Drug-induced mitochondrial dysfunction and cardiotoxicity Varga, Zoltán V; Ferdinandy, Peter; Liaudet, Lucas ...
American journal of physiology. Heart and circulatory physiology,
11/2015, Letnik:
309, Številka:
9
Journal Article
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Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent ...cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult. Cardiotoxic agents affecting mitochondria include several widely used anticancer drugs anthracyclines (Doxorubicin/Adriamycin), cisplatin, trastuzumab (Herceptin), arsenic trioxide (Trisenox), mitoxantrone (Novantrone), imatinib (Gleevec), bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nevaxar), antiviral compound azidothymidine (AZT, Zidovudine) and several oral antidiabetics e.g., rosiglitazone (Avandia). Illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids (spice, K2) may also induce mitochondria-related cardiotoxicity. Mitochondrial toxicity develops due to various mechanisms involving interference with the mitochondrial respiratory chain (e.g., uncoupling) or inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Györgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential and an increase in mitochondrial oxidative/nitrative stress, eventually culminating into cell death. This review aims to discuss the mechanisms of mitochondrion-mediated cardiotoxicity of commonly used drugs and some potential cardioprotective strategies to prevent these toxicities.
Some decades ago, biogeographers distinguished three major faunal types of high importance for Europe: (i) Mediterranean elements with exclusive glacial survival in the Mediterranean refugia, (ii) ...Siberian elements with glacial refugia in the eastern Palearctic and only postglacial expansion to Europe and (iii) arctic and/or alpine elements with large zonal distributions in the periglacial areas and postglacial retreat to the North and/or into the high mountain systems. Genetic analyses have unravelled numerous additional refugia both of continental and Mediterranean species, thus strongly modifying the biogeographical view of Europe. This modified notion is particularly true for the so-called Siberian species, which in many cases have not immigrated into Europe during the postglacial period, but most likely have survived the last, or even several glacial phases, in extra-Mediterranean refugia in some climatically favourable but geographically limited areas of southern Central and Eastern Europe. Recently, genetic analyses revealed that typical Mediterranean species have also survived the Last Glacial Maximum in cryptic northern refugia (e.g. in the Carpathians or even north of the Alps) in addition to their Mediterranean refuge areas.
Because of the relative ease of embryonic manipulation and observation, the ability to produce a great number of genetic mutations, efficient screening methods, and the continued advance of molecular ...genetic tools, such as the progress in sequencing and mapping of the zebrafish genome, the use of zebrafish (Danio rerio) as a biomedical model organism continues to expand. However, studies involving zebrafish husbandry and veterinary care struggle to keep pace with scientific progress. This article outlines some of the current, acceptable methods for providing anesthesia and euthanasia and provides some examples of how performance-based approaches can be used to advance the relatively limited number of anesthetic and euthanizing techniques available for zebrafish.
The oreal fauna is connected with orographically limited non-arboreal habitats. Its chorological centres can be recognised by the high species-diversity of numerous typical genera, and by the ...accumulated occurrence of endemic species and/or subspecies of disjunct species. The oreal fauna is partitioned to the alpine type, as the faunal type of humid high-mountains with strong connections to the tundral zonobiome, and the xeromontane type, as the faunal type of arid high-mountains with close connections to the eremic zonobiomes. As the results of revisions of several Noctuinae genera, species groups and/or sister species were recognised and their distributions were mapped. The restricted areas of allopatric sister species, often described by us as new for science, fulfil the criteria of the “areas of endemism”. Core areas of the Palaearctic xeromontane Noctuidae, outlined by the distribution of endemic species, have been proven by the occurrence of allopatric subspecies of polytypic species, and/or by the presence of allopatric sister species. In the revised genera of Noctuidae several types of allopatric speciation have been identified based on the analysis of the areas of endemism and of vicariance patterns. As a result of these analyses, it is proved that allopatric sister species, as elementary monophyletic supraspecific units, are suitable for phylogenetic biogeographical surveys. Although the major part of the xeromontane fauna appears to be range-restricted, a considerable fraction of the species could have expanded into the steppic zonobiome due to adaptive changes of their life cycles. High diversity of cold-adapted species originated from the Sino-Himalayan mountains by passing two main filtercorridors. One track of this bifurcation was directed across the “Rhododendron-corridor” to the Holarctic taiga zone while the other one, across the “Xeromontane filter-corridor” to the mountain systems of Central and Inner Asia. This bifurcation becomes apparent from the taxonomic division of the genera, composing both of these main faunal types. Supposedly, the faunal movements of the xeromontanean species in the West Palaearctic had been shaped by the Messinian salinity crisis and, additionally, significantly influenced by the Mid-Pleistocene climatic transition which deeply transformed the zonality of the vegetation by cooling and aridisation of vast areas.
