The Radioprotective Activity of Resveratrol-Metabolomic Point of View.

Resveratrol, a plant-derived polyphenol, is an intensively studied compound with widely documented positive effects on health. Antioxidant activity is the property most often mentioned as responsible for its beneficial effects. Therefore, since the adverse effect of ionizing radiation is primarily related to the induction of oxidative stress, the question arises of whether the use of resveratrol could have a radioprotective effect. This paper summarizes the data on the cytoprotective activity of resveratrol and pieces of evidence for the potential interplay between response to radiation and resveratrol activity. The paper focuses on changes in the metabolic profile of cells and organisms induced by ionizing radiation and exposure to resveratrol. The comparison of metabolic changes induced by both factors provides a rationale for the potential mechanism of the radioprotective effects of resveratrol.

The periphilin 1-like BFAR isoform 3 is highly expressed in transcriptionally silent oocytes and involved in RNA metabolism.

The mouse 3110001I22Rik gene located in the first intron of Bfar is considered as a Bfar variant coding for the BFARv3 protein. However, it differs from other BFAR isoforms and resembles periphilin 1 (PPHLN1) due to its two (Lge1 and serine-rich) conserved domains. We identified the BFARv3/EGFP-interacting proteins by co-immunoprecipitation coupled to mass spectrometry, which revealed 40S ribosomal proteins (RPS3, RPS14, RPS19, RPS25, RPS27), histones (H1.2, H1.4, H3.3C), proteins involved in RNA processing and splicing (SFPQ, SNRPA1, HNRNPA3, NONO, KHDRBS3), calcium signaling (HPCAL1, PTK2B), as well as HSD17B4, GRB14, POSTN, and MYO10. Co-immunoprecipitation revealed that both Lge1 and Ser-rich domains of BFARv3 were necessary for binding to RNA-interacting factors NONO and SFPQ, known to be components of paraspeckles. Reciprocal co-immunoprecipitation and the proximity ligation assay confirmed that both BFARv3 and PPHLN1 could interact with NONO and SFPQ, suggesting a new function for PPHLN1 as well. BFARv3 and its Lge1 or Ser-rich-deficient mutants preferentially localize in the nucleus. We found an accumulation of BFARv3/EGFP (but not its mutated forms) in the nuclear granules, which was enhanced in response to arsenite treatment and ionizing radiation. Although Bfar v3 is expressed ubiquitously in mouse tissues, its expression is the highest in metaphase II oocytes. The BFARv3 interactome suggests its role in RNA metabolism, which is critical for the transcriptionally silent MII oocyte. Mouse BFARv3 has no ortholog in the human genome, thus it may contribute to the differences between these two species observed in oocyte maturation and early embryonic development.

Resveratrol administration prevents radiation-related changes in metabolic profiles of hearts 20 weeks after irradiation of mice with a single 2 Gy dose.

We aimed to evaluate whether resveratrol affects radiation-induced changes in metabolite profiles of the mouse heart. Hearts were irradiated in vivo with a single 2 Gy dose during the resveratrol administration and metabolite profiles of heart tissue were analyzed by the untargeted HR-MAS NMR approach twenty weeks after irradiation. The administration of resveratrol mitigated the radiation-induced decline in the content of choline-containing compounds and unsaturated lipids, which might reflect the stabilization of cell membrane structure against radiation-related damage. Results obtained with this mouse model suggest that the resveratrol supplementation may prevent metabolic changes related to radiation-induced damage in the heart.

Radiation metabolomics in the quest of cardiotoxicity biomarkers: the review.

