No description available.

We hypothesized that with exercise training and the subsequent attenuation of hyperglycemia, β-cell adaptation to worsening insulin resistance would be maintained. Also, because classical stress-activated systems and oxidative stress are involved in hepatic insulin resistance we examined if exercise would be associated with improvements in hepatic markers of oxidative stress and inflammation. Exercise maintained fasted hyperinsulinemia and preserved normoglycemia in male Zucker diabetic fatty (ZDF) rats. β-cell function calculations indicate prolonged β-cell adaptation in exercised animals. Such improved β-cell function was associated with increased β-cell mass. Hypertrophy and replication contributed to expansion of β-cell mass; exercised animals had increased β-cell size and bromodeoxyuridine (BrdU) incorporation rates versus controls. Furthermore, we observed augmented β-cell-specific immunohistochemical staining of GLUT2 and Akt/PKB in exercised versus sedentary controls. We also observed large cytoplasmic ubiquitinated structures which form in response to oxidative stress in pancreatic tissue samples from hyperglycemic ZDF rats. In the exercised groups such aggregate numbers were reduced to numbers compared to those seen in younger non-diabetic basal ZDF animals and age-matched lean Zucker rats. With respect to the liver we investigated whether exercise alters kinases such as c-Jun NH2-terminal kinase (JNK) and IKKβ (as evidenced by IκBα levels) and related insulin receptor substrate-1 (IRS-1) serine phosphorylation which are associated with hepatic insulin resistance in obesity. On average, exercised animals ran 5250m/day which improved insulin sensitivity based on the homeostasis model assessment for insulin resistance (HOMA-IR) calculations, and maintained fed and fasted glucoregulation and glucose tolerance. Ten weeks of running decreased whole-body markers of inflammation and oxidative stress in the blood and in the liver. Exercise lowered circulating interleukin-6 (IL-6), haptoglobin, malondialdehyde (MDA) levels, and protein oxidation in the liver. Exercise reduced phosphorylated JNK (pJNK) indicating decreased JNK activity; in accordance serine phosphorylated IRS-1 was reduced in exercised rats. In conclusion, improvements in glucoregulation were associated with increased β-cell compensation at least in part due to a reduction in oxidative stress. Furthermore, we show exercise attenuates development of hyperglycemia in ZDF rats in association with decreases in plasma and hepatic markers of inflammation, oxidative stress, JNK activation, and serine phosphorylation of IRS-1.

A nutrição é um dos principais fatores que afetam a eficiência reprodutiva por influenciar o crescimento, maturação e capacidade ovulatória do folículo bem como o perfil e estado metabólico do animal, gerando cenários que prejudicam ou corroboram o desenvolvimento e estabelecimento da prenhez. Diferentes fontes energéticas utilizadas na nutrição são capazes de alterar os padrões de fermentação ruminal e causar respostas endócrinas distintas. A partir disso, os objetivos desse estudo foram avaliar de que forma duas fontes energéticas da dieta influenciam a produção embrionária, a expressão gênica de enzimas hepáticas que metabolizam progesterona (P4) e a insulinemia. Em um delineamento em crossover, 22 vacas holandesas não lactantes e não gestantes foram distribuídas em dois grupos: um recebendo milho e outro polpa cítrica como fonte de energia da dieta. A quantidade de alimento fornecida foi de 1,3% do peso corporal em matéria seca por dia. O estudo foi composto por dois períodos de 71 dias de duração e em cada um deles foram realizadas duas superovulações (aos 35 e aos 70 dias) e uma biópsia hepática (aos 71 dias). Amostras sanguíneas foram colhidas imediatamente antes do fornecimento do alimento e 4 horas após, em dias pré-determinados, para dosagem de glicose, insulina e P4. Ao final do estudo as vacas passaram por teste de tolerância à glicose (TTG). Foi quantificada a expressão gênica de enzimas que metabolizam a P4 por RT-qPCR. A análise estatística foi realizada por meio de regressão logística pelo Proc MIXED do SAS 9.3. Os dados de expressão gênica foram avaliados por meio de delta CT. Imediatamente antes do fornecimento do alimento, a insulina circulante foi maior para o grupo milho (P < 0,01) e a P4 circulante foi maior para o grupo polpa cítrica (P < 0,01). Quatro horas após a alimentação, a P4 foi igual entre os tratamentos. A relação da P4 circulante na hora 4 e 0 foi maior para o grupo milho (P < 0,01). Tanto a glicose basal como o Homa-IR (Homeostasis model assessment of insulin resistance) foram maiores para o grupo milho. No TTG, o grupo milho apresentou maior pico de glicose no momento 5 minutos, maior taxa de decaimento da glicose (P = 0,01) e menor tempo de meia vida da glicose (P = 0,05). Não houve efeito de tratamento na resposta superestimulatoria, superovulatória, produção de embriões e na expressão gênica das enzimas que metabolizam a P4, mas as superovulações realizadas aos 70 dias produziram