Due to the increasing volume of air transportation, the demand for jet fuels has grown significantly in the past decade. Hydrocarbon processing companies and different research groups began ...investigating the possible production routes of suitable kerosene fractions in order to produce fuel for jet engines not only on a crude oil basis but also from alternative sources, too. The Carbon Offset and Reduction Scheme for International Aviation program will be started in the near future with the target to decrease the carbon dioxide emissions of aviation significantly. This carbon dioxide reduction can only be achieved when using jet fuels derived from alternative sources. The aim of this experimental work was to study the catalytic conversion of waste coconut oil which was mixed in straight-run kerosene fractions at 10, 30, and 50% to produce an alternative component containing jet fuel at various process parameters (temperature = 280–360 °C, liquid hourly space velocity = 1.0–3.0 h–1, pressure = 30 bar, hydrogen/feedstock volume ratio = 600 N m3/m3) on a sulfided nickel molybdenum/alumina catalyst. Based on the experimental results, the yield of the target product changed between 65 and 95% depending on the rate of desulfurization, deoxygenation, and aromatic saturation. The target products had a very high smoke point (>40 mm) resulting in very low particle emissions during the use of this biojet fuel.
Cell loss and subsequent deterioration of contractile function are hallmarks of chronic heart failure (HF). While apoptosis has been investigated as a participant in the progression of HF, it is ...unlikely that it accounts for the total amount of non-functional tissue. In addition, there is evidence for the presence of necrotic cardiomyocytes in HF. Therefore, the objective of this study was to investigate the necroptotic proteins regulating necroptosis, a form of programmed necrosis, and thereby assess its potential role in human end-stage HF.
Left ventricular samples of healthy controls (C) and patients with end-stage HF due to myocardial infarction (CAD) or dilated cardiomyopathy (DCM) were studied. Immunoblotting for necroptotic and apoptotic markers was performed. Triton X-114 fractionated samples were analyzed to study differences in subcellular localization.
Elevated expression of RIP1 (receptor-interacting protein), pSer
-RIP3 and its total levels were observed in HF groups compared to controls. On the other hand, caspase-8 expression, a proapoptotic protease negatively regulating necroptosis, was downregulated suggesting activation of necroptosis signaling. Total mixed-lineage kinase domain-like protein (MLKL) expression did not differ among the groups; however, active cytotoxic forms of MLKL were present in all HF samples while they were expressed at almost undetectable levels in controls. Interestingly, pThr
-MLKL unlike pSer
-MLKL, was higher in DCM than CAD. In HF, the subcellular localization of both RIP3 and pThr
-MLKL was consistent with activation of necroptosis signaling. Expression of main apoptotic markers has not indicated importance of apoptosis.
This is the first evidence showing that human HF of CAD or DCM etiology is positive for markers of necroptosis which may be involved in the development of HF.
Zebrafish,
Danio rerio, are frequently handled during husbandry and experimental procedures in the laboratory, yet little is known about the physiological responses to such stressors. We measured the ...whole-body cortisol levels of adult zebrafish subjected to net stress and air exposure at intervals over a 24
h period; cortisol recovered to near control levels by about 1
h post-net-stress (PNS). We then measured cortisol at frequent intervals over a 1
h period. Cortisol levels were more than 2-fold higher in net stressed fish at 3
min PNS and continued to increase peaking at 15
min PNS, when cortisol levels were 6-fold greater than the control cortisol. Mean cortisol declined from 15 to 60
min PNS, and at 60
min, net-stressed cortisol was similar to control cortisol. Because the age of fish differed between studies, we examined resting cortisol levels of fish of different ages (3, 7, 13, and 19
months). The resting cortisol values among tanks with the same age fish differed significantly but there was no clear effect of age. Our study is the first to report the response and recovery of cortisol after net handling for laboratory-reared zebrafish.
