Effects of regular exercise plus food restriction on left ventricular pathological remodeling in heart failure­induced rats.

BACKGROUND: Cardiac remodeling is the main pathophysiological process leading to heart failure. Exercise and food restriction have been shown to exert some profound physiological benefits. OBJECTIVES: This study investigated the effects of exercise plus food restriction (FR) on rat left ventricular remodeling. METHODS: Fifty male rats were randomly divided into 5 groups. 1) Sham (saline injection), 2) ISO (isoproterenol injection), 3) FR+ ISO (8 weeks with 60 % food restriction and then isoproterenol injection), 4) E+ISO (run-in period of 4 weeks on treadmill and then isoproterenol injection), and 5) FR+E+ISO. Serum levels of creatine kinase, nitric oxide, gene expression of microtubule-associated protein 1 light chain 3-I and II, Beclin-1, Bax and Bcl2 and TUNEL staining were investigated. RESULTS: ISO increased the plasma CK-MB level, gene expression of Bax and TUNEL­positive cells in left ventricle and at the same time, decreased the serum level of NO. Regular exercise plus food restriction enhanced the expression of LC3B-II, Beclin-1, Bcl2 genes and elevated LC3B-II / LC3B-Ι, while decreasing the gene expression of Bax and TUNEL­positive cells in the left ventricle. CONCLUSION: Our results propose that exercise plus food restriction is more effective than either therapy alone for possibly preserving cardiac internal defenses against heart failure consequences and remodeling (Tab. 2, Fig. 3, Ref. 20).

Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome.

Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology.

Witches'-Broom Disease of Lime Affects Seed Germination and Seedling Growth But Is Not Seed Transmissible.

Witches'-broom disease of lime (WBDL), caused by 'Candidatus Phytoplasma aurantifolia', has devastated many Mexican lime orchards and is currently a threat to lime production in neighboring provinces of southern Iran. Several reports have suggested transmission and spread of WBDL phytoplasma through the seed of infected plants. In the present study, claims of seed transmission of this phytoplasma were examined. Fruit were collected from infected trees in the infested areas of Minab (Hormozgan Province) and from symptomless trees in noninfested areas. Lime seed from symptomless and witches'-broom-affected trees were sown in separate beds in an insect-proof screenhouse and the resulting seedlings were examined for phytoplasmal infection. Leaf, stem, and root samples were collected from both groups of seedlings every 3 months for 2 years and tested for WBDL phytoplasma using direct and nested polymerase chain reaction (PCR). Repeated PCR tests on the seedlings did not reveal the presence of phytoplasmal DNA. Likewise, symptoms of the disease were not observed on these seedlings after 2 years. PCR assays detected the phytoplasma in coats of some seed from infected trees; however, no excised embryos were positive for the phytoplasma. All positive PCR results were confirmed by restriction fragment length polymorphism assay. One-year-old seedlings derived from seed of noninfected plants appeared more vigorous in terms of height, number of leaves, and fresh weight of shoot compared with those from infected trees. The germination percentage, mean daily germination, peak value, and germination value were significantly higher for seed of fruit from noninfected trees and seed from fruit on asymptomatic branches of infected trees than those from fruit on symptomatic branches of infected trees.

Development of a Gas Empowered Drug Delivery system for peptide delivery in the small intestine.

The aim of this investigation was to design a novel Gas Empowered Drug Delivery (GEDD) system for CO(2) forced transport of peptide drugs together with mucoadhesive polymers to the surface of the small intestine. The GEDD effect of the core tablet was achieved using CO(2) gas to push insulin together with the mucoadhesive excipients poly(ethyleneoxide) (PEO) and the permeation enhancer trimethyl chitosan (TMC) to the surface of the small intestine. The in-vitro insulin release showed that almost 100% of the insulin was released from enterically coated tablets within 30 min at pH 6.8. The designed GEDD system was shown to increase the insulin transport by approximately 7 times in comparison with the free insulin across sheep's intestine ex-vivo. Three different peroral formulations were administered to male rabbits: F1 containing no TMC or PEO, F2 containing PEO but no TMC and F3 containing both PEO and TMC. The administrations of insulin using the formulation F1 resulted in a low FR value of 0.2%+/-0.1%, while the formulations F2 and F3 resulted in a much higher FR values of 0.6+/-0.2% and 1.1%+/-0.4%, respectively. Hence, the insulin permeation achieved by the GEDD system is primarily due to the enhancing effect of TMC and the mucoadhesive properties of PEO both of which synergistically increase the bioavailability of insulin.