embriões de qualidade inferior em relação às realizadas aos 35 dias, independente de tratamento. Conclui-se que, embora tenha sido possível alterar a insulina circulante através da dieta, a quantidade e qualidade de embriões produzidos não foram alteradas. O aumento pós-prandial da P4 circulante não foi relacionado a menor expressão gênica das enzimas hepáticas que metabolizam a P4. / Nutrition is one of the main factors affecting reproductive efficiency by influencing the growth, maturation and ovulatory capacity of the follicle and metabolic status of the animal, leading to scenarios that impair or corroborate the development and establishment of pregnancy. Different energy sources in the composition of the diet can alter ruminal fermentation patterns and cause different endocrine responses. The objectives of this study were to evaluate how two different energy sources in the diet can influence embryo production, gene expression of liver enzymes that metabolize progesterone (P4) and circulating insulin. In a crossover design, 22 non-lactating and non-pregnant Holstein cows were allocated into two groups: one receiving corn and other receiving citrus pulp as the energy supply of the diet. The amount of feed provided was 1.3% of body weight of dry matter per day. The study consisted of two 71-days periods and cows were superovulated twice on each period (at 35 and 70 days). Liver biopsy was performed after 71 days from the beginning of each replicate. Blood was sampled immediately before feeding and 4 hours later, at predetermined days, for measurement of glucose, insulin and P4. At the end of the study cows underwent a glucose tolerance test (GTT). Gene expression of liver enzymes that metabolize P4 was quantified by RT-qPCR. Statistical analysis was performed using logistic regression of Proc Mixed of SAS 9.3. Gene expression data were evaluated using delta CT. Immediately before feeding, the circulating insulin was greater for the corn group (P < 0.01) and circulating P4 was greater for the citrus pulp group (P < 0.01). Four hours after feeding, circulating P4 was similar. The relationship of circulating P4 between hour 4 and 0 was greater for the corn group (P < 0.01). Both basal circulating glucose and HOMA-IR (Homeostasis model assessment of insulin resistance) were greater for the corn group. The corn group had also greater glucose peak at the time 5 minutes of the GTT, greater glucose rate of decay (P = 0.01) and a shorter half-life of glucose (P = 0.05). There was no treatment effect on superstimulatory and superovulatory response, on embryo production and on gene expression of liver enzymes that metabolize P4. However, superovulations performed at 70 days produced lower embryo quality compared to those performed at 35 days, regardless of treatment. In conclusion, although it was possible to change circulating insulin by feeding different diets, the quantity and quality of embryos produced were not affected by the diets. The postprandial increase in circulating P4 was not associated with altered gene expression of hepatic enzymes that metabolize P4.

A capacidade extraordinária de crescimento do tecido hepático pode ser estimulada por dois processos, a hepatectomia parcial ou pelo fornecimento de substâncias hepatotróficas. Neste trabalho, foi adotada a segunda opção para tratar fígados de rata com fibrose, verificando-se o efeito dos fatores hepatotróficos sobre o quadro histopatológico, a proporção volumétrica do colágeno e a condição funcional do fígado de ratas Wistar com fibrose induzida por dimetilnitrosamina. Após 5 semanas de tratamento. Os animais foram submetidos à biópsia hepática e divididos em 2 grupos: o Grupo C recebeu 40 ml/kg de solução fisiológica por via intraperitoneal a cada 12h, durante 10 dias consecutivos e o Grupo F recebeu fatores hepatotróficos na mesma dosagem e freqüência que as do Grupo C. O sangue foi colhido momentos antes do sacrifício e em seguida amostras dos fígados foram levadas à rotina de fixação e inclusão para microscopia de luz. O exame histopatológico mostrou a presença de lesões características de fibrose hepática, tais como: nódulos regenerativos, proliferação de ductos biliares, infiltrado inflamatório com presença de células ovais e megalocitose de hepatócitos, sendo que os animais do Grupo F apresentaram redução do quadro acima descrito. O peso dos animais do grupo F aumentou 13%, o peso do fígado aumentou 12,2% e o peso do fígado em relação ao peso da carcaça aumentou 16%. A densidade volumétrica do colágeno no lóbulo hepático reduziu-se em 43% no grupo F, enquanto que no Grupo C houve aumento de 6%. O colágeno perivascular na veia centrolobular aumentou 42,7% no grupo C e reduziu-se 43,4% no grupo F. No espaço porta o colágeno perivascular aumentou 6,7% no grupo C e reduziu 67,3% no grupo F. A concentração sérica de albumina no Grupo C foi de 3,8g/l e no Grupo F de 4,7g/l. A proteína total foi 6,1g/l no Grupo C e no Grupo F de 7g/l. A aspartato aminotransferase AST foi 148,3 U/l no Grupo C e 94,9 U/lno Grupo F, a alanina aminotransferase ALT foi 86,9 U/l no Grupo C e 