Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A trans-desidrocrotonina (t-DCTN) Ã o principal composto diterpenÃide presente no extrato da casca do caule de Croton cajucara (Euphorbiaceae). Este diterpeno possui um amplo espectro de atividades farmacolÃgicas que inclui antiinflamatÃria, antinociceptiva, e efeitos hipoglicemiante e hipolipidÃmico. SubstÃncias com esse perfil farmacolÃgico sÃo comumente associadas a efeitos deletÃrios sobre o fÃgado. Tendo em vista que estudos in vitro e in vivo mostraram uma hepatotoxicidade da t-DCTN, o presente estudo objetivou analisar em maior profundidade o seu potencial em causar dano hepÃtico e, entÃo, buscar estratÃgias farmacolÃgicas para mitigar tal toxicidade. Desta forma, os experimentos iniciais foram direcionados para observaÃÃo do dano hepÃtico em camundongos que receberam, por gavagem, uma Ãnica (aguda) ou repetidas administraÃÃes de t-DCTN, em doses que variam de 10 a 300 mg/kg. A segunda sÃrie de experiÃncias foi projetada para avaliar os efeitos do (i) prÃ-condicionamento com a menor dose de t-DCTN (10 mg/kg) ou etanol (1 g/kg), e do (ii) prÃ-tratamento com Vitamina E ou N-acetilcisteÃna (NAC) no dano hepÃtico associado a altas doses de t-DCTN em camundongos. Um possÃvel envolvimento de NO tambÃm foi verificado no efeito prÃ-condicionante de t-DCTN e/ou Etanol. t-DCTN em doses mais altas (100 e 300 mg/kg, v.o.) causou dano hepÃtico severo, comprovado por aumentos significativos (p <0,001) nos nÃveis sÃricos de ALT e AST e por alteraÃÃes histopatolÃgicas, quando administrada isolada ou repetidamente. Em contraste, as doses de 10 e 30 mg/kg nÃo promoveram alteraÃÃes significantes, sugerindo que a toxicidade da t-DCTN Ã dose dependente. O prÃ-condicionamento farmacolÃgico com t-DCTN (10 mg/kg, v.o.) e Etanol (1 g/kg, v.o.) atenuaram significativamente (p <0,001) a hepatotoxicidade associada a alta dose (100 mg/kg) de t-DCTN, como comprovado pela reduÃÃo na atividade das transaminases sÃricas, como tambÃm nas lesÃes hepÃticas. A suplementaÃÃo em camundongos com L-arginina, um substrato para geraÃÃo de NO, preveniu parcialmente o efeito hepatotÃxico da t-DCTN, possivelmente devido a um aumento na microcirculaÃÃo hepÃtica. Adicionalmente, o prÃ-tratamento com Vitamina E, mas nÃo com NAC, reduziu efetivamente os efeitos hepatotÃxicos de t-DCTN, comprovado pela diminuiÃÃo dos nÃveis sÃricos de ALT e AST, de TBARS hepÃtico e das alteraÃÃes histolÃgicas. Isto sugere que Vitamina E protege contra o aumento da peroxidaÃÃo lipÃdica hepÃtica promovido por alta dose de t-DCTN. Paradoxalmente, comparada a outros hepatotoxicantes relatados na literatura, a t-DCTN aumenta os nÃveis de glutationa hepÃtica que pode ser uma conseqÃÃncia do estresse oxidativo prolongado. Em conjunto, estes resultados confirmam as observaÃÃes anteriores sobre o potencial hepatotÃxico da t-DCTN e sugerem que um aumento no estresse oxidativo e na peroxidaÃÃo lipÃdica das membranas dos hepatÃcitos contribui para o dano hepÃtico desse diterpeno. A suplementaÃÃo com Vitamina E, um antioxidante lipossolÃvel, ou o prÃ-condicionamento com doses menores de t-DCTN ou etanol poderiam ser profilaticamente Ãtil para superar os efeitos hepatotÃxicos de t-DCTN / The trans-dehydrocrotonin (t-DCTN) is a major diterpenoid compound present in bark extracts of Croton cajucara (Euphorbiaceae) stem. This diterpene possesses a wide spectrum of pharmacological activity that include anti-inflammatory, antinociceptive, hypoglycemic and antihyperlipidemic effects. Deleterious effects on liver are not uncommon with substances having this pharmacological profile. Keeping in view the reported hepatotoxicity of t-DCTN in vitro and in vivo, the present study was carried out to analyse in greater depth its potential to cause hepatic damage and then to seek pharmacological strategies to mitigate such a toxicity. Accordingly, our initial experiments were aimed to observe the hepatic damage in mice that received the single (acute) or repeated administrations of t-DCTN by oral gavage, at doses ranging from 10 to 300 mg/kg. The second series of experiments were designed to evaluate the effects of (i) pre-conditioning with a smaller dose t-DCTN or ethanol, and (ii) pre-treatments with Vitamin E or NAC on high-dose -associated hepatic injury in mice. A possible involvement of NO was also verified on the pre-conditioning effects of t-DCTN and or Ethanol. t-DCTN at higher doses (100 e 300 mg/kg, v.o.) caused severe hepatic damage as evidenced by significant (p<0,001) increases in the serum levels of ALT and AST and histopathological alterations, whether administered singly or repeatedly. In contrast, at the doses of 10 e 30 mg/kg, there were no significant alterations suggesting that the toxicity is a dose-related one. Pharmacological pre-conditioning with t-DCTN (10 mg/kg, p.o.) e Ethanol (1 g/kg, p.o.) significantly (p<0,001) attenuated the high-dose t-DCTN (100 mg/kg) -associated hepatotoxicity, as evidenced by reductions in serum enzyme activities as well as the hepatic lesions. In mice supplemented with L-arginine, the substrate for NO generation only partially prevented the hepatotoxic effect of t-DCTN most possibly due to an improved hepatic microcirculation. Additionally, pre-treatment with Vitamin E but not the NAC effectively reduced hepatotoxic effect of t-DCTN, evidenced by diminished serum levels of ALT, AST and hepatic TBARS and histological alterations. This suggests that Vitamine E protects against the increased hepatic lipid peroxidation promoted by high-dose t-DCTN. Paradoxically, compared to other hepatotoxicants reported in literature, t-DCTN enhanced the hepatic glutathione levels, which may be a consequence of prolonged oxidative stress. Taken together, these results confirm the earlier observations on the hepatotoxic potential of t-DCTN and suggest that an increased oxidative stress and lipid peroxidation of hepatocyte membranes contributes to hepatic damage. Supplementation with liposoluble antioxidant Vitamina E, or prÃ-conditioning with smaller doses of t-DCTN or ethanol might be useful prophylactically to overcome hepatotoxic effects of t-DCTN

Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2015-03-17T11:16:45Z No. of bitstreams: 2 Dissertação - Barbara Martins Vieira - 2014.pdf: 1451459 bytes, checksum: 595a3718c8c4e83f9334cf6513f85119 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-03-20T14:04:37Z (GMT) No. of bitstreams: 2 Dissertação - Barbara Martins Vieira - 2014.pdf: 1451459 bytes, checksum: 595a3718c8c4e83f9334cf6513f85119 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-03-20T14:04:37Z (GMT). No. of bitstreams: 2 Dissertação - Barbara Martins Vieira - 2014.pdf: 1451459 bytes, checksum: 595a3718c8c4e83f9334cf6513f85119 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2014-08-22 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / The carbon tetrachloride (CCl4) is recognized as a classic hepatotoxin, being considered the best method to induce liver injury, commonly used as a model to test the hepatoprotective effect of drugs and natural substances and for investigation of hepatotoxicity, cytotoxicity and oxidative stress, in both in vivo and in vitro studies. This study aimed to standardize the lowest dose of CCl4 to cause acute liver injury by oxidative stress in Wistar rats. The in vivo experiment was carried out with 12 male Wistar rats (180-240g),which were maintained for 16 days under controlled environment and supplied with water and Purina® rodent ad libitum. The animals were separated into four groups: CG - control group; G0,5 - dose of 0.5 ml / kg body weight (bw); G0,75 - dose of 0.75 ml / kg bw and G1 - dose of 1 ml / kg bw. CCl4 was administered by intraperitoneal