Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity

OBJECTIVES: We aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity. BACKGROUND: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions, and these effects can be reversed by CB1 antagonists. METHODS: Left ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques. RESULTS: Five days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium. Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, which were prevented by the preincubation of the cells with either CB1 antagonist, but not with CB1 and CB2 agonists and CB2 antagonists. CONCLUSIONS: These data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity

New insights on Celtic migration in Hungary and Italy through the analysis of non-metric dental traits

The Iron Age is characterized by an extended interweaving of movements by Celts in Europe. Several waves of Celts from Western and Central Europe migrated southeast and west from the core area of the La Téne culture (between Bourgogne and Bohemia). Through the analysis of non-metric dental traits, this work aims to understand the biological relationship among Celtic groups arrived in Italy and the Carpathian Basin, as well as between local populations and Celtic newcomers. A total of 10 non-metric dental traits were analyzed to evaluate biological affinities among Celts (Sopron-Krautacker and Pilismarót-Basaharc) and Scythians-related populations from Hungary (Tápiószele), Celts from continental Europe (Switzerland and Austria), two Iron Age Etruscan-Celtic sites from northern Italy (Monterenzio Vecchio and Monte Bibele), 13 Iron Age central-southern Italic necropolises, and the northern Italian Bronze Age necropolis of Scalvinetto. Strontium isotopes were measured on individuals from the necropolis of Monte Bibele to infer their local or non-local origin. Results highlight the existence of statistically significant differences between Celts and autochthonous Italian groups. Celtic groups from Hungary and Italy (i.e., non-local individuals of Monterenzio Vecchio and Monte Bibele) share a similar biological background, supporting the historical records mentioning a common origin for Celts migrated to the eastern and southern borders of today’s Europe. The presence of a supposed Steppean ancestry both in Celts from Hungary and Celts from northern Italy corroborates the hypothesis of the existence of a westward migration of individuals and genes from the Steppe towards northern Italy during the Bronze and Iron Age, which contributed to the biological variability of pre-Celtic and later Celtic populations, respectively. Conversely, individuals from central-southern Italy show an autochthonous pre-Iron Age background. Lastly, this work supports the existence of Celtic migratory routes in northern Italy, as shown by biological and cultural admixture between Celts and Italics living together

Ancient genomes reveal origin and rapid trans-Eurasian migration of 7^th century Avar elites

The Avars settled the Carpathian Basin in 567/68 CE, establishing an empire lasting over 200 years. Who they were and where they came from is highly debated. Contemporaries have disagreed about whether they were, as they claimed, the direct successors of the Mongolian Steppe Rouran empire that was destroyed by the Turks in ∼550 CE. Here, we analyze new genome-wide data from 66 pre-Avar and Avar-period Carpathian Basin individuals, including the 8 richest Avar-period burials and further elite sites from Avar’s empire core region. Our results provide support for a rapid long-distance trans-Eurasian migration of Avar-period elites. These individuals carried Northeast Asian ancestry matching the profile of preceding Mongolian Steppe populations, particularly a genome available from the Rouran period. Some of the later elite individuals carried an additional non-local ancestry component broadly matching the steppe, which could point to a later migration or reflect greater genetic diversity within the initial migrant population.- Introduction - Results -- Ancient DNA dataset and quality control -- The genomic structure of the pre-Avar-period population -- The genomic structure of the Avar-period population -- Modeling the eastern steppe ancestry of the elites in the core of the Avar empire -- The heterogeneous ancestry in the regions surrounding the Avar empire’s core - Discussion -- Limitations of the study - Star Method

Csokonai könyvtár (Bibliotheca studiorum litterarium)