Purpose: Ionizing radiation is a risk factor to the whole organism, including the heart. Cardiac damage is considered to be a late effect of radiation exposure. While the acute cardiotoxicity of high doses is well characterized, the knowledge about nature and magnitude of the cardiac risk following lower doses exposure is incomplete. It has been shown that the cardiotoxic effects of radiation are source-, dose- and time-dependent. This paper provides an overview on these dependencies with regard to the molecular responses at the cellular and tissue levels. Main focus is put on the Nuclear Magnetic Resonance (NMR)-based and Mass Spectrometry (MS)-based metabolomic approaches in search of toxicity markers of relatively small doses of radiation.Conclusions: Available literature indicates that radiation exposure affects metabolites associated with: energy production, degradation of proteins and cell membranes, expression of proteins and stress response. Such effects are common for both animal and human studies. However, the specific metabolic response depends on several factors, including the examined organ. Radiation metabolomics can be used to explain the mechanisms of development of radiation-induced heart disease and to find an organ-specific biomarker of radiation exposure. The main aim of this review was to collect the information on the human cardiotoxicity biomarkers. In addition it also summarizes results of the studies on the metabolic responses to ionizing radiation for other organs, as well as the comparative data concerning animal studies.

Metabolic changes in mice cardiac tissue after low-dose irradiation revealed by 1H NMR spectroscopy.

Ionizing radiation may cause cardiotoxicity not only at high, but even at low (considered as harmless) doses, yet the molecular mechanisms of the heart's response to low doses are not clear. In this work, we used high-resolution nuclear magnetic resonance (NMR) spectroscopy to detect the early and late effects of radiation on the metabolism of murine hearts. The hearts of C57Bl/6NCrl female mice were irradiated in vivo with single 0.2 Gy or 2 Gy doses using 6 MV photons, then tissues were collected 48 h and 20 weeks after exposure. The most distinct changes in the profile of polar metabolites were detected 48 h after irradiation with 2 Gy, and included increased levels of pantothenate and glutamate as well as decreased levels of alanine, malonate, acetylcarnitine, glycine and adenosine. Significant effects of the 2 Gy dose were also observed 20 weeks after irradiation and included decreased levels of glutamine and acetylcarnitine when compared with age-matched controls. Moreover, several differences were observed between hearts irradiated with 2 Gy and analyzed either 48 h or 20 weeks after the exposure, which included changes in levels of acetylcarnitine, alanine, glycine, glutamate, glutamine, formate, myo-inositol and trimethylamine. No statistically significant effects induced by the 0.2 Gy dose were observed 20 weeks after irradiation. In general, radiation-affected compounds were associated with energy metabolism, fatty acid beta-oxidation, oxidative stress and damage to cell structures. At the same time, radiation-related effects were not detected at the level of tissue histology, which indicated a higher sensitivity of metabolomics-based tests for cardiac tissue response to radiation.

Nuclear magnetic resonance spectroscopy reveals metabolic changes in living cardiomyocytes after low doses of ionizing radiation.

Several lines of evidence indicate that exposure of heart to ionizing radiation increases the risk of cardiotoxicity manifested by heart dysfunction and cardiovascular diseases. It was initially believed that the heart is an organ relatively resistant to radiation. Currently, however, it is suspected that even low doses of radiation (< 2 Gy) may have a negative impact on the cardiovascular system. Cardiotoxicity of ionizing radiation is associated with metabolic changes observed in cardiac cells injured by radiation. In this study, we used human cardiomyocytes as a model system, and studied their metabolic response to radiation using high-resolution magic angle spinning nuclear magnetic resonance techniques (HR-MAS NMR). Human cardiomyocytes cultured in vitro were exposed to ionizing radiation and their survival was assessed by clonogenic assay. Changes in apoptosis intensity and cell cycle distribution after the irradiation were measured as well. NMR spectra of cardiomyocytes were acquired using Bruker Avance 400 MHz spectrometer at a spinning rate of 3200 Hz. Survival of cardiomyocytes after NMR experiments was assessed by the Trypan blue exclusion assay. Exposure of cardiomyocytes to small doses of ionizing radiation had no effect on cell proliferation potential and intensity of cell death. However, analysis of metabolic profiles revealed changes in lipids, threonine, glycine, glycerophosphocholine, choline, valine, isoleucine, glutamate, reduced glutathione and taurine metabolism. The results of this study showed that ionizing radiation affects metabolic profiles of cardiomyocytes even at low doses, which potentially have no effect on cell viability.

Biomechanical properties of hybrid heart valve prosthesis utilizing the pigs that do not express the galactose-α-1,3-galactose (α-Gal) antigen derived tissue and tissue engineering technique.

The aim of the study was to estimate the biomechanical properties of heart valves conduit derived from transgenic pigs to determine the usefulness for the preparation of tissue-engineered heart valves. The acellular aortic and pulmonary valve conduits from transgenic pigs were used to estimate the biomechanical properties of the valve. Non-transgenic porcine heart valve conduits were used as a reference. The biomechanics stability of acellular valve conduits decreased both for the transgenic and non-transgenic porcine valves. The energy required to break the native pulmonary valve derived from transgenic pigs was higher (20,475 ± 7,600 J m(-2)) compared with native non-transgenic pigs (12,140 ± 5,370 J m(-2)). After acellularization, the energy to break the valves decreased to 14,600 and 8,800 J m(-2) for the transgenic pulmonary valve and non-transgenic valve, respectively. The native transgenic pulmonary valve showed a higher extensibility (42.70 %) than the non-transgenic pulmonary valve (35.50 %); the extensibility decreased after acellularization to 41.1 and 31.5 % for the transgenic and non-transgenic valves, respectively. The pulmonary valves derived from transgenic pigs demonstrate better biomechanical properties compared with non-transgenic. Heart valves derived from transgenic pigs can be valuable for the preparation of tissue-engineered bioprostheses, because of their biomechanical properties, stability, reduced immune response, making them safer for clinical applications.

Age-related changes in biomechanical properties of transgenic porcine pulmonary and aortic conduits.

The limitations associated with conventional valve prosthesis have led to a search for alternatives. One potential approach is tissue engineering. Most tissue engineering studies have described the biomechanical properties of heart valves derived from adult pigs. However, because one of the factors affecting the function of valve prosthesis after implantation is appropriate sizing for a given patient, it is important to evaluate the usefulness of a heart valve given the donor animal's weight and age. The aim of this study was to evaluate how the age of a pig can influence the biomechanical and hemodynamical properties of porcine heart valve prosthesis after acellularization. Acellular porcine aortic and pulmonary valve conduits were used. Hearts were harvested from animals differing in weight and age. The biomechanical properties of the valves were then characterized using a uniaxial tensile test. Moreover, computer simulations based on the finite element method (FEM) were used to study the influence of biomechanical properties on the hemodynamic conditions. Studying biomechanical and morphological changes in porcine heart valve conduits according to the weight and age of the animals can be valuable for developing age-targeted therapy using tissue engineering techniques.

[Cardiotoxicity as undesired side effect in the treatment of breast cancer]. / Kardiotoksycznosc jako niepozadane dzialanie w terapii raka piersi.

Improvement of methods used in breast cancer therapy resulted in increased treatment effectiveness and prolonged survival of patients. However, this is accompanied by increased frequency of adverse side effects, including cardiac toxicity, which is becoming a serious problem affecting the quality of life and overall survival of cancer patients. The risk of developing cardiovascular complications depends on the type and dose of therapeutic agent used. The highest risk of cardiotoxicity is associated with anthracyclines. They are used frequently in cancer therapy due to their high efficiency but show a dose-dependent toxicity to the cardiovascular system. Cardiotoxicity can also occur with other substances used in breast cancer chemotherapy, as well as with radiotherapy. Combining potentially cardiotoxic therapeutic agents, commonly used in combination therapy, may result in escalation of toxic side effects. Mechanisms of heart damage are different for various cardiotoxic agents, but symptoms usually involve heart failure, ischemic heart disease, arrhythmias, hypertension, valvular diseases or pericarditis and myocarditis. The practices used to reduce the risk of cardiotoxic effects of cancer therapy include evaluation of cardiac functions before treatment and constant monitoring during and after treatment. Furthermore, limited doses and modifications of anticancer agent administration patterns are employed, as well as simultaneous application of cardioprotective agents. Understanding of cardiotoxic mechanisms of agents used in breast cancer treatment can help to develop efficient cardioprotective substances. Because oxidative stress plays an important role in the toxicity of cancer therapy, compounds with antioxidant properties are a very promising target of research.