Takotsubo Syndrome: Clinical Manifestations,Etiology and Pathogenesis

The purpose of the review is the analysis of clinical and experimental data on the etiology and pathogenesis of takotsubo syndrome (TS). TS is characterized by contractile dysfunction, which usually affects the apical region of the heart without obstruction of coronary artery, moderate increase in myocardial necrosis markers, prolonged QTc interval (in 50% of patients), sometimes elevation of ST segment (in 19% of patients), increase N-Terminal Pro-B-Type Natriuretic Peptide level, microvascular dysfunction, sometimes spasm of the epicardial coronary arteries (in 10% of patients), myocardial edema, and life-threatening ventricular arrhythmias (in 11% of patients). Stress cardiomyopathy is a rare disease, it is observed in 0.6 - 2.5% of patients with acute coronary syndrome. The occurrence of takotsubo syndrome is 9 times higher in women, who are aged 60-70 years old, than in men. The hospital mortality among patients with TS corresponds to 3.5% - 12%. Physical or emotional stress do not precede disease in all patients with TS. Most of patients with TS have neurological or mental illnesses. The level of catecholamines is increased in patients with TS, therefore, the occurrence of TS is associated with excessive activation of the adrenergic system. The negative inotropic effect of catecholamines is associated with the activation of β₂ adrenergic receptors. An important role of the adrenergic system in the pathogenesis of TS is confirmed by studies which were performed using ¹²⁵I-metaiodobenzylguanidine (¹²⁵I -MIBG). TS causes edema and inflammation of the myocardium. The inflammatory response in TS is systemic. TS causes impaired coronary microcirculation and reduces coronary reserve. There is a reason to believe that an increase in blood viscosity may play an important role in the pathogenesis of microcirculatory dysfunction in patients with TS. Epicardial coronary artery spasm is not obligatory for the occurrence of TS. Cortisol, endothelin-1 and microRNAs are challengers for the role of TS triggers. A decrease in estrogen levels is a factor contributing to the onset of TS. The central nervous system appears to play an important role in the pathogenesis of TS.     

Molecular pathways of liver regeneration: A comprehensive review

The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70% of its volume. Although knowledge of this phenomenon dates back to Greek mythology(the story of Prometheus), many aspects of liver regeneration are still not understood. A variety of different factors, including inflammatory cytokines, growth factors, and bile acids, promote liver regeneration and control the final size of the organ during typical regeneration, which is performed by mature hepatocytes, and during alternative regeneration, which is performed by recently identified resident stem cells called "hepatic progenitor cells". Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass, such as in cases of chronic injury or excessive acute injury. In liver maintenance, the body mass ratio is essential for homeostasis because the liver has numerous functions; therefore, a greater understanding of this process will lead to better control of liver injuries, improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases. The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries. Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.     

Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo

Aging tissues present a progressive decline in homeostasis and regenerative capacities, which has been associated with degenerative changes in tissue-specific stem cells and stem cell niches. We hypothesized that amino acids could regulate the stem cell phenotype and differentiation ability of human bone marrow-derived mesenchymal stromal cells (hBMSCs). Thus, we performed a screening of 22 standard amino acids and found that D-tryptophan (10 μM) increased the number of cells positive for the early stem cell marker SSEA-4, and the gene expression levels of OCT-4, NANOG, and SOX-2 in hBMSCs. Comparison between D- and L-tryptophan isomers showed that the latter presents a stronger effect in inducing the mRNA levels of Oct-4 and Nanog, and in increasing the osteogenic differentiation of hBMSCs. On the other hand, L-tryptophan suppressed adipogenesis. The migration and colony-forming ability of hBMSCs were also enhanced by L-tryptophan treatment. In vivo experiments delivering L-tryptophan (50 mg/kg/day) by intraperitoneal injections for three weeks confirmed that L-tryptophan significantly increased the percentage of cells positive for SSEA-4, mRNA levels of Nanog and Oct-4, and the migration and colony-forming ability of mouse BMSCs. L-kynurenine, a major metabolite of L-tryptophan, also induced similar effects of L-tryptophan in enhancing stemness and osteogenic differentiation of BMSCs in vitro and in vivo, possibly indicating the involvement of the kynurenine pathway as the downstream signaling of L-tryptophan. Finally, since BMSCs migrate to the wound healing site to promote bone healing, surgical defects of 1 mm in diameter were created in mouse femur to evaluate bone formation after two weeks of L-tryptophan or L-kynurenine injection. Both L-tryptophan and L-kynurenine accelerated bone healing compared to the PBS-injected control group. In summary, L-tryptophan enhanced the stemness and osteoblastic differentiation of BMSCs and may be used as an essential factor to maintain the stem cell properties and accelerate bone healing and/or prevent bone loss.     