Hogyan jönnek létre a magyar irodalmi klasszikusok szövegkiadásai? Milyen megoldásokat kíván Arany János, Kazinczy és Kölcsey műveinek sajtó alá rendezése? miféle elméleti és materiális természetű feladványok elé állít a kiadói tevékenység? Ez a tematikus tanulmánykötet a 18-19. századi textológia területére kalauzol, s szövegkiadással foglalkozó kutatók eredményeiről ad számot. Tanulmányaik azokra az elméleti kihívásokra reagálnak, amelyek munkájukat az utóbbi időkben érték – olyan tapasztalatokból építkezve, amelyek a tevékenységüket mindenkor kísérik. A kötet egy 2013-as, Miskolcon megrendezett konferencián alapul, amely egy átfogó, a magyarországi szövegkiadások helyzetét áttekinteni kívánó sorozat részeként valósult meg. A tanácskozás a klasszikus magyar irodalom textológiai feldolgozásának időszerű kérdéseit kívánta áttekinteni számos kutatóhely munkatársai bevonásával. Az ebből a vállalkozásból létrejövő, átdolgozott és újrafogalmazott tanulmányok, textológiai és filológiai eredetükre építve, az értelmezés kereteit, műfaji határait kihasználva válnak egy történeti-poétikai szövegértemlezés hordozóivá, elmélyítve az irodalomtörténeti reflexió lehetőségeit. Az esettanulmányok, illetve a teoretikus és módszertani általánosításra is vállalkozó dolgozatok sokrétű, változatos képét rajzolják fel a textológia tudományterületének, s kijelölik a közeljövő számos feladatát is.Kecskeméti Gábor: Előszó - 7 A textológiai reflexió időszerűsége Szilágyi Márton: Textológia, filológia, értelmezés - 15 Debreczeni Attila: Kritikai kiadás papíron és képernyőn - 26 Teoretikus dilemmák a szerzői kritikai kiadásokban Bodrogi Ferenc Máté: Dologi hurok a szellemi műveleten: a szöveg mint nyomtatott termék. A Kazinczy Ferencz’ Munkáji: Szép Literatúra kiadástörténetéhez - 43 Czifra Mariann: A szöveg történeti feltárásának materiális feltételeiről - 57 Granasztói Olga: Kazinczy Ferenc, avagy Abafi Lajos Magyar Pantheonja. Egy új Kazinczy-kiadás előkészületei - 75 Orbán László: A szövegváltozatok öröme. Kapcsolatépítési stratégiák a Kazinczy-levelezésben - 93 S. Varga Pál: „…a keverék-mű a fejedre támad…”. Arany János 1860 és 1882 között keletkezett verseinek alapszövegéről - 116 Hajdu Péter: Szövegváltozat – novellaváltozat – műfajváltozat. A Mikszáth kritikai kiadás némely tapasztalatai - 136 Orosz Beáta: Csokonai költői életművének elektronikus kiadása. Problémák, tanulságok - 153 Kollektív szövegforrások kiadásának kérdései Labádi Gergely: A filológiai tudás formái - 173 Porkoláb Tibor: Szempontok a francia háborúk inszurrekciós költészetének textológiai és filológiai vizsgálatához - 191 Gábori Kovács József: A textológus felelőssége a Pesti Hirlap szerzőségi azonosításainak tapasztalatai alapján - 215 Steinmacher Kornélia: Élclapok a kiegyezés idejében (1865–1867) - 237 A nem szépirodalmi szövegek textológiai dilemmái Balogh Piroska: „Temptare volui possentne proferri in lucem”. Latin nyelvű esztétikai szövegek kiadásának fordításelméleti kérdései - 257 Bátori Anna: Kompilációs olvasás. Hivatkozások és keresőeszközök Paullus Wallaszky historia literariájában - 268 Völgyesi Orsolya: Hogyan dokumentálható egy reformkori politikus tevékenysége? A Kölcsey Ferenc országgyűlési működéséhez kapcsolódó szövegtípusok közléséről - 287 Textológia és értelmezés Biró Annamária: Aranka György: titoknok és magánember. Szerepértelmezési problémák az Aranka-levelezésben - 303 Csonki Árpád: „Arad munkás ’s jó szívű Lantosa”. Peretsenyi Nagy László mint Vörösmarty elődje - 323 Doncsecz Etelka: „Ez az írás éppen nem kedvez a’ németnek.” Szaicz Leó Magyar Világ című történeti munkájáról - 351 Hermann Zoltán: A Himfy-strófa műfaji határai - 373 Rövidítésjegyzék - 391 Névmutató - 39

Cannabinoid pharmacology in cancer research: A new hope for cancer patients?

Cannabinoids have been used for many centuries to ease pain and in the past decade, the endocannabinoid system has been implicated in a number of pathophysiological conditions, such as mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis, spinal cord injury, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity, and osteoporosis. Several studies have demonstrated that cannabinoids also have anti-cancer activity and as cannabinoids are usually well tolerated and do not produce the typical toxic effects of conventional chemotherapies, there is considerable merit in the development of cannabinoids as potential anticancer therapies. Whilst the presence of psychoactive effects of cannabinoids could prevent any progress in this field, recent studies have shown the value of the non-psychoactive components of cannabinoids in activating apoptotic pathways, inducing anti-proliferative and anti-angiogenic effects. The aforementioned effects are suggested to be through pathways such as ERK, Akt, mitogen-activated protein kinase (MAPK) pathways, phosphoinositide 3-kinase (PI3K) pathways and hypoxia inducible factor 1 (HIF1), all of which are important contributors to the hallmarks of cancer. Many important questions still remain unanswered or are poorly addressed thus necessitating further research at basic pre-clinical and clinical levels. In this review, we address these issues with a view to identifying the key challenges that future research needs to address

Low vitamin D status is associated with systemic and gastrointestinal inflammation in dogs with a chronic enteropathy

Vitamin D is traditionally known for its role in calcium homeostasis and bone metabolism. However, it has been demonstrated that numerous types of cells express the vitamin D receptor and it is now clear that the physiological roles of vitamin D extend beyond the maintenance of skeletal health. Vitamin D insufficiency, which is typically assessed by measuring the major circulating form of vitamin D, 25 hydroxyvitamin D (25(OH)D), has been associated with a number of disorders in people including hypertension, diabetes, cardiovascular diseases, cancer, autoimmune conditions and infectious diseases. Meta-analyses have demonstrated that serum 25(OH)D concentrations are an important predictor of survival in people with a wide variety of illnesses and have been linked to all-cause mortality in the general human population. The role of vitamin D in non-skeletal disorders in cats and dogs is poorly understood. This is surprising since cats and dogs could act as excellent models for probing the biology of vitamin D. Vitamin D status in people is largely dependent on cutaneous production of vitamin D. This is influenced by many factors such as season, latitude and exposure to ultraviolet (UV) radiation. The interpretation of human studies investigating the effects vitamin D status on disease outcomes are therefore influenced by a number of confounding variables. Unlike humans, domesticated cats and dogs do not produce vitamin D cutaneously and obtain vitamin D only from their diet. The physiological functions and regulation of vitamin D are otherwise similar to humans. Most pets are fed commercial diets containing a relatively standard amount of vitamin D. Consequently, companion animals are attractive model systems in which to examine the relationship vitamin D status and health outcomes. Furthermore, spontaneously occurring model systems which did not require disease to be induced in healthy animals would allow the numbers of animals used in scientist research to be reduced. This thesis aimed to define vitamin D homeostasis in companion animals in three disease settings; in cats with feline immunodeficiency virus (FIV) infection, dogs with chronic enteropathies (CE) and in hospitalised ill cats. Additional aims were to assess the prognostic significance of serum 25(OH)D concentrations in companion animals and the relationship between serum 25(OH)D concentrations and markers of inflammation. The hypothesis of this thesis was that vitamin status D would negatively correlate with presence of disease, markers of inflammation and disease outcomes. As similar findings have been demonstrated in human medicine, the hypothesis was that cats and dogs would be suitable models to investigate the role of vitamin D in human disease. This thesis demonstrates that in dogs with a CE serum 25(OH)D concentrations are negatively correlated with inflammation and are predictive of clinical outcomes. Vitamin D status was also lower in cats with FIV and importantly vitamin D status was predictive of short term mortality in hospitalised ill cats. This research will be of interest to veterinary surgeons and opens the possibility for clinical trials which examine if low vitamin D status is causally associated with ill health and whether vitamin D supplementation results in superior treatment outcomes in companion animals. This thesis also demonstrates the potential of cats and dogs as model systems in which to examine the role of vitamin D in human health