injection twice a week. 24h after the last CCl4 administration, all animals were anesthetized (xylazine: ketamine - 1: 1 v / v) for performing cardiac puncture, euthanasia and dissection of the liver for removal and analysis. Results obtained were subjected to normality test, and followed by the analysis of variance (ANOVA) and comparison of means (Tukey at 5% probability - post-hoc). It was observed that the mean weights of rats treated with CCl4 were higher than that of to the GC and the liver protein content (in g / 100 g) was lower in the treated groups, with no statistical difference between the test groups. Histopathological analysis showed changes in the structure, increased numbers of macrophages with intracellular lipid accumulation and increased cellular infiltration in groups treated with CCl4. By quantifying the enzymes alanine aminotransferase (ALT), aspartate and alanine aminotransferase (AST), it was found that the CCl4-treated groups showed significantly higher levels than CG, being higher in G1 compared to the other groups tested. All tested concentrations of CCl4 induced liver injury in vivo, in different degrees, and the concentration of 0.5 mL / kg bw, administered twice weekly, was the lowest dose tested that could cause changes in all the parameters evaluated. Therefore, this is the ideal dose for induction of acute liver injury, aiming to test the modulatory role of dietary and nutritional factors. / O Tetracloreto de Carbono (CCl4) é reconhecido como hepatotoxina clássica, sendo considerada a melhor substância para induzir lesão hepática, comumente utilizado como modelo para testar o efeito hepatoprotetor de drogas e substâncias naturais e para investigação de hepatotoxicidade, citotoxicidade e estresse oxidativo, tanto para estudos in vivo quanto in vitro. O presente estudo visou padronizar a menor dose de CCl4 capaz de provocar lesão hepática aguda por estresse oxidativo em ratos Wistar. O experimento in vivo foi realizado com 12 ratos Wistar adultos, machos, mantidos em condições de ambiente controladas e fornecimento de água e ração distribuídos ad libitum. O ensaio teve duração de 16 dias. Os animais foram separados em quatro grupos, sendo: GC – grupo controle; G0,5 – dose de 0,5 mL/kg de peso corporal (pc); G0,75 – dose de 0,75 mL/kg de pc e G1 – dose de 1 mL/kg de pc. O CCI4 foi administrado via injeção intraperitoneal, duas vezes por semana. Após 24h da última administração de CCI4, todos os animais foram anestesiados para realização de punção cardíaca, eutanásia e dissecação para retirada do fígado e análises. Os resultados obtidos foram submetidos ao teste de normalidade e, posteriormente, à análise de variância e comparação de médias. Observou-se que o peso do fígado dos ratos tratados com CCl4 foi maior em todos os grupos tratados em comparação ao GC e o teor protéico do fígado (em g/100g) foi menor nos grupos tratados, sem diferença estatística entre os grupos teste. As análises histopatológicas mostraram alteração na estrutura do tecido hepático, aumento do número de macrófagos com acúmulo intracelular de lipídeos e aumento do infiltrado celular nos grupos tratados com CCl4. Por meio da quantificação das enzimas alanina aminotransferase (ALT) e alanina aspartato aminotransferase (AST), verificou-se que os grupos tratados com CCl4 apresentaram concentrações significativamente mais elevadas em relação ao GC, sendo maiores no G1 em comparação aos demais grupos testados. Todas as concentrações de CCl4 testadas induziram lesão hepática, em diferentes graus, sendo a concentração de 0,5 mL/kg de pc, administrada duas vezes por semana, a menor dose testada que conseguiu provocar alterações em todos os parâmentos avaliados. Portanto, esta é a dose mais indicada para indução de lesão hepática aguda, objetivando testar o papel modulador de fatores alimentares e nutricionais.

A distrofia muscular dos cães Golden Retriever (GRMD), uma miopatia degenerativa causada pela ausência da distrofina é geneticamente homóloga a distrofia muscular de Duchenne que acomete humanos, portanto, estes cães são considerados modelos experimentais para estudos em terapia celular. Seu sucesso depende da imunossupressão adequada. A ciclosporina A (CsA) é indicada para tal, a monitorização de suas concentrações sangüíneas e efeitos adversos são essenciais para viabilizar a terapia. Foram estudados cães GRMD, e normais da mesma raça, submetidos a terapia com CsA, associada, nos GRMD, ao transplante. Foram avaliados as concentrações sangüíneas do fármaco e seus possíveis efeitos sobre as funções renal e hepática sendo consideradas as manifestações clínicas relacionadas, urinálise, hemograma, testes de função glomerular, e concentrações séricas de uréia, creatinina, alanina amino transferase (ALT), fosfatase alcalina (FA), cálcio, fósforo, sódio e potássio. Como resultados houve aumento discreto na uréia sérica de ambos os grupos; reações adversas como vômito, diarréia, tricose, periodontite e gengivite; diminuição dos níveis de ALT, cilindrúria e proteinúria e aumento da densidade urinária no grupo dos GRMD. As concentrações séricas de CsA oscilaram muito, em seis dos oito animais. Concluímos que maiores estudos devem ser realizados quanto à função renal dos GRMD e que as doses variam individualmente sendo de maior importância avaliar a concentração do fármaco no sangue e sua viabilização no uso da terapia celular. / The muscular dystrophy of Golden Retriever (GRMD) is a degenerative miopaty caused by the absence of dystrophy and it is genetically homologue of the Duchenne muscular dystrophy in humans, so, these dogs are considerably experimental models for studies on cellular therapy. Their successful depends of the adequate immunosuppression. Cyclosporin A (CsA) is indicated for that, the monitoring of the blood concentration and adverse effects are essential to viabilise the therapy. It was studied GRMD dogs, and normal dogs from the same breed, submitted for therapy with CsA, associated, on GRMD, of cell transplantation. It was evaluated blood concentration of the drug, and their possible effects on renal and hepatic functions has been considerate the clinic manifestations, urinalisis, blood counts, testis of glomerular function and blood concentrations of urea, cretinine, alanine aminotransferase, alkaline fosfatase, calcium, phosphorus, sodium and potassium. In our results we found a discrete increase of blood urea on booth groups; adverse reactions like vomits, diarrhea, tricose, periodontitis and gingivitis; decrease of blood alanine aminotransferase, increased levels of urine?s cylinders and protein and also increase of urinary density on GRMD group. The CsA blood concentrations oscillated too much on six than eight of our animals. We concluded that more researches wants to be done to evaluated renal functions of GRMD dogs and also that the doses varieties individually and the correct dosage as to important as the evaluation of the blood concentration of the drug and became viable for cell therapy.