Ethanol-induced activation of myosin light chain kinase leads to dysfunction of tight junctions and blood-brain barrier compromise

BACKGROUND: Brain endothelial cells form the blood-brain barrier (BBB) that regulates solute and macromolecule flux in and out of the brain, leukocyte migration, and maintains the homeostasis of the central nervous system. BBB dysfunction is associated with disruption of tight junctions (TJ) in the brain endothelium. We propose that alcohol abuse may impair BBB permeability through TJ modification. METHODS: Primary cultured bovine brain microvascular endothelial cells (BBMEC) were treated with 50 mM ethanol (EtOH), and monolayer tightness was assessed by measurement of transendothelial electrical resistance (TEER). Changes in TEER were correlated with alterations in TJ protein distribution [occludin, zonula occludens-1 (ZO-1), claudin-5] using immunofluorescence (IF). Expression of myosin light chain (MLC) kinase (MLCK), ZO-1, claudin-5, and phosphorylated MLC, occludin and claudin-5 were determined by immunoprecipitation and Western blot. EtOH-induced changes in monocyte migration across in vitro BBB constructs were also examined. RESULTS: EtOH induced a decrease in TEER of BBMEC monolayers that was reversed by EtOH withdrawal. Treatment of BBMEC with EtOH or its metabolite, acetaldehyde, prior to monocyte application resulted in a 2-fold increase in monocyte migration across the BBB. IF demonstrated decrease in claudin-5 staining, occludin translocation from cell borders to cytoplasm and gap formation in EtOH-treated BBMEC monolayer. These changes paralleled significant increase in phosphorylation of MLC, occludin and claudin-5. EtOH-treated BBMEC showed reduction of total occludin and claudin-5 without changes in ZO-1 or MLC. TEER decrease, changes in occludin/claudin staining, increase in MLC, occludin and claudin-5 phosphorylation and enhanced monocyte migration across the BBB were all reversed by inhibition of MLCK. Inhibition of EtOH metabolism in BBMEC also reversed these events. CONCLUSION: These results suggest that EtOH activates MLCK leading to phosphorylation of MLC, occludin and claudin-5. Cytoskeletal alterations (MLC) and TJ changes (occludin and claudin-5 phosphorylation) result in BBB impairment (decrease in TEER). TJ compromise is associated with increased monocyte migration across the BBB.     

Factor analysis of lifestyle-related factors in 12,525 urban Japanese subjects

This study describes the clustering patterns of several lifestyle-related factors in urban Japanese subjects. The effect of aging on these patterns was also investigated. Data of 8 factors that included body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLc), gamma-glutamyl-transferase (GGT), and cigarette smoking were analyzed for 12,525 individuals (4,591 men and 7,934 women) aged either 40, 50, or 60 years. Factor analysis showed eight factors clustered into 3 unrelated groups. BMI and BP were excluded in subjects aged 60 years. Our data showed that the effect of obesity on the prevalence of type 2 diabetes mellitus was age dependent. In spite of the established inverse relationship between TG and HDLc, we found that TG had an association with GGT. These results indicated that aging may have a major influence on the expression of multiple risk factors. The influence of BMI on the lifestyle-related factors appeared to be mostly expressed in younger people, while these factors appeared to be independent of BMI at age 60.     

Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis

Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. IDO activity is linked with immunosuppression by its ability to inhibit lymphocyte proliferation, and with neurotoxicity through the generation of quinolinic acid and other toxins. IDO is induced in macrophages by HIV-1 infection, and it is up regulated in macrophages in human brain tissue with HIV-1 encephalitis (HIVE). Using a model of HIVE, we investigated whether IDO inhibitor 1-methyl-d-tryptophan (1-MT) could affect the generation of cytotoxic T lymphocytes (CTLs) and clearance of virus-infected macrophages from the brain. Severe combined immunodeficient mice were reconstituted with human peripheral blood lymphocytes, and encephalitis was induced by intracranial injection of autologous HIV-1-infected monocyte-derived macrophages (MDMs). Animals treated with 1-MT demonstrated increased numbers of human CD3+, CD8+, CD8+/interferon-gamma+ T cells, and HIV-1(gag/pol)-specific CTLs in peripheral blood compared with controls. At week 2 after MDM injection in the basal ganglia, mice treated with 1-MT showed a 2-fold increase in CD8+ T lymphocytes in the areas of the brain containing HIV-1-infected MDMs compared with untreated controls. By week 3, 1-MT-treated mice showed 89% reduction in HIV-infected MDMs in brain as compared with controls. Thus, manipulation of immunosuppressive IDO activity in HIVE may enhance the generation of HIV-1-specific CTLs, leading to elimination of HIV-1-infected macrophages in brain.