Large amounts of heat is wasted through air coolers and water coolers for cooling low temperature (<150 °C) streams in many technologies. This paper summarizes the results of a study for partial ...substitute of air cooler, which cools down a hydrocarbon stream from 130 °C to 70 °C and dissipating heat of 12.1 MW into the environment, by applying organic Rankine cycle (ORC) and Kalina systems. Results showed that the heat energy (QH) recovered in the evaporator were 8.0–8.6 MW for ORC using i-pentane as working fluid and 8.2–8.3 MW for Kalina cycle, respectively. Efficiency (η) of selected systems obtained at the highest power generated (WT) was 10.0% (WT = 862 kW) for ORC and 10.57% (WT = 996 kW) for Kalina cycle within the design boundaries. Calculated carbon dioxide (CO2) emission reduction potential was 2260 t/y for ORC and 2600 t/y for Kalina system, respectively, at advantageous process conditions. Results showed that Kalina cycle provided higher efficiency and power generation ability on expense of higher system pressure (29 bar–7 bar). Economic calculations showed that the payback time is about 5.0 year for both systems.
•Waste heat recovery methods applicable for low temperature streams were investigated.•Organic Rankine cycle (ORC) of different arrangements and Kalina cycle were compared.•Advantageous working fluid (i-C5) and process conditions for the ORC were determined.•The highest power output was 862 kW for ORC and 994 kW for Kalina cycle.•Economic calculations showed that payback time is about 5.0 year for both systems.
Biodegradable nanoparticle-based emulsions exhibit immense potential in various applications, particularly in the pharmaceutical, cosmetic, and food industries. This study delves into the intricate ...interfacial behavior of Pluronic F127 modified poly(lactic-co-glycolic acid) (PLGA-F127) nanoparticles, a crucial determinant of their ability to stabilize Pickering emulsions. Employing a combination of Langmuir balance, surface tension, and diffusion coefficient measurements, we investigate the interfacial dynamics of PLGA-F127 nanoparticles under varying temperature and ionic strength conditions. Theoretical calculations are employed to elucidate the underlying mechanisms governing these phenomena. Our findings reveal a profound influence of temperature-dependent Pluronic layer behavior and electrostatic and steric interactions on the interfacial dynamics. Nonlinear changes in surface tension are observed, reflecting the interplay of these factors. Particle aggregation is found to be prevalent at elevated temperatures and ionic strengths, compromising the stability and emulsification efficiency of the formed emulsions. This work provides insights into the rational design of stable and efficient biodegradable nanoparticle-based Pickering emulsions, broadening their potential applications in various fields.
The particle size distribution (PSD) of extracellular vesicles (EVs) and other submicron particles in biofluids is commonly measured by nanoparticle tracking analysis (NTA) and tunable resistive ...pulse sensing (TRPS). A new technique for measuring the PSD is microfluidic resistive pulse sensing (MRPS). Because specific guidelines for measuring EVs together with other particles in biofluids with MRPS are lacking, we developed an operating procedure to reproducibly measure the PSD. The PSDs of particles in human plasma, conditioned medium of PC3 prostate cancer cell line (PC3 CM), and human urine were measured with MRPS (nCS1, Spectradyne LLC) to investigate: (i) the optimal diluent that reduces the interfacial tension of the sample while keeping EVs intact, (ii) the lower limit of detection (LoD) of particle size, (iii) the reproducibility of the PSD, (iv) the optimal dilution for measuring the PSD, and (v) the agreement in measured concentration between microfluidic cartridges with overlapping detection ranges. We found that the optimal diluent is 0.1% bovine serum albumin (w/v) in Dulbecco's phosphate-buffered saline. Based on the shape of the PSD, which is expected to follow a power-law function within the full detection range, we obtained a lower LoD of 75 nm for plasma and PC3 CM and 65 nm for urine. Normalized PSDs are reproducible (R2 > 0.950) at dilutions between 10-100x for plasma, 5-20x for PC3 CM, and 2-4x for urine. Furthermore, sample dilution does not impact the dilution-corrected concentration when the microfluidic cartridges are operated within their specified concentration ranges. PSDs from microfluidic cartridges with overlapping detection ranges agreed well (R2 > 0.936) and when combined the overall PSD spanned 5 orders of magnitude of measured concentration. Based on these findings, we have developed operating guidelines to reproducibly measure the PSD of EVs together with other particles in biofluids with MRPS.
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