L’objectif principal de l’étude était d’identifier les principaux médicaments associés aux hépatites aiguës (HA) associé aux médicaments (HAM) en France. Trois approches méthodologiques ont été définies. L’approche méthodologique principale est l’analyse cas-population. Les autres approches sont cas-propre témoin et cas témoins.Les cas ont été identifiés parmi les patients adultes présents dans le SNIIRAM, ayant une première hospitalisation entre 01/01/2010-31/12/2014 dont le diagnostic principal est une atteinte hépatique toxique (Classification Internationale des Maladies (CIM-10) K71.1, K71.2, K71.6, K71.9) ou une insuffisance hépatique(CIM-10 K72.0). La population de référence a été définie à partir de l’EGB. La date index (DI) considérée est la date de première hospitalisation pour HA. Les délivrances de l’ensemble des traitements précédant la DI ont été étudiées en considérant une exposition variant de 7 à 60 jours avant la DI. Les produits les plus fréquemment retrouvés sont classiques: antalgiques et en premier lieu le paracétamol, puis les produits à visée digestive symptomatique (inhibiteur de la pompe à protons, prokinétique, antispasmodique). Les suivants sont l’amoxicilline seule ou associée à l’acide clavulanique, l’ibuprofène, la codéine associée et le furosémide. L’ensemble de ces résultats pourra informer les autorités sanitaires, les praticiens et les patients sur le risque associé à chacune de ces molécules tant au plan individuel (risque absolu, risque attribuable), qu’au sein d’une famille de produits(risque relatif) ainsi que plus globalement pour la population et le système de santé(nombre absolu de cas attribuables). / The main objective of EPIHAM study is to identify the main drugs associated with drug induced liver injury leading to hospital admission (DILIH) in France and the event rates associated with DILIH. Three methodological approaches were defined. Principal approach is case-population. The others are case-crossover and case control analyses. Cases were identified among adult patients present in SNIIRAM database having a first hospitalization between 01/01/2010-2010/31/12/1204, the main diagnosis of which is toxic liver disease (diagnostic codes according to the International Classification of Diseases (ICD-10) K71.1, K71.2, K71.6, K71.9) orK72.0. Reference population was defined from the EGB. Index date (ID) was considered as the date of hospital admission for DILI. The dispensations of all treatments preceding the ID were studied by considering an exposure windowvarying from 7 to 60 days before ID. The most frequently found are classical: analgesics and firstly paracetamol, followed by drugs acting on digestive system (proton pump inhibitors, prokinetics, antispasmodics). The following were amoxicillinalone or combined with clavulanic acid, ibuprofen, codeine combinations, and furosemide. These results can inform health authorities, practitioners and patients about the acute hepatitis risk leading to hospitalisation associated with each of these molecules, both individually (absolute risk, attributable risk) and within a therapeutic drug family (relative risk) as well as more generally for the population and the health system (absolute number of attributable cases).

No description available.

Submitted by Adriana Martinez (amartinez@unoeste.br) on 2018-05-10T22:40:35Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Isabella Saneshigue.pdf: 688383 bytes, checksum: dcc746f15532dd8ee811a23185cc4201 (MD5) / Made available in DSpace on 2018-05-10T22:40:35Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Isabella Saneshigue.pdf: 688383 bytes, checksum: dcc746f15532dd8ee811a23185cc4201 (MD5) Previous issue date: 2017-11-24 / Accidents caused by venom of Crotalus snakes, popularly known in Brazil as rattlesnake, cause the highest number of deaths in humans and animals, mainly due to the great neurotoxic, myotoxic, coagulant, nephrotoxic and hepatotoxic potential of their venom. The present study had the objective of analyzing by histology and fractal dimension liver samples of Wistar rats experimentally poisoned with venom of the snake Crotalus durissus terrificus. The hypothesis is that the venom of Crotalus durissus terrificus is capable of inducing hepatic damage at the dose recommended in this study, that its alterations can be quantified by the fractal dimension and that the antiofidic serum be able to minimize the hepatic lesions induced by the venom. Ninety rats were divided into different groups and treated with: control group (GC, n = 30) 0.9% sodium chloride solution; venom group (GV, n = 30) crotalic venom; (GVS, n = 30) Crotalic venom and antiofidic serum 6 hours after the application of the venom. Liver samples were collected at 2h (M1), 8h (M2) and 24h (M3) after venom administration and submitted to histological analysis and fractal dimension (DF) using the ImageJ® software and box-counting method. Procedures for collecting, processing and analyzing samples were standardized. No significant lesions were observed in GC and GV. Necrosis, cytoplasmic and nuclear vacuolization and absence of inflammatory infiltrate were observed in M2 and M3, whereas in GVS, mononuclear inflammatory infiltrate was evident at all times, in addition to the lesions found in GV. The lesions of necrosis, cytoplasmic and nuclear vacuolization, considered of greater severity were visualized in M3 in both GV and GVS. There was an increase in DF for the same changes in GV and GVS over time, but with no difference between them, but with a significant difference compared to CG. The lesions evidenced in the liver were not minimized by the application of the antiofidic serum. This study agrees with other authors about the hepatotoxicity of crotalic venom in relation to histological findings and the results indicate an increase in FD for the findings of vacuolization and necrosis, proving to be an efficient method for the quantitative evaluation of morphological changes induced by venom without observer interference. In addition, non-protection of the liver by antiofidic serum was evident. It is concluded that Crotalus durissus terrificus venom has hepatotoxic effects; FD is effective in the quantitative morphological evaluation of the liver for vacuolization and necrosis, and antiofidic serum did not protect the liver from venom-induced lesions. / Os acidentes causados pelo veneno das serpentes do gênero Crotalus, conhecidas popularmente no Brasil como cascavel, causam o maior índice de óbitos em seres humanos e animais, principalmente pelo grande potencial neurotóxico, miotóxico, coagulante, nefrotóxico e hepatotóxico do seu veneno. O presente estudo teve por objetivo analisar pela a dimensão fractal e achados histológicos em amostras de fígado de ratos Wistar intoxicados experimentalmente com veneno da serpente Crotalus durissus terrificus. A hipótese é que o veneno da Crotalus durissus terrificus seja capaz de induzir lesão hepática na dose preconizada neste estudo, que suas alterações possam ser quantificadas pela dimensão fractal e que o soro antiofídico seja capaz de minimizar as lesões hepáticas induzidas pelo veneno. Noventa ratos, foram distribuídos em diferentes grupos e tratados com: grupo controle (GC, n=30) solução de cloreto de sódio 0,9%; grupo veneno (GV, n=30) veneno crotálico; grupo veneno/soro antiofídico (GVS, n=30) veneno crotálico e soro antiofídico 6 horas após aplicação do veneno. As amostras do fígado foram realizadas nos momentos 2h (M1), 8h (M2) e 24h (M3) após administração do veneno e submetidas a análise histológica e dimensão fractal (DF) utilizou o software ImageJ® e método de box-counting. Os procedimentos para coletar, processar e analisar as amostras foram padronizados. Não foram observadas lesões significativas no GC e no GV foram evidenciadas necrose, vacuolização citoplasmática e nuclear e ausência de infiltrado inflamatório nos M2 e M3, enquanto que no GVS evidenciou-se infiltrado inflamatório mononuclear em todos os momentos, além das lesões constatadas no GV. As lesões de necrose, vacuolização citoplasmática e nuclear, consideradas de maior severidade foram visualizadas no M3 tanto no GV quanto no GVS. Observou-se uma elevação da DF para as mesmas alterações nos GV e GVS ao longo do tempo, porém sem diferença entre eles, mas com diferença significativa comparado ao GC. As lesões evidenciadas em fígado não foram minimizadas pela aplicação do soro antiofídico. Este estudo concorda com outros autores quanto a hepatotoxicidade do veneno crotálico frente aos achados histológicos e os resultados apontam aumento da DF para os achados de vacuolização e necrose, mostrando ser um método eficaz na avaliação quantitativa de alterações morfológicas induzidas pelo veneno, sem a interferência do observador. Além disso, a não proteção do fígado pelo soro antiofídico foi evidente. Conclui-se que o veneno de Crotalus durissus terrificus apresenta efeitos hepatotóxicos; a DF é eficaz na avaliação morfológica quantitativa do fígado para vacuolização e necrose, e o soro antiofídico não protegeu o fígado de lesões induzidas pelo veneno.

