The alpha-1A adrenergic receptor agonist A61603 reduces cardiac polyunsaturated fatty acid and endocannabinoid metabolites associated with inflammation in vivo

Introduction

Alpha-1-adrenergic receptors (α1-ARs) are G-protein coupled receptors (GPCRs) with three highly homologous subtypes (α1A, α1B, and α1D). Of these three subtypes, only the α1A and α1B are expressed in the heart. Multiple pre-clinical models of heart injury demonstrate cardioprotective roles for the α1A. Non-selective α1-AR activation promotes glycolysis in the heart, but the functional α1-AR subtype and broader metabolic effects have not been studied.

Objectives

Given the high metabolic demands of the heart and previous evidence indicating benefit from α1A activation, we chose to investigate the effects of α1A activation on the cardiac metabolome in vivo.

Methods

Mice were treated for 1 week with a low, subpressor dose of A61603, a highly selective and potent α1A agonist. Cardiac tissue and serum were analyzed using a non-targeted metabolomics approach.

Results

We identified previously unrecognized metabolic responses to α1A activation, most notably broad reduction in the abundance of polyunsaturated fatty acids (PUFAs) and endocannabinoids (ECs).

Conclusion

Given the well characterized roles of PUFAs and ECs in inflammatory pathways, these findings suggest a possible role for cardiac α1A-ARs in the regulation of inflammation and may offer novel insight into the mechanisms underlying the cardioprotective benefit of selective pharmacologic α1A activation.

     

Next-generation bis-locked nucleic acids with stacking linker and 2′-glycylamino-LNA show enhanced DNA invasion into supercoiled duplexes

Targeting and invading double-stranded DNA with synthetic oligonucleotides under physiological conditions remain a challenge. Bis-locked nucleic acids (bisLNAs) are clamp-forming oligonucleotides able to invade into supercoiled DNA via combined Hoogsteen and Watson–Crick binding. To improve the bisLNA design, we investigated its mechanism of binding. Our results suggest that bisLNAs bind via Hoogsteen-arm first, followed by Watson–Crick arm invasion, initiated at the tail. Based on this proposed hybridization mechanism, we designed next-generation bisLNAs with a novel linker able to stack to adjacent nucleobases, a new strategy previously not applied for any type of clamp-constructs. Although the Hoogsteen-arm limits the invasion, upon incorporation of the stacking linker, bisLNA invasion is significantly more efficient than for non-clamp, or nucleotide-linker containing LNA-constructs. Further improvements were obtained by substituting LNA with 2′-glycylamino-LNA, contributing a positive charge. For regular bisLNAs a 14-nt tail significantly enhances invasion. However, when two stacking linkers were incorporated, tail-less bisLNAs were able to efficiently invade. Finally, successful targeting of plasmids inside bacteria clearly demonstrates that strand invasion can take place in a biologically relevant context.     

Lung injury-induced skeletal muscle wasting in aged mice is linked to alterations in long chain fatty acid metabolism

Introduction

Older patients are more likely to acquire and die from acute respiratory distress syndrome (ARDS) and muscle weakness may be more clinically significant in older persons. Recent data implicate muscle ring finger protein 1 (MuRF1) in lung injury-induced skeletal muscle atrophy in young mice and identify an alternative role for MuRF1 in cardiac metabolism regulation through inhibition of fatty acid oxidation.

Objectives

To develop a model of lung injury-induced muscle wasting in old mice and to evaluate the skeletal muscle metabolomic profile of adult and old acute lung injury (ALI) mice.

Methods

Young (2 month), adult (6 month) and old (20 month) male C57Bl6 J mice underwent Sham (intratracheal H₂O) or ALI [intratracheal E. coli lipopolysaccharide (i.t. LPS)] conditions and muscle functional testing. Metabolomic analysis on gastrocnemius muscle was performed using gas chromatography-mass spectrometry (GC–MS).

Results

Old ALI mice had increased mortality and failed to recover skeletal muscle function compared to adult ALI mice. Muscle MuRF1 expression was increased in old ALI mice at day 3. Non-targeted muscle metabolomics revealed alterations in amino acid biosynthesis and fatty acid metabolism in old ALI mice. Targeted metabolomics of fatty acid intermediates (acyl-carnitines) and amino acids revealed a reduction in long chain acyl-carnitines in old ALI mice.

Conclusion

This study demonstrates age-associated susceptibility to ALI-induced muscle wasting which parallels a metabolomic profile suggestive of altered muscle fatty acid metabolism. MuRF1 activation may contribute to both atrophy and impaired fatty acid oxidation, which may synergistically impair muscle function in old ALI mice.

     

Untargeted metabolomics analysis of ischemia–reperfusion-injured hearts ex vivo from sedentary and exercise-trained rats

Introduction

The effects of exercise on the heart and its resistance to disease are well-documented. Recent studies have identified that exercise-induced resistance to arrhythmia is due to the preservation of mitochondrial membrane potential.

Objectives

To identify novel metabolic changes that occur parallel to these mitochondrial alterations, we performed non-targeted metabolomics analysis on hearts from sedentary and exercise-trained rats challenged with isolated heart ischemia–reperfusion injury (I/R).

Methods

Eight-week old Sprague–Dawley rats were treadmill trained 5 days/week for 6 weeks (exercise duration and intensity progressively increased to 1 h at 30 m/min up a 10.5% incline, 75–80% VO_2max). The recovery of pre-ischemic function for sedentary rat hearts was 28.8?±?5.4% (N?=?12) compared to exercise trained hearts, which recovered 51.9%?±?5.7 (N?=?14) (p?<?0.001).

Results

Non-targeted GC–MS metabolomics analysis of (1) sedentary rat hearts; (2) exercise-trained rat hearts; (3) sedentary rat hearts challenged with global ischemia–reperfusion (I/R) injury; and (4) exercise-trained rat hearts challenged with global I/R (10/group) revealed 15 statistically significant metabolites between groups by ANOVA using Metaboanalyst (p?<?0.001). Enrichment analysis of these metabolites for pathway-associated metabolic sets indicated a?>?10-fold enrichment for ammonia recycling and protein biosynthesis. Subsequent comparison of the sedentary hearts post-I/R and exercise-trained hearts post-I/R further identified significant differences in three metabolites (oleic acid, pantothenic acid, and campesterol) related to pantothenate and CoA biosynthesis (p?≤?1.24E?05, FDR?≤?5.07E?4).

Conclusions

These studies shed light on novel mechanisms in which exercise-induced cardioprotection occurs in I/R that complement both the mitochondrial stabilization and antioxidant mechanisms recently described. These findings also link protein synthesis and protein degradation (protein quality control mechanisms) with exercise-linked cardioprotection and mitochondrial susceptibility for the first time in cardiac I/R.

     

The use of one-bead one-compound combinatorial library method to identify peptide ligands for α4β1 integrin receptor in non-Hodgkin's lymphoma

Summary Using a ‘one-bead one-compound’ combinatorial library method and whole cell binding assay, we have identified peptide ligands that bind preferentially to human lymphoid malignant cells but not to normal human peripheral lymphocytes. These peptides have a common motif of Leu-Asp-Ile, Leu-Asp-Phe, or Leu-Asp-Val. Anti-α4 integrin antibody blocks binding of cells to these peptides which indicates that the target receptor for these peptides is α4β1 integrin. These findings may have important therapeutic and diagnostic implications in the treatment of lymphoma, leukemia, and various immunologic disorders.     

Citrus Leafminer Management: Jasmonic Acid versus Efficient Pesticides

The citrus leafminer (Phyllocnistis citrella Stainton) is a significant pest for Citrus spp. worldwide. Hence, the effectiveness of jasmonic acid (JA) was compared to three pesticides, abamectin, thiamethoxam, and acetamiprid, against P. citrella infesting mandarin (Citrus reticulata L.) and lime (C. aurantifolia L.) seedlings. Mortality rate was significantly different due to JA and other pesticides treatments. Moreover, on the 3rd day after treatment, JA demonstrated the highest reduction percentage of leafminer (77.08 and 33.33%) on mandarin and lime, respectively. By the 10th day after treatment, JA and abamectin displayed 100% reduction in both plant species. Furthermore, the foliar application of JA enhanced the most vegetative characteristics in the treated seedlings, including growth rate (shoot length/root length), fresh and dry weights of shoot and root as well as the number of leaves/seedling. Moreover, soluble protein content was increased significantly under JA treatment in the two Citrus spp. Jasmonic acid showed a good biological activity, which gives a practical reason to recommend it to be integrated in pest management programs as an alternative product for controlling P. citrella.

     

Increased genetic differentiation in a specialist versus a generalist bee: implications for conservation

Oligolectic bees are specialists that collect pollen from one or a few closely related species of plants, while polylectic bees are generalists that collect pollen from both related and unrelated species of plants. Because of their more restricted range of floral hosts, it is expected that specialists persist in more isolated populations than do generalists. We present data on the population structure of two closely related bee species sampled from a super abundant floral host in the southern Atacama Desert. Pairwise comparisons of population subdivision over identical distances revealed that the specialist bee had significantly more differentiated populations in comparison to the generalist. Further, populations of the specialist had significantly less genetic variation, measured as observed and expected heterozgyosity, than those of the generalist. Our data support the hypothesis of decreased gene flow among populations of the specialist bee even at equivalent geographic distances. The resulting reductions in effective population size for specialists make them particularly prone to extinction due to both demographic and genetic reasons. Our findings have important implications for the conservation of bees and other specialist insects. Deceased     

Genetic polymorphism of Algerian Leishmania infantum strains revealed by multilocus microsatellite analysis

The present study applies multilocus microsatellite typing (MLMT) for studying the polymorphism among 55 strains of Leishmania infantum from Algeria. These strains from different Algerian foci representing different zymodemes, hosts and clinical forms were analysed using 14 microsatellite markers. All 55 strains had individual MLMT profiles and no relationship was observed between them and different host or geographical origins. Three populations of Algerian L. infantum were identified by a Bayesian clustering approach implemented in STRUCTURE software and supported by genetic distance analysis. Two populations, A and B, consisted mainly of strains belonging to zymodeme MON-1, and the third population, C, mainly of MON-24 strains isolated from cutaneous leishmaniasis cases. Interestingly, a small group of strains appeared as a mixture of different populations and might be putative hybrids. Genetic migration was noticed among the two MON-1 populations, A and B, as well as between populations A and C. Due to its high discriminatory power MLMT could be also successfully applied for differentiating relapses or re-infection for patients suffering from multiple episodes of visceral leishmaniasis.     

Efficacy of Hospital at Home in Patients with Heart Failure: A Systematic Review and Meta-Analysis

Background

Heart failure (HF) is the commonest cause of hospitalization in older adults. Compared to routine hospitalization (RH), hospital at home (HaH)—substitutive hospital-level care in the patient’s home—improves outcomes and reduces costs in patients with general medical conditions. The efficacy of HaH in HF is unknown.

Methods and Results

We searched MEDLINE, Embase, CINAHL, and CENTRAL, for publications from January 1990 to October 2014. We included prospective studies comparing substitutive models of hospitalization to RH in HF. At least 2 reviewers independently selected studies, abstracted data, and assessed quality. We meta-analyzed results from 3 RCTs (n = 203) and narratively synthesized results from 3 observational studies (n = 329). Study quality was modest. In RCTs, HaH increased time to first readmission (mean difference (MD) 14.13 days [95% CI 10.36 to 17.91]), and improved health-related quality of life (HrQOL) at both, 6 months (standardized MD (SMD) -0.31 [-0.45 to -0.18]) and 12 months (SMD -0.17 [-0.31 to -0.02]). In RCTs, HaH demonstrated a trend to decreased readmissions (risk ratio (RR) 0.68 [0.42 to 1.09]), and had no effect on all-cause mortality (RR 0.94 [0.67 to 1.32]). HaH decreased costs of index hospitalization in all RCTs. HaH reduced readmissions and emergency department visits per patient in all 3 observational studies.

Conclusions

In the context of a limited number of modest-quality studies, HaH appears to increase time to readmission, reduce index costs, and improve HrQOL among patients requiring hospital-level care for HF. Larger RCTs are necessary to assess the effect of HaH on readmissions, mortality, and long-term costs.