quality of life and us-PCR was significantly reduced. Larger studies are required to confirm these findings and explore the mechanisms involved in this improvement.

Clinical and Functional Outcome of Percutaneous alcohol septal ablation in Obstructive Hypertrophic Cardiomyopathy / Resultados clínicos y funcionales de la ablación septal percutánea con alcohol en la miocardiopatía hipertrófica obstructiva

background: Percutaneous septal ablation is a therapeutic option for patients with obstructive hypertrophic cardiomyopathy refrac-tory to optimal medical therapy. However, results of initial persistence and long-term safety are still controversial. Objectives: The aim of this study was to report percutaneous alcohol septal ablation technique, clinical and functional outcome, cardiovascular events and its impact on long-term follow-up. Methods: A total of 23 patients were included in the study. Functional class (FC), left ventricular outflow tract gradient before and after the procedure and long-term cardiovascular events were evaluated. results: Median follow-up was 52 months (IR 33-72). All patients were in FC III or IV prior to the procedure, under maximum tolerated medical therapy. The procedure was successful in 91% of cases, with 85% of patients currently in FC I and 15% in FC II. Baseline left ventricular outflow tract gradient decreased from 75 mmHg (95% CI 51-89) to 25 mmHg (95% CI 10-37) (p <0.003) and with Valsalva maneuver from 118 mmHg (95% CI 88-152) to 38 mmHg (95% CI 16-69) (p <0.0002), persisting in the long-term follow-up. During hospitalization, two patients presented with complete atrioventricular block requiring permanent pacemaker implantation. No cardiovascular deaths occurred during follow up. Conclusions: Alcohol septal ablation is a promising option for the treatment of a selected population with hypertrophic obstructive cardiomyopathy, generating sustained clinical and functional improvement with low incidence of events in the long-term follow up.

Caracterización espectroscópica del D-003 obtenido de la cera de caña de azúcar (Saccharum officinarum L. ) / Spectroscopic characterization of D-003 obtained from the sugar cane (Saccharum officinarum L. ) wax

Introducción: el D-003 es un ingrediente farmacéutico activo purificado a partir de la cera de caña de azúcar (Saccharum officinarum L.) con efectos como reductor del colesterol y antioxidante, el cual está compuesto por una mezcla de ácidos grasos libres saturados de elevado peso molecular, cada uno dentro de un intervalo de concentración específica determinada por cromatografía de gases (CG). La caracterización espectroscópica del D-003, sin embargo, no ha sido previamente informada. Objetivo: caracterizar el ingrediente farmacéutico activo nombrado D-003 de acuerdo con sus espectros ultravioleta (UV), infrarrojo (FTIR), resonancia magnética nuclear (RMN) y de masas (EM). Métodos: se evaluaron muestras de seis lotes de D-003 (CNIC, Cuba) mediante las técnicas de UV, FTIR, RMN-¹H, RMN-13C y CG-EM. Para obtener los espectros de masas de los ácidos del D-003, estos se derivaron como ésteres metílicos y trimetilsilil. La cuantificación de los ácidos grasos libres saturados de elevado peso molecular, analizados como ésteres metílicos, se llevó a cabo por CG con detector de ionización por llama (DILL). Resultados: los espectros UV, IR, RMN-¹H y RMN-13C mostraron que el ingrediente farmacéutico activo D00-3 está constituido por una mezcla de ácidos grasos libres saturados de elevado peso molecular, mientras las técnicas de CG-EM y CG-DILL permitieron asegurar la presencia de 13 ácidos grasos libres saturados de elevado peso molecular en proporciones definidas: C24:0 (0,2-0,6 por ciento), C25:0 (0,4-0,9 por ciento), C26:0 (2,0-3,1 por ciento), C27:0 (2,1-2,7 por ciento), C28:0 (30,0-37,5 por ciento), C29:0 (1,5-1,7 por ciento), C30:0 (17,0-18,6 por ciento), C31:0 (0,9-1,2 por ciento), C32:0 (6,9-8,9 por ciento), C33:0 (0,9-1,3 por ciento), C34:0 (7,2-11,1 por ciento), C35:0 (0,3-0,6 por ciento) y C36:0 (2,2-3,8 por ciento)(AU)

Introduction: D-003, an active pharmaceutical ingredient (API) purified from sugar cane (Saccharum officinarum L.) wax with cholesterol-lowering and antioxidant effects, is composed of a mixture of free saturated very long chain fatty acids (VLCFAs), each within specific relative concentration ranges as determined by the gas chromatography (GC). However, the spectroscopic characterization of D-003 had not been previously reported. Objective: to characterize the active pharmaceutical ingredient named D003 in accordance to its ultraviolet (UV), infrared (FTIR), nuclear magnetic resonance (NMR) and mass (MS) spectra. Methods: samples of six batches of D-003 (CNIC, Cuba) were evaluated by UV, FTIR, NMR-¹H, NMR-13C, and GC-MS techniques. For obtaining the mass spectra of D-003 acids, methyl (FAME) and trimethylsilyl ester derivatives were used. Quantification of free very long chain saturated fatty acids , analyzed as methyl ester derivatives, was made by GC with flame ionisation detector (FID). Results: UV, FTIR, and ¹H-NMR, 13C-NMR spectra showed that active pharmaceutical ingredient D-003 was composed of a mixture of free very long chain fatty acids, whereas the GC-MS and GC-FID techniques allowed ensuring the occurrence of 13 VLCFAs in set proportions: C24:0 (0.2-0.6 percent), C25:0 (0.4-0.9 percent), C26:0 (2.0-3.1 percent), C27:0 (2.1-2.7 percent), C28:0 (30.0-37.5 percent), C29:0 (1.5-1.7 percent), C30:0 (17.0-18.6 percent), C31:0 (0.9-1.2 percent), C32:0 (6.9-8.9 percent), C33:0 (0.9-1.3 percent), C34:0 (7.2-11.1 percent), C35:0 (0.3-0.6 percent) and C36:0 (2.2-3.8 percent). Conclusions: evidences from the UV, FTIR, NMR and GC-MS spectroscopic techniques prove that D-003 is composed of 13 saturated very long chain fatty acids, including octacosanoic acid as the most abundant one(AU)

Efecto in vitro del D-003 sobre la actividad enzimática de la 5-lipoxigenasa (5-LOX) / Effect in vitro of D-003 on 5-lipooxygenase (5-LOX) enzyme activity

Introducción: el D-003, mezcla de ácidos alifáticos primarios superiores purificada de la cera de la caña, inhibe la síntesis de colesterol. Trabajos recientes han demostrado que el D-003 resulta efectivo en modelos experimentales de osteoartritis y que inhibe la actividad de las enzimas COX1 y COX2, preferentemente la COX1, sin producir gastrotoxicidad. Ha sido referido que los inhibidores duales de las enzimas COX y 5-LOX presentan efectos antinflamatorios desprovistos de gastrotoxicidad o que incluso, pueden resultar gastroprotectores. De acuerdo con estos antecedentes, el D-003 podría ser un inhibidor dual de dichas enzimas. Objetivo: investigar el efecto in vitro del D-003 sobre la actividad enzimática de la 5-LOX, utilizando la fracción citosólica de leucocitos polimorfonucleares de ratas. Métodos: se utilizaron las condiciones de ensayo siguientes: fracción citosólica (50 µg de proteína) disuelta en solución reguladora borato 0,2 mol/L (pH 9) y ácido linoleico (7,8-250 mmol/L) como sustrato, ensayándose muestras paralelas incubadas con Tween-20/H2O (2 por ciento) (vehículo), D-003 (0,6-6 000 µg/mL) o extracto de Perna canaliculus (50 µg/mL) (sustancia de referencia). Se evaluó la actividad enzimática mediante el cambio de absorbancia a 234 nm producido por la formación de dienos conjugados y medido en espectrofotómetro UV-visible. Resultados: la adición de D-003 produjo una inhibición dosis dependiente de la actividad enzimática de la 5-LOX (r= 0,975; p< 0,05) (CI50= 23,06 µg/mL) in vitro. La magnitud de esta inhibición fue moderada, ya que la inhibición máxima, alcanzada a partir de 1 250 µg/mL, resultó de solo un 30 por ciento. Conclusiones: el estudio demuestra que el D-003 es capaz de inhibir la actividad enzimática de la 5-LOX in vitro, pero moderadamente(AU)

Introduction: D-003, a mix of higher primary aliphatic acids purified from sugarcane, inhibits cholesterol synthesis. Recent studies have demonstrated that D-003 is effective in experimental models of osteoarthritis and inhibits the enzymatic activities of COX1 and COX2, mainly that of COX1, without causing gastrotoxicity. It has been mentioned that the dual inhibitors of COX and 5-LOX enzymes present with anti-inflammatory effects and no gastrotoxicity or even they can have gastroprotective actions. According to this background, D-003 could be a dual inhibitor of COX and 5-LOX enzymes. Objective: to study the effects of D-003 on the enzymatic activity of 5-LOX in vitro, by using the cytosolic fraction of polymorphonuclear leukocytes of rats. Methods: the following testing conditions were used: cytosolic fraction (50 µg of protein) dissolved into 0,2 mol/L borate buffer solution (pH 9) and linoleic acid (7,8-250 mmol/L) as substrate. Parallel samples were incubated with Tween-20/H2O (2 percent) only (vehicle), D-003 (0,6-6 000 µg/mL) or green-lipped mussel (Perna canaliculus) extract (50 µg/mL) (reference substance). The enzymatic activity, evaluated by the conjugated diene formation, was assessed by the absorbance changes at 234 nm (5-LOX) measured in a UV-visible spectrophotometer. Results: by adding D-003, produced a dose dependent (r= 0,975; p< 0,05) (IC50= 23,06 µg/mL) in vitro inhibition of 5-LOX enzyme activity. The size of the inhibition was moderate, since the maximal inhibition, achieved from 1 250 µg/mL) on was only 30 percent. Conclusions: this study demonstrates that D-003 may inhibit in vitro the 5-LOX enzymatic activity, but in a moderate way(AU)

Efectos del D-003 sobre el perfil lipídico y la agregación plaquetaria en pacientes con diabetes tipo 2 / Effects of D-003 on lipid profile and platelet aggregation of type 2 diabetic patients

Los eventos coronarios constituyen la primera causa de muerte en sujetos con diabetes mellitus tipo 2. Un incremento en la agregación plaquetaria y altos niveles de colesterol asociado a la lipoproteína de baja densidad (C-LDL) contribuyen al riesgo coronario en diabéticos. El D-003, una mezcla de ácidos grasos obtenida de la caña de azúcar, ha mostrado reducir la agregación plaquetaria y los niveles séricos de C-LDL en sujetos normo e hipercolesterolémicos. Este estudio a doble ciego, controlado con placebo, investigó los efectos del D-003 sobre la agregación plaquetaria y el perfil lipídico en 50 diabéticos tipo 2, los que fueron aleatorizados para recibir después de un periodo inicial, D-003 (10 mg/día) o placebo por 10 semanas. Todos los sujetos completaron el estudio. El D-003 redujo significativamente la agregación plaquetaria inducida por ácido araquidónico (52,9%) y por colágeno (54,4%) y los niveles séricos de C-LDL (26,7%), colesterol total (CT) (19,6%) y triglicéridos (23,9%), mientras que incrementó el C-HDL (12,4%) en relación a los niveles básales y al grupo placebo. El D-003 fue seguro y bien tolerado. Se concluye que el D-003 redujo significativamente la agregación plaquetaria y los niveles séricos de C-LDL en pacientes con diabetes tipo 2, pero otros estudios deben confirmar estos resultados.

Coronan/ events are the leading cause of death in subjects with type 2 diabetes, and increased platelet aggregation and serum low-density lipoprotein-cholesterol (C-LDL) contribute to coronary risk in diabetes patients. D-003, a mixture of sugarcane wax acids, has shown to reduce platelet aggregation and serum C-LDL in normocholesterolemic and hypercholesterolemic subjects. This doubleblinded, placebo-controlled study investigated the effects of D-003 on platelet aggregation and lipid profile in 50 type 2 diabetes patients who were randomized, after a baseline phase, to D-003 (10 mg/d) or placebo for 10 weeks. Al I the subjects completed the study. D-003 significantly lowered arachidonic acid- (52.9%) and collagen-induced (54.4%) platelet aggregation, C-LDL (26-7%), total cholesterol (TC) (19.6%) and triglycerides (23.9%), while increased high-density lipoprotein-cholesterol (C-HDL) (12.4%) vs baseline and placebo. D-003 was safe and well tolerated. To conclude with, D-003 significantly reduced platelet aggregation and serum C-LDL in type 2 diabetes, but further studies should confirm these results.

A Case of Successful Combination Therapy of Systemic Steroid and Topical 0.03% Tacrolimus for Pyoderma Gangrenosum in a Patient with Myelodysplastic Syndrome / 대한피부과학회지

Pyoderma gangrenosum is one of the neutrophilic dermatoses, which is usually related to many systemic diseases such as inflammatory bowel diseases, hematologic diseases, etc. Its typical clinical feature is usually a solitary, painful, margin-elevated ulcer. We herein report a case of myelodysplastic syndrome-related pyoderma gangrenosum, treated with a combination therapy of systemic steroid and topical 0.03% tacrolimus oint.

Hypoglycemic effect and its mechanism of novel compound G-003 / 中国药理学通报

Aim To study the hypoglycemic effect and the mechanism of novel sulfonyluric compound G-003. Methods ① After compound G-003 was givenig for 7 days, the levels of fasting plasma glucose of normal mouse was assayed with glucose oxidase kit. ② Rat pancreatic islets, adipocytes and mouse heaptocytes were isolated and cultured. Effects of compound G-003 on insulin release, glucose transport and utilization and glycogen synthesis were studied. Results Compound G-003 markedly decreased the levels of fasting plasma glucose of normal mouse, stimulated isolated pancreatic rat islets to release insulin and increased glucose transport and utilization in isolated rat adipocytes. Compound G-003 has no effect on glycogen synthesis in isolated mouse hepatocytes. Conclusion Compound G-003 has a significantly hypoglycemic effect. The hypoglycemic mechanism of novel compound G-003 may be attributed to stimulate secretion of insulin and increase glucose transport and utilization.