L’overdose au paracétamol est l’une des intoxications médicamenteuses la plus fréquente au monde, caractérisée par une atteinte hépatique dont l’issue peut être fatale. Les études réalisées sur ce phénomène ont montré que la phase initiale de la toxicité est induite par le métabolite actif du paracétamol, le N-acétyl-p-benzoquinone imine (NAPQI). Ce dernier, en l’absence de quantité suffisante de glutathion, s’accumulent dans la cellule et finit par se lier à d’autres protéines, principalement mitochondriales, formant alors des adduits. Cette liaison va altérer la fonction primaire des protéines et conduire, en cas d’overdose sévère, à la mort des hépatocytes. La mort cellulaire s’accompagne alors de la libération de composants cellulaire dont le rôle sera d’alerter le système immunitaire des lésions tissulaires. Ces composants prennent alors le nom d’«alarmines» ou de « damage-associated molecular patterns » (DAMPs). La protéine HMGB1 (High Mobility Group Box 1) fait partie de cette catégorie.Au cours de cette thèse nous nous sommes intéressés de plus près à la protéine HMGB1, à son origine ainsi qu’à son rôle dans l’amplification et la propagation des lésions hépatiques initialement induites par l’overdose au paracétamol. Nos travaux se sont d’abord portés sur l’étude de la protéine HMGB1 dans un modèle murin d’hépatite au paracétamol. Nos expériences nous permettent, d’une part, de confirmer que la libération d’HMGB1 est liée à la sévérité des lésions hépatiques et d’autre part, de démontrer que l’amplification et la propagation de ces lésions, dans les phases précoces de l’intoxication au paracétamol, peuvent se produire indépendamment des cellules immunitaires. Sur base de ces résultats, nous avons émis l’hypothèse de l’existence d’un dialogue entre la protéine HMGB1 et les hépatocytes plutôt que du dialogue, généralement décrit dans la littérature, entre la protéine HMGB1 et les cellules du système immunitaire Nos travaux se sont donc poursuivis, in vitro, sur une lignée cellulaire d’hépatocytes humains, les cellules HepaRG. Ces expériences nous ont permis, d’une part, de confirmer l’implication de la protéine HMGB1 dans l’hépatotoxicité au paracétamol et de mettre en évidence la capacité de cette protéine à provoquer, sans intermédiaire, la mort des cellules HepaRG. D’autre part, ces expériences nous permettent de suggérer la participation de la protéine HMGB1 dans la propagation et l’amplification de la mort des hépatocytes exposés au paracétamol par une voie de signalisation impliquant l’axe TLR4/TRIF/RIPK3. Finalement, l’inhibition de la protéine HMGB1 semblant être bénéfique, nous avons investigué la potentielle efficacité de l’administration d’une combinaison de N-acétylcystéine et de glycyrrhizine dans notre modèle murin. L’idée était de combiner une drogue qui agit sur l’accumulation du métabolite toxique et une seconde qui agit sur la phase de propagation du signal. Nos résultats, bien que préliminaires, ont démontré l’efficacité de cette combinaison à la fois sur la nécrose hépatique et sur la survie des souris. En conclusion, nos travaux confirment l’importance du rôle joué par la protéine HMGB1 dans l’hépatotoxicité induite par le paracétamol et nous permettent de mettre en évidence un nouveau mécanisme, impliquant la protéine HMGB1, qui pourrait contribuer à l’amplification et la propagation des lésions hépatiques induites par une overdose de paracétamol. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

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Niacin is a highly effective, lipid regulating drug associated with a number of metabolically induced side effects such as prostaglandin (PG) mediated flushing and hepatic toxicity. In an attempt to reduce the development of these adverse effects, scientists have investigated differing methods of niacin delivery designed to control drug release and alter metabolism. However, despite successful formulation of various orally based capsule and tablet delivery systems, patient adherence to niacin therapy is still compromised by adverse events such as PG-induced flushing. While the primary advantage of orally dosed formulations is ease of use, alternative delivery options such as transdermal delivery or polymeric micro/nanoparticle encapsulation for oral administration have shown promise in niacin reformulation. However, the effectiveness of these alternative delivery options in reducing inimical effects of niacin and maintaining drug efficacy is still largely unknown and requires more in-depth investigation. In this paper, we present an overview of niacin applications, its metabolic pathways, and current drug delivery formulations. Focus is placed on oral immediate, sustained, and extended release niacin delivery as well as combined statin and/or prostaglandin antagonist niacin formulation. We also examine and discuss current findings involving transdermal niacin formulations and polymeric micro/nanoparticle encapsulated niacin delivery.

Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets.