PharmOmics: A species- and tissue-specific drug signature database and gene-network-based drug repositioning tool.

Drug development has been hampered by a high failure rate in clinical trials due to our incomplete understanding of drug functions across organs and species. Therefore, elucidating species- and tissue-specific drug functions can provide insights into therapeutic efficacy, potential adverse effects, and interspecies differences necessary for effective translational medicine. Here, we present PharmOmics, a drug knowledgebase and analytical tool that is hosted on an interactive web server. Using tissue- and species-specific transcriptome data from human, mouse, and rat curated from different databases, we implemented a gene-network-based approach for drug repositioning. We demonstrate the potential of PharmOmics to retrieve known therapeutic drugs and identify drugs with tissue toxicity using in silico performance assessment. We further validated predicted drugs for nonalcoholic fatty liver disease in mice. By combining tissue- and species-specific in vivo drug signatures with gene networks, PharmOmics serves as a complementary tool to support drug characterization and network-based medicine.

Disparate Metabolomic Responses to Fructose Consumption between Different Mouse Strains and the Role of Gut Microbiota.

High fructose consumption has been linked to metabolic syndrome, yet the fructose-induced phenotypes, gene expression, and gut microbiota alterations are distinct between mouse strains. In this study, we aim to investigate how fructose consumption shapes the metabolomic profiles of mice with different genetic background and microbiome. We used fructose-sensitive DBA/2J (DBA) and fructose-resistant C57BL/6J (B6) mice given 8% fructose or regular water for 12 weeks. Plasma and fecal metabolites were profiled using a liquid chromatography-tandem mass spectrometry based global metabolomic approach. We found that the baseline metabolomic profiles were different between DBA and B6 mice, particularly plasma metabolites involved in lipid metabolism and fecal metabolites related to dipeptide/amino acid metabolism. In response to fructose, DBA mice showed a distinct decrease of plasma branched chain fatty acids with concordantly increased branched chain amino acids, which were correlated with adiposity; B6 mice had significantly increased plasma cholesterol and total bile acids, accompanied by decreased fecal levels of farnesoid X receptor antagonist tauro-ß-muricholate, which were correlated with fructose-responsive bacteria Dehalobacterium, Magibacteriaceae, and/or Akkermansia. Our results demonstrate that baseline metabolomic profiles differ and respond differentially to fructose between mice with different genetic background and gut microbiota, which may play a role in individualized risks to fructose-induced metabolic syndrome.

Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to Fructose Consumption in Mice.

BACKGROUND: It is unclear how high fructose consumption induces disparate metabolic responses in genetically diverse mouse strains. OBJECTIVE: We aimed to investigate whether the gut microbiota contributes to differential metabolic responses to fructose. METHODS: Eight-week-old male C57BL/6J (B6), DBA/2J (DBA), and FVB/NJ (FVB) mice were given 8% fructose solution or regular water (control) for 12 wk. The gut microbiota composition in cecum and feces was analyzed using 16S ribosomal DNA sequencing, and permutational multivariate ANOVA (PERMANOVA) was used to compare community across mouse strains, treatments, and time points. Microbiota abundance was correlated with metabolic phenotypes and host gene expression in hypothalamus, liver, and adipose tissues using Biweight midcorrelation. To test the causal role of the gut microbiota in determining fructose response, we conducted fecal transplants from B6 to DBA mice and vice versa for 4 wk, as well as gavaged antibiotic-treated DBA mice with Akkermansia for 9 wk, accompanied with or without fructose treatment. RESULTS: Compared with B6 and FVB, DBA mice had significantly higher Firmicutes to Bacteroidetes ratio and lower baseline abundance of Akkermansia and S24-7 (P < 0.05), accompanied by metabolic dysregulation after fructose consumption. Fructose altered specific microbial taxa in individual mouse strains, such as a 7.27-fold increase in Akkermansia in B6 and 0.374-fold change in Rikenellaceae in DBA (false discovery rate <5%), which demonstrated strain-specific correlations with host metabolic and transcriptomic phenotypes. Fecal transplant experiments indicated that B6 microbes conferred resistance to fructose-induced weight gain in DBA mice (F = 43.1, P < 0.001), and Akkermansia colonization abrogated the fructose-induced weight gain (F = 17.8, P < 0.001) and glycemic dysfunctions (F = 11.8, P = 0.004) in DBA mice. CONCLUSIONS: Our findings support that differential microbiota composition between mouse strains is partially responsible for host metabolic sensitivity to fructose, and that Akkermansia is a key bacterium that confers resistance to fructose-induced metabolic dysregulation.

Enhanced external counterpulsation for the treatment of angina pectoris.

The treatment of refractory chronic angina pectoris presents an increasing problem for all physicians caring for patients with coronary artery disease because of the large number of individuals who have either failed multiple revascularization procedures or are not appropriate candidates for such procedures. The aim of this study was to review the safety, efficacy, and clinical applicability of a noninvasive technique (external counterpulsation) for the treatment of angina pectoris. A MEDLINE search for all English language abstracts, meeting presentations, journal articles, and reviews from 1960 through December 2005 was conducted. Of the 194 citations in the literature, 60 appeared before 1983 when the enhanced version of the technique (the one that is presently used) was first reported. Criteria for further evaluation of the 134 post-1983 citations were either (1) randomized trial, (2) observational study of at least 10 patients, or (3) investigations into possible mechanisms. Of the 134 citations, 45 were used for data extraction. Observational studies from the United States, Asia, and Europe have demonstrated improvement in symptoms, reduction in anginal episodes, better quality of life, and improved exercise performance in over 5000 patients. The only randomized study (Multicenter Study of Enhanced External Counterpulsation) confirmed these findings as well as the continuation of clinical benefits at least 1 year posttreatment. Although the mechanisms by which diastolic augmentation achieves these beneficial results are still under investigation, this is a promising noninvasive therapy in a group of patients with limited treatment options.

Silent myocardial ischemia: recent developments.

Silent myocardial ischemia is now in its fourth decade of recognition as a clinical syndrome within the spectrum of coronary artery disease. Prior decades have seen important research into the pathophysiology, detection, prevalence, prognosis, and therapy of this syndrome. More recent developments have continued to add data to each of these areas, with particular emphasis on the comparative value of various diagnostic procedures and the effect of therapy on prognosis. While controversy still exists concerning proper screening guidelines for the asymptomatic population, there is a growing consensus that some form of stress testing in high-risk individuals (ie, those with multiple coronary risk factors) is appropriate.

False aneurysm of the mitral-aortic intervalvular fibrosa after uncomplicated aortic valve replacement.

False aneurysms of the mitral-aortic intervalvular fibrosa are rare and usually complicate aortic valve endocarditis. We report a case of a false aneurysm of the mitral-aortic intervalvular fibrosa after recent bioprosthetic aortic valve replacement in the absence of endocarditis.

Carga isquêmica total: definiçäo, mecanismos e implicaçöes terapêuticas / Total ischemic load: definition, action mechanism, therapeutic implications

O conceito de carga isquêmica total inclui todos os tipos de isquemia englobando tanto episódio silenciosos como sintomáticos. Presentemente, este conceito está causando uma reavaliaçäo dos objetivos terapêuticos atuais para pacientes com doença cardíaca coronariana. Embora o mecanismo da dor cardíaca ainda näo esteja esclarecido, temos algumas informaçöes acerca de outros mecanismos patofisiológicos que atuam neste distúrbio. Pensamos em isquemia como ocorrendo secundariamente a uma diminuiçäo de suprimento (isquemia primária), aumento de demanda (isquemia secundária), ou uma combinaçäo dos dois fatores (isquemia mista). Devido ao fato da menor freqüência cardíaca estar sendo associada a muitos episódios de isquemia durante as atividade diárias, sugerindo que a vasoconstricçäo está desempenhamdo um papel de desequilíbrio na relaçäo oferta/demanda, os antagonistas do cálcio parecem ser particularmente úteis no tratamento da vasoconstricçäo em pacientes anginosos