44,1 U/l no Grupo F. Concluiu-se assim, que os fatores hepatotróficos injetados intraperitonealmente, reduziram o quadro histopatológico e a densidade volumétrica do colágeno, promovendo melhor resposta da função hepática no Grupo F quando comparado com o Grupo C. / The extraordinary capacity of growth of hepatic tissue can be stimulated by two processes, by the partial hepatectomy or by hepatotrophic substance supply. In this work, it was adopted the second option to treat rats with induced-fibrosis, verifying the effect of the hepatotrophic factors on the histopathological evaluation, the ratio volumetric of the collagen and the functional condition of the liver of Wistar rats with induced-fibrosis by dimetilnitrosamine. After 5 weeks of treatment, the animals had been submitted to hepatic biopsies and divided in 2 groups: Group C received 40 ml/kg of physiological solution by intraperitoneal application each 12h, during 10 consecutive days and Group F received hepatotrophic factors in same dosage and frequency of Group C. Blood collection was proceeded moments before the sacrifice and samples of the liver had been submitted to the light microscopy routine of fixation and inclusion. The histopathologic evaluation showed the presence of characteristic injuries of hepatic fibrosis, such as: regenerative nodules, biliar ducts proliferation, inflammatory infiltrated with presence of oval cells and hepatocyte megalocytes, and the animals of Group F presented reduction of the above description. The weight of the animals of group F increased 13%, the weight of the liver increased 12.2% and the weight of the liver in relation to the weight of the carcass increased 16%. The volumetric collagen density in hepatic lobe decreased 43% in group F, while in Group C it icreased 6%. The central lobular vein perivascular collagen increased in 42.7% in group C and decreased 43.4% in group F. In the portal space, the perivascular collagen increased 6.7% in group C and reduced 67.3% in group F. The serum concentration of albumen in Group C was 3,8g/l and in Group F 4,7g/l. The total protein was 6,1g/l in Group C and in Group F 7g/l. The aspartate aminotransferase AST was 148,3 U/l in 94,9 Group C and U/l in Group F, alanine aminotransferase ALT was 86,9 U/l in 44.1 Group C and U/l in Group F. We concluded the intraperitoneal hepatotrophic factors injection had reduced the histopathological signs and the collagen volumetric density, promoted better recovery of the hepatic function in Group F when compared to Group C.

A conexina 32 (Cx32) é uma estrutura protéica que constitui os canais que promovem as comunicações intercelulares via junções comunicantes (GJIC), permitindo difusão de pequenas moléculas citoplasmáticas de uma célula à outra. Este trabalho objetivou os estudos destas estruturas devido a sua importância em processos hepáticos, mais especificamente, a fibrose hepática. O presente estudo foi realizado através da administração oral da droga hepatotoxica dimetilnitrosamina (DMN) em ratas Wistar duas vezes por semana em dias consecutivos no prazo de cinco semanas. A necropsia destes animais foi realizada após cinco semanas da última administração da droga e revelou um quadro de fibrose hepática, em contra partida aos resultados obtidos em um grupo controle com a mesma quantidade de animais. O material fibrótico foi submetido à análise imunohistoquímica que revelou uma presença preferencial de Cx32 dispersa no citoplasma, o que pode levar à hipótese de problemas no mecanismo de transporte citoplasmático destas estruturas, em contrapartida ao material pertencente ao grupo controle que evidenciou a presença das Cx32 na membrana plasmática formando placas juncionais. Quando submetido à análises moleculares o fígado fibrótico revelou uma diminuição da expressão gênica embora o produto protéico deste material quando comparado ao grupo controle não tenha se mostrado diminuído. / The connexin 32 (Cx32) is a proteic structure that constitute the channels that promote the cell communication by means of the gap junction (GJIC), allowing the diffusion of short cytoplasmic molecules from a cell to another. This work aimed to study these structures due to their importance in the hepatic metabolic processes. The hepatic fibrosis was triggered by the oral administration of dimethylnitrosamine (DMN) in the female rat Wistars twice a week in consecutive days during five weeks. The necropsy of these animals was carried out after the last drug administration. They presented a hepatic fibrosis state. The fibrotic material was submitted to the imunohistochemical analysis, which showed a preferencial presence of Cx32 in the cytoplasm, whereas in the control group the Cx32 was located at the membranes, in the junctional plaques. The molecular analysis showed a decrease of the genic expresson of the fibrotic material, however the proteic product wasn? t reduced in comparison with the control group as it was shown by western blot. We concluded that the fibrotic state introduced a disturbance in the intracellular distribution and genic expression of the connexin 32.