Importance of timing of magnesium administration in the isolated ischemic-reperfused rat heart: role of K(ATP) channels.

There is a growing interest for the beneficial effect of magnesium (Mg) in cardiovascular disorders. A number of cardiovascular disorders including myocardial infarction, arrhythmias and congestive heart failure have been associated with low extra- cellular or intracellular concentrations of Mg. The efficiency of the preconditioning effect of Mg on cardiac function and infarct size in the globally ischemic-reperfused isolated rat heart was studied together with the role of ATP-sensitive potassium (K(ATP)) channels in protection induced by Mg. Rat hearts were Langendorff perfused, subjected to 30 min of global ischemia and 90 min of reperfusion, including treatment groups which focused on different times of Mg (8 mmol/l) use. Infarct size was measured by triphenyltetrazolium chloride (TTC) method. The left ventricular function was assessed by left ventricular developed pressure (LVDP), heart rate (HR) and coronary flow (CF). The administration of Mg before ischemia had an anti-infarct effect in rat hearts and improved cardiac function. The protective effects of magnesium was abolished by the blocking of K(ATP) channels and suggests that K-ATP channel has an important role in the heart protection effect of Mg as a preconditioning agent.

Antisense transcription in the mammalian transcriptome.

Antisense transcription (transcription from the opposite strand to a protein-coding or sense strand) has been ascribed roles in gene regulation involving degradation of the corresponding sense transcripts (RNA interference), as well as gene silencing at the chromatin level. Global transcriptome analysis provides evidence that a large proportion of the genome can produce transcripts from both strands, and that antisense transcripts commonly link neighboring "genes" in complex loci into chains of linked transcriptional units. Expression profiling reveals frequent concordant regulation of sense/antisense pairs. We present experimental evidence that perturbation of an antisense RNA can alter the expression of sense messenger RNAs, suggesting that antisense transcription contributes to control of transcriptional outputs in mammals.

Anti-infarct effect of magnesium is not mediated by adenosine A1 receptors in rat globally ischaemic isolated hearts.

1. The aim of present study was to investigate the effects of magnesium (Mg) on cardiac function and infarct size and to compare it effects with those of adenosine. The mechanism of Mg-mediated cardioprotection was explored by combined use of Mg and a selective adenosine A(1) receptor antagonist. 2. Rat isolated hearts were used for Langendorff perfusion. Hearts were either non-preconditioned or preconditioned with Mg (6 mmol/L) or adenosine (1 mmol/L) before 30 min sustained ischaemia followed by 120 min reperfusion. Within each of these protocols, hearts were divided into two groups; one group was exposed to the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 200 nmol/L). Infarct size was measured by the triphenyltetrazolium chloride method. Left ventricular function was assessed by left ventricular developed pressure (LVDP), the product of heart rate x LVDP and coronary flow (CF). 3. The administration of Mg had an anti-infarct effect independent of its effect on postischaemic functional recovery in rats. Both Mg and adenosine equipotently reduced infarct size, but this effect of Mg was not blocked by the simultaneous administration of DPCPX. Cardiac function was improved by both adenosine and Mg and blockade of adenosine A(1) receptors attenuated these effects for both agents. 4. In conclusion, the results of the present study indicate that stimulation of adenosine A(1) receptors is not responsible for the anti-infarct effect of Mg in ischaemic myocardium in rats, but that the Mg-mediated protection of postischaemic functional recovery in rats is mediated by these receptors.

Primary sclerosing cholangitis.

Two new cases of primary sclerosing cholangitis with a rapid fatal course, particularly the patient in Case 2, are presented. Primary sclerosing cholangitis is a rare condition of unknown cause presenting with extrahepatic biliary obstruction due to a chronic inflammatory obliterative process with the absence of stones, cancer, or previous biliary surgery. This condition is often associated with ulcerative colitis, retroperitoneal fibrosis, and Riedel's thyroiditis. Surgical treatment for promoting bile drainage and long-term corticosteroid therapy are effective palliative measures.