64 research outputs found
Effect of Metformin and Sitagliptin on Doxorubicin-Induced Cardiotoxicity in Rats: Impact of Oxidative Stress, Inflammation, and Apoptosis
Doxorubicin (DOX) is a widely used antineoplastic drug whose efficacy is limited by its cardiotoxicity. The aim of this study was to investigate the possible protective role of the antidiabetic drugs metformin (250 mg/kg dissolved in DW p.o. for seven days) and sitagliptin (10 mg/kg dissolved in DW p.o. for seven days) in a model of DOX-induced (single dose 15 mg/kg i.p. at the fifth day) cardiotoxicity in rats. Results of our study revealed that pretreatment with metformin or sitagliptin produced significant (P<0.05) cardiac protection manifested by a significant decrease in serum levels of LDH and CK-MB enzymes and cardiac MDA and total nitrites and nitrates levels, a significant increase in cardiac SOD activity, and remarkable improvement in the histopathological features as well as a significant reduction in the immunohistochemical expression of COX-2, iNOS, and caspase-3 enzymes as compared to DOX group. These results may suggest using metformin and/or sitagliptin as preferable drugs for diabetic patients suffering from cancer and receiving DOX in their chemotherapy regimen
Response of Ectomycorrhizal Fungal Fruiting to Nitrogen and Phosphorus Additions in Bartlett Experimental Forest, New Hampshire
Forest productivity and recovery is limited by nutrients including nitrogen and phosphorus. Ectomycorrhizal fungi (EMF) form mutualistic symbioses with trees and aid roots in acquiring soil nutrients. The composition of EMF in forests may be sensitive to changes in soil nutrients in ways not fully understood. This research investigates EMF fruiting responses to nutrient manipulation in a project on Multiple Element Limitation in Northern Hardwood Ecosystems where N and P have been added annually in a factorial design since 2011. Sporocarp abundance, biomass, species richness, and fruiting community composition were compared between nutrient addition plots and control plots. While some ectomycorrhizal fungi are known to respond to N fertilization, this work is among the first to observe sporocarp community response to P fertilization, and to N and P fertilization together, which will be important to predicting how fungal communities will respond to changing soil nutrient conditions in a changing world
Mitochondrial dysfunction is an early indicator of doxorubicin-induced apoptosis
AbstractGeneration of reactive oxygen species and mitochondrial dysfunction has been implicated in doxorubicin-induced cardiotoxicity. This study examined pro-apoptotic mitochondrial cell death signals in an H9C2 myocyte rat cell line and in isolated rat heart mitochondria exposed to doxorubicin. Mitochondrial and cellular viability were assessed using an MTT viability assay (formazan product formed by functional mitochondrial dehydrogenases) and calcein AM dye (fluoresces upon cleavage by cytosolic esterases). Mitochondrial dysfunction followed by cell death was observed using nM concentrations of doxorubicin. Significant doxorubicin-induced cell death was not apparent until after 6 h following doxorubicin exposure using the calcein AM assay. The involvement of apoptosis is evidenced by an increase in TUNEL (terminal (TdT)-mediated dUTP-biotin nick end labeling)-positive nuclei following doxorubicin treatment. Furthermore, doxorubicin administered to isolated mitochondria induced a rapid increase in superoxide production, which persisted for at least 1 h and was followed by increased cytochrome c efflux. In addition, caspase-3 activity was increased with doxorubicin administration in the H9C2 myocyte cell line. An oxidant-mediated threshold of mitochondrial death may be required for doxorubicin-induced apoptosis
К ВОПРОСУ ОБ ИШЕМИЧЕСКОЙ ДИСФУНКЦИИ МИОКАРДА
The authors of the review have analyzed papers published on the problem of ischemic myocardial dysfunction. They begin with a definition of the term “ischemia” (derived from two Greek words: ischō, meaning to hold back, and haima, meaning blood) - a condition at which the arterial blood flow is insufficient to provide enough oxygen to prevent intracellular respiration from shifting from the aerobic to the anaerobic form. The poor rate of ATP generation from this process causes a decrease in cellular ATP, a concomitant rise in ADP, and ultimately, to depression inotropic (systolic) and lusitropic (diastolic) function of the affected segments of the myocardium. But with such simplicity of basic concepts, the consequences of ischemia so diverse. Influence of an ischemia on myocardial function so unequally at different patients, which is almost impossible to find two identical cases (as in the case of fingerprints). It depends on the infinite variety of lesions of coronary arteries, reperfusion (time and completeness of restoration of blood flow) and reactions of a myocardium which, apparently, has considerable flexibility in its response. Ischemic myocardial dysfunction includes a number of discrete states, such as acute left ventricular failure in angina, acute myocardial infarction, ischemic cardiomyopathy, stunning, hibernation, pre- and postconditioning. There are widely differing underlying pathophysiologic states. The possibility exists that several of these states can coexist.