by Ho Wai-chun. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references. / Abstract also in Chinese. / Title / Dedication / Abstract --- p.i / Table of Contents --- p.iv / Glossary of abbreviation used in the thesis --- p.vi / List of figures --- p.viii / List of tables --- p.xvii / Acknowledgement --- p.xix / Statement of Originality --- p.xx / Chapter Chapter 1 ...... --- Introduction --- p.14 / Chapter Chapter 2...... --- Basic Principle / Chapter 2.1 --- The liver - a vital organ --- p.2-1 / Chapter 2.2 --- Blood supply to the liver --- p.2-7 / Chapter 2.3 --- Normal arterial anatomy of the coeliac axis --- p.2-11 / Chapter 2.4 --- Common anomalies of the coeliac axis --- p.2-17 / Chapter 2.5 --- Previous classification of coeliac anomaies --- p.2-24 / Chapter 2.6 --- Knowledge of arterial anomaly in relation to surgery --- p.2-31 / Chapter 2.7 --- Trans-catheter treatment of hepatocellular carcinoma --- p.2-33 / Chapter 2.8 --- Prevalence of hepatocellular carcinoma in H.K Chinese --- p.2-42 / Chapter 2.9 --- Management of hepatocellular carcinoma in Hong Kong --- p.2-43 / Chapter Chapter 3...... --- Definitions --- p.3-1 / Chapter Chapter 4...... --- Objectives of the study --- p.4-1 / Chapter Chapter 5...... --- "Materials, methods and subjects" / Chapter 5.1 --- Materials --- p.5-1 / Chapter 5.2 --- Methods --- p.5-3 / Chapter 5.3 --- Subjects --- p.5-10 / Chapter Chapter 6...... --- Results / Chapter 6.1 --- Coeliac axis --- p.6-5 / Chapter 6.2 --- Common hepatic artery --- p.6-9 / Chapter 6.3 --- Proper hepatic artery --- p.6-11 / Chapter 6.4 --- Right hepatic artery --- p.6-12 / Chapter 6.5 --- Middle hepatic artery --- p.6-20 / Chapter 6.6 --- Left hepatic artery --- p.6-28 / Chapter 6.7 --- Gastroduodenal artery --- p.6-33 / Chapter 6.8 --- Right gastric artery --- p.6-37 / Chapter 6.9 --- Left gastric artery --- p.5-45 / Chapter 6.10 --- Splenic artery --- p.6-49 / Chapter 6.11 --- Summary of results --- p.6-51 / Chapter Chapter 7...... --- Discussion / Chapter 7.1 --- Introduction --- p.74 / Chapter 7.2 --- Selective Internal Radiation --- p.7-3 / Chapter 7.3 --- Coeliac axis --- p.7-10 / Chapter 7.4 --- Common hepatic & proper hepatic artery --- p.7-7 / Chapter 7.5 --- Right hepatic artery --- p.7-14 / Chapter 7.6 --- Middle hepatic artery --- p.7-18 / Chapter 7.7 --- Left hepatic artery --- p.7-25 / Chapter 7.8 --- Gastroduodenal artery --- p.7-30 / Chapter 7.9 --- Right gastric artery --- p.7-35 / Chapter 7.10 --- Left gastric artery --- p.7-43 / Chapter 7.11 --- Splenic artery --- p.7-45 / Chapter 7.12 --- Comparison with the golden classics --- p.7-47 / Chapter 7.13 --- Comparison of subjects with HCC & without HCC --- p.7-50 / Chapter 7.14 --- Comparison of the male group and the female group --- p.7-51 / Chapter Chapter 8...... --- Conclusions / References --- p.B-1 / Bibliography --- p.B-1 / Appendix I Schematic diagram of histological anatomy of the liