Circulating biomarkers of hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy assessed by cardiac magnetic resonance

Abstract

Background: Myocardial fibrosis in hypertrophic cardiomyopathy (HCM) is associated with worse clinical outcomes. The availability of circulating biomarkers of myocardial fibrosis and hypertrophy would be helpful in clinical practice.

Objective: The aim of this study was to evaluate usefulness of various biomarkers of myocardial fibrosis and hypertrophy in HCM.

Methods: Levels of biomarkers: soluble ST2 (sST2), galectin-3 (Gal-3), growth differentiation factor-15 (GDF-15), NT-proBNP and high-sensitivity cardiac troponin T (hs-cTnT) were measured in 60 patients with HCM. All patients underwent cardiac magnetic resonance imaging to calculate parameters of hypertrophy and fibrosis.

Results: We observed positive correlations among sST2 levels and left ventricular mass (LVM) (r?=?0.32, p?=?0.012), LV mass indexed for the body surface area (LVMI) (r?=?0.27, p?=?0.036) and maximal wall thickness (MWT) (r?=?0.31, p?=?0.015). No correlation was found between Gal-3 and GDF-15 levels and hypertrophy and fibrosis parameters. We observed positive correlations among hs-cTnT levels and LVM (r?=?0.58, p?<?0.0001), LVMI (r?=?0.48, p?=?0.0001), MWT (r?=?0.31, p?=?0.015) and late gadolinium enhancement (LGE) mass (r?=?0.37, p?=?0.003). There were positive correlations between NT-proBNP levels and LVM (r?=?0.33, p?=?0.01), LVMI (r?=?0.41, p?=?0.001), MWT (r?=?0.42, p?<?0.001) and LGE mass (r?=?0.44, p?<?0.001).

Conclusions: Although no correlation between sST2 levels and myocardial fibrosis was found, sST2 may provide some additional information about hypertrophy extension. NT-proBNP and hs-cTnT are useful biomarkers in assessment of hypertrophy and fibrosis in HCM.     

Trypsin inhibitors from the garden four o'clock (Mirabilis jalapa) and spinach (Spinacia oleracea) seeds: isolation, characterization and chemical synthesis

Five serine proteinase inhibitors (Mirabilis jalapa trypsin inhibitors, MJTI I and II and Spinacia oleracea trypsin inhibitors, SOTI I, II, and III) from the garden four-o'clock (M. jalapa) and spinach (S. oleracea) seeds were isolated. The purification procedures included affinity chromatography on immobilized methylchymotrypsin in the presence of 5M NaCl, ion exchange chromatography and/or preparative electrophoresis, and finally RP-HPLC on a C-18 column. The inhibitors, crosslinked by three disulfide bridges, are built of 35 to 37 amino-acid residues. Their primary structures differ from those of known trypsin inhibitors, but showed significant similarity to the antimicrobial peptides isolated from the seeds of M. jalapa (MJ-AMP1, MJ-AMP2), Mesembryanthemum crystallinum (AMP1), and Phytolacca americana (AMP-2 and PAFP-S) and from the hemolymph of Acrocinus longimanus (Alo-1, 2 and 3). The association equilibrium constants (K(a)) with bovine beta-trypsin for the inhibitors from M. jalapa (MJTI I and II) and S. oleracea (SOTI I-III) were found to be about 10(7)M(-1). Fully active MJTI I and SOTI I were obtained by solid-phase peptide synthesis. The disulfide bridge pattern in both inhibitors (Cys1-Cys4, Cys2-Cys5 and Cys3-Cys6) was established after their digestion with thermolysin and proteinase K followed by the MALDI-TOF analysis.     

Synthesis and Biological Activity of New 4‐tert‐Butylcyclohexanone Derivatives

In the synthesis performed in this study, derivatives of 4‐tert‐butylcyclohexanone 1 were obtained using typical reactions of organic synthesis. The bioactivity of the selected compounds was evaluated. 1‐(Bromomethyl)‐8‐tert‐butyl‐2‐oxaspiro[4.5]decan‐3‐one ( 5 ) was characterized by attractant properties against larvae and a weak feeding deterrent activity against adults of Alphitobius diaperinus Panzer . This bromolactone was a moderate antifeedant towards Myzus persicae Sulzer . In addition, ethyl (4‐tert‐butylcyclohexylidene)acetate ( 2 ) and bromolactone 5 displayed antibacterial activity. The strongest bacteriostatic effect was observed against Gram‐positive strains: Bacillus subtilis and Staphylococcus aureus. The bromolactone 5 also limited the growth of Escherichia coli strain.     

Effects of RuBisCO and CO2 concentration on cyanobacterial growth and carbon isotope fractionation

Carbon isotope biosignatures preserved in the Precambrian geologic record are primarily interpreted to reflect ancient cyanobacterial carbon fixation catalyzed by Form I RuBisCO enzymes. The average range of isotopic biosignatures generally follows that produced by extant cyanobacteria. However, this observation is difficult to reconcile with several environmental (e.g., temperature, pH, and CO₂ concentrations), molecular, and physiological factors that likely would have differed during the Precambrian and can produce fractionation variability in contemporary organisms that meets or exceeds that observed in the geologic record. To test a specific range of genetic and environmental factors that may impact ancient carbon isotope biosignatures, we engineered a mutant strain of the model cyanobacterium Synechococcus elongatus PCC 7942 that overexpresses RuBisCO across varying atmospheric CO₂ concentrations. We hypothesized that changes in RuBisCO expression would impact the net rates of intracellular CO₂ fixation versus CO₂ supply, and thus whole-cell carbon isotope discrimination. In particular, we investigated the impacts of RuBisCO overexpression under changing CO₂ concentrations on both carbon isotope biosignatures and cyanobacterial physiology, including cell growth and oxygen evolution rates. We found that an increased pool of active RuBisCO does not significantly affect the ¹³C/¹²C isotopic discrimination (ε_p) at all tested CO₂ concentrations, yielding ε_p of ≈ 23‰ for both wild-type and mutant strains at elevated CO₂. We therefore suggest that expected variation in cyanobacterial RuBisCO expression patterns should not confound carbon isotope biosignature interpretation. A deeper understanding of environmental, evolutionary, and intracellular factors that impact cyanobacterial physiology and isotope discrimination is crucial for reconciling microbially driven carbon biosignatures with those preserved in the geologic record.     

Multiproxy study of anthropogenic and climatic changes in the last two millennia from a small mire in central Poland

The Żabieniec kettle hole is the first peatland in central Poland analyzed quantitatively with four biotic proxies (plant macrofossils, pollen, testate amoebae and chironomids) to reconstruct the past environmental change. Palaeoecological data were supported by historical and archaeological records. We focused on autogenic vegetation change and human impact in relation to climatic effects. The aims of our study were (a) to describe the development history of the mire during the last 2,000 years, (b) to date and reconstruct the anthropogenic land-use changes and (c) to discuss a possible climatic signal in the peat archive. The combination of proxies revealed dramatic shifts that took place in the peatland since the Roman Period. Żabieniec was a very wet telmatic habitat until ca. AD 600. Then, the water table declined, and the site transformed into a Sphagnum-dominated mire. This dry shift took place mainly during the Early Medieval Period. Human impact was gradually increasing, and it was particularly emphasized by deforestation since AD 1250 (beginning of the Late Medieval Period). Consequently, surface run-off and aeolian transport from the exposed soils caused the eutrophication of the mire. Furthermore, chironomids and testate amoebae reveal the beginning of a wet shift ca. AD 1350. Openness considerably increased in the Late Medieval and the Modern Periods. The highest water table during the last 1,000 years was recorded between AD 1500 and 1800. This wet event is connected with deforestation, but it could be also associated with the Little Ice Age. Our study shows plant succession in the Żabieniec peatland, which can be explained with the recent landscape transformation. However, such changes are also possibly linked with the major climatic episodes during the last two millennia, such as the Medieval Warm Period and the Little Ice Age. Guest editors: K. Buczkó, J. Korponai, J. Padisák & S. W. Starratt Palaeolimnological Proxies as Tools of Environmental Reconstruction in Fresh Water     

Cretaceous roots of the amphisbaenian lizards

Amphisbaenians are highly specialized limbless burrowing lizards of controversial relationships. Among fossil lizards, the Eocene (47 Ma) Cryptolacerta is allegedly closest to the amphisbaenian ancestor, but this is put in doubt in this study. Similarities between Cryptolacerta and amphisbaenians, such as limb reduction and expansion of the skull roof, may be a result of parallel evolution. Instead, the Late Cretaceous lizard Slavoia with well‐developed limbs and several plesiomorphic skull characters is proposed to be the oldest known stem amphisbaenian. This is supported by two different phylogenetic analyses and observations on numerous specimens together representing almost the whole skeleton. Among the unique features, that Slavoia shares with amphisbaenians, the most significant are vomers strongly underlapping palatines and pterygoid quadrate ramus tightly wrapping around posteromedial surface of quadrate. The anatomy of Slavoia suggests that the reinforcement of the snout in amphisbaenian evolution preceded the elongation of the postorbital part of the skull, and that of the body, as well as modification of the limbs. Reduction of its hindlimbs was more advanced than that of the forelimbs. The ancient geological age of the central Asiatic Slavoia suggests that diversification of the main North American amphisbaenian groups may have resulted from a faunal dispersals from Asia after the Late Cretaceous.     

Immunotherapy: a way to improve the therapeutic outcome of photodynamic therapy?

Photodynamic therapy (PDT) is a treatment for cancer and non-cancerous lesions involving light and a sensitizing drug, a so-called photosensitizer. Photosensitizers for PDT usually accumulate in tumour tissues with some selectivity. Thus, malignant and abnormal cells can be destroyed by PDT which acts by producing singlet oxygen and possible other reactive oxygen species. However, the efficiency of PDT is often limited by shallow light penetration into tissue. In some cases one treatment modality cannot cure a patient because of treatment limitations and/or side effects. In recent years, many preclinical studies have indicated that the therapeutic outcome of PDT can be improved, doses and side effects lowered by combination with immunotherapy. Most experiments have been done with animals and cell lines. This review summarizes the current knowledge about different immunotherapeutic approaches which can be used to improve effectiveness and extend the applications of PDT in clinics.     

Disorders in NADPH generation via pentose phosphate pathway influence the reproductive potential of the Saccharomyces cerevisiae yeast due to changes in redox status

Intermediary metabolites have a crucial impact on basic cell functions. There is a relationship between cellular metabolism and redox balance. To maintain redox homoeostasis, the cooperation of both glutathione and nicotine adenine dinucleotides is necessary. Availability of nicotinamide adenine dinucleotide phosphate (NADPH) as a major electron donor is critical for many intracellular redox reactions. The activity of glucose-6-phosphate dehydrogenase (Zwf1p) and 6-phosphogluconate dehydrogenase (Gnd1p and Gnd2p) is responsible for NADPH formation in a pentose phosphate (PP) pathway. In this study, we examine the impact of redox homoeostasis on cellular physiology and proliferation. We have noted that the Δzwf1 mutant lacking the rate-limiting enzyme of the PP pathway shows changes in the cellular redox status caused by disorders in NADPH generation. This leads to a decrease in reproductive potential but without affecting the total lifespan of the cell. The results presented in this paper show that nicotine adenine dinucleotides play a central role in cellular physiology.     

Phosphonic Analogs of Alanine as Acylpeptide Hydrolase Inhibitors

Acylpeptide hydrolase is a serine protease, which, together with prolyl oligopeptidase, dipeptidyl peptidase IV and oligopeptidase B, belongs to the prolyl oligopeptidase family. Its primary function is associated with the removal of N-acetylated amino acid residues from proteins and peptides. Although the N-acylation occurs in 50–90 % of eukaryotic proteins, the precise functions of this modification remains unclear. Recent findings have indicated that acylpeptide hydrolase participates in various events including oxidized proteins degradation, amyloid β-peptide cleavage, and response to DNA damage. Considering the protein degradation cycle cross-talk between acylpeptide hydrolase and proteasome, inhibition of the first enzyme resulted in down-regulation of the ubiquitin-proteasome system and induction of cancer cell apoptosis. Acylpeptide hydrolase has been proposed as an interesting target for the development of new potential anticancer agents. Here, we present the synthesis of simple derivatives of (1-aminoethyl)phosphonic acid diaryl esters, phosphonic analogs of alanine diversified at the N-terminus and ester rings, as inhibitors of acylpeptide hydrolase and discuss the ability of the title compounds to induce apoptosis of U937 and MV-4-11 tumor cell lines.