Проведен анализ работ, опубликованных по проблеме ишемической дисфункции миокарда. Ишемия (от греч. ischō – задерживать и haima – кровь) -состояние, при котором артериальный кровоток становится недостаточным, чтобы обеспечить необходимое количество кислорода для предотвращения перехода внутриклеточного дыхания с аэробной формы на анаэробную. Низкая скорость генерации аденозинтрифосфата (АТФ) при этом процессе приводит к снижению в клетке АТФ, конкоминантному повышению аденозиндифосфата и в конечном счете к депрессии инотропной (систолической) и люситропной (диастолической) функций пораженных сегментов миокарда. Но при всей простоте этих основных положений последствия ишемии крайне разнообразны. Влияние ишемии на функцию миокарда настолько неодинаково у различных пациентов, что практически невозможно встретить два идентичных случая (также как одинаковые отпечатки пальцев). Зависит это от бесконечного разнообразия поражений коронарных артерий, реперфузии (время и полнота восстановления кровотока) и реакции миокарда, который, по-видимому, имеет значительную гибкость в этом ответе. Ишемическая дисфункция миокарда включает в себя ряд дискретных состояний, таких как острая левожелудочковая недостаточность при стенокардии, острый инфаркт миокарда, ишемическая кардиомиопатия, оглушение, гибернация и пре- и посткондиционирование. Механизмы этих состояний в значительной степени различаются, что необходимо учитывать при разработке программ профилактики (первичной и вторичной). При этом следует принимать во внимание возможность того, что некоторые из этих состояний могут сосуществовать
Uncertain Associations of Major Bleeding and Concurrent Use of Antiplatelet Agents and Chinese Medications: A Nested Case-Crossover Study
Despite the evidence that some commonly used Chinese medications (CMs) have antiplatelet/anticoagulant effects, many patients still used antiplatelets combined with CMs. We conducted a nested case-crossover study to examine the associations between the concomitant use of antiplatelets and CMs and major bleeding using population-based health database in Taiwan. Among the cohort of 79,463 outpatients prescribed antiplatelets (e.g., aspirin and clopidogrel) continuously, 1,209 patients hospitalized with new occurring bleeding in 2012 and 2013 were included. Those recruited patients served as their own controls to compare different times of exposure to prespecified CMs (e.g., Asian ginseng and dong quai) and antiplatelet agents. The periods of case, control 1, and control 2 were defined as 1–4 weeks, 6–9 weeks, and 13–16 weeks before hospitalization, respectively. Conditional logistic regression analyses found that concurrent use of antiplatelet drugs with any of the prespecified CMs in the case period might not significantly increase the risks of bleeding over that in the control periods (OR = 1.00, 95% CI 0.51 to 1.95 and OR = 1.13, 95% CI 0.65 to 1.97). The study showed no strong relationships between hospitalization for major bleeding events and concurrent use of antiplatelet drugs with the prespecified CMs
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Liver X Receptor cis-Repression and Cholesterol Efflux Restrain Innate Immunity and Coronary Artery Disease
Atherosclerotic cardiovascular disease secondary to deposition of apolipoprotein B-containing lipoproteins in the artery wall is a leading cause of mortality. Therapies that reduce serum levels of atherogenic lipoprotein-cholesterol have been successful in reducing cardiovascular mortality, but this approach requires long-term treatment and substantial residual risk remains. Here, we investigate mechanistic determinants of atherosclerosis protection by two potential therapeutic approaches for lowering of residual cardiovascular risk. Using mouse models, we show that the nuclear receptor liver X receptor exerts an anti-inflammatory activity on innate immunity and atherosclerosis through both promotion of cholesterol efflux and a direct cis-repressive activity affecting neutrophil inflammation. We then assess the causal role of the cholesterol efflux pathway in human cardiovascular events by using genetic variants that modify high density lipoprotein-cholesterol in instrumental variable analysis. We show that this pathway is associated with protection from cardiovascular disease in a precise and robust Mendelian randomization analysis on an FDR-controlled set of variants, which suggests a causal effect. Thus, agents that target the cholesterol efflux and liver X receptor cis-repression pathways may be protective in atherosclerosis
Lipid-Associated Variants near ANGPTL3 and LPL Show Parent-of-Origin Specific Effects on Blood Lipid Levels and Obesity
Parent-of-origin effects (POE) and sex-specific parental effects have been reported for plasma lipid levels, and a strong relationship exists between dyslipidemia and obesity. We aim to explore whether genetic variants previously reported to have an association to lipid traits also show POE on blood lipid levels and obesity. Families from the Botnia cohort and the Hungarian Transdanubian Biobank (HTB) were genotyped for 12 SNPs, parental origin of alleles were inferred, and generalized estimating equations were modeled to assess parental-specific associations with lipid traits and obesity. POE were observed for the variants at the TMEM57, DOCK7/ANGPTL3, LPL, and APOA on lipid traits, the latter replicated in HTB. Sex-specific parental effects were also observed; variants at ANGPTL3/DOCK7 showed POE on lipid traits and obesity in daughters only, while those at LPL and TMEM57 showed POE on lipid traits in sons. Variants at LPL and DOCK7/ANGPTL3 showed POE on obesity-related traits in Botnia and HTB, and POE effects on obesity were seen to a higher degree in daughters. This highlights the need to include analysis of POEs in genetic studies of complex traits.Peer reviewe
Ischaemic heart disease in patients with neoplasm
Duża częstość występowania choroby wieńcowej i nowotworów w krajach europejskich sprawia, że prawie
codziennie spotyka się osoby, u których współistnieją oba te schorzenia. Ich wzajemny wpływ powoduje
zwiększone ryzyko zarówno leczenia kardiologicznego, jak i onkologicznego. Leczenie stosowane w onkologii,
radioterapia i chemioterapia istotnie wpływają na przyspieszenie rozwoju miażdżycy i wystąpienia
klinicznych objawów choroby wieńcowej. Chemioterapia może dodatkowo wywoływać skurcz tętnic wieńcowych.
Obecność choroby niedokrwiennej serca często ogranicza możliwości intensywnego leczenia nowotworu.
W takich przypadkach zabiegi rewaskularyzacyjne mogą umożliwić intensywniejsze leczenie
onkologiczne i poprawić jego wyniki. Celem niniejszej pracy jest omówienie związków między chorobą
nowotworową i chorobą wieńcową oraz zasadniczych problemów, z jakimi wiąże się leczenie kardiologiczne
pacjentów obciążonych tymi chorobami.High incidence of coronary artery and neoplastic diseases in European countries results in coexistence of
both in many patients. Interactions between malignancy and ischaemic heart disease may enhance the risk
of oncologic and cardiologic treatment. Potential adverse effects of therapeutic mediastinal irradiation and
chemotherapy include initiation and acceleration of atherosclerosis and cardiac ischaemia symptoms occurring.
Chemotherapy can cause additional coronary vasospasm. Aggressive oncologic treatment may be
limited by coronary artery disease, and revascularization can lead to improved results. In our article we
discuss most common problems in patients with coronary artery disease and neoplasm
Coagulation and coagulation signalling in fibrosis
AbstractFollowing tissue injury, a complex and coordinated wound healing response comprising coagulation, inflammation, fibroproliferation and tissue remodelling has evolved to nullify the impact of the original insult and reinstate the normal physiological function of the affected organ. Tissue fibrosis is thought to result from a dysregulated wound healing response as a result of continual local injury or impaired control mechanisms. Although the initial insult is highly variable for different organs, in most cases, uncontrolled or sustained activation of mesenchymal cells into highly synthetic myofibroblasts leads to the excessive deposition of extracellular matrix proteins and eventually loss of tissue function. Coagulation was originally thought to be an acute and transient response to tissue injury, responsible primarily for promoting haemostasis by initiating the formation of fibrin plugs to enmesh activated platelets within the walls of damaged blood vessels. However, the last 20years has seen a major re-evaluation of the role of the coagulation cascade following tissue injury and there is now mounting evidence that coagulation plays a critical role in orchestrating subsequent inflammatory and fibroproliferative responses during normal wound healing, as well as in a range of pathological contexts across all major organ systems. This review summarises our current understanding of the role of coagulation and coagulation initiated signalling in the response to tissue injury, as well as the contribution of uncontrolled coagulation to fibrosis of the lung, liver, kidney and heart. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease
HDL Subclass Proteomic Analysis and Functional Implication of Protein Dynamic Change During HDL Maturation
Recent clinical trials reported that increasing high-density lipoprotein-cholesterol (HDL-C) levels does not improve cardiovascular outcomes. We hypothesize that HDL proteome dynamics determine HDL cardioprotective functions. In this study, we characterized proteome profiles in HDL subclasses and established their functional connection. Mouse plasma was fractionized by fast protein liquid chromatography, examined for protein, cholesterial, phospholipid and trigliceride content. Small, medium and large (S/M/L)-HDL subclasseses were collected for proteomic analysis by mass spectrometry. Fifty-one HDL proteins (39 in S-HDL, 27 in M-HDL and 29 in L-HDL) were identified and grouped into 4 functional categories (lipid metabolism, immune response, coagulation, and others). Eleven HDL common proteins were identified in all HDL subclasses. Sixteen, 3 and 7 proteins were found only in S-HDL, M-HDL and L-HDL, respectively. We established HDL protein dynamic distribution in S/M/L-HDL and developed a model of protein composition change during HDL maturation. We found that cholesterol efflux and immune response are essential functions for all HDL particles, and amino acid metabolism is a special function of S-HDL, whereas anti-coagulation is special for M-HDL. Pon1 is recruited into M/L-HDL to provide its antioxidative function. ApoE is incorporated into L-HDL to optimize its cholesterial clearance function. Next, we acquired HDL proteome data from Pubmed and identified 12 replicated proteins in human and mouse HDL particle. Finally, we extracted 3 shared top moleccular pathways (LXR/RXR, FXR/RXR and acute phase response) for all HDL particles and 5 top disease/bio-functions differentially related to S/M/L-HDL subclasses, and presented one top net works for each HDL subclass. We conclude that beside their essencial functions of cholesterol efflux and immune response, HDL aquired antioxidative and cholesterol clearance functions by recruiting Pon1 and ApoE during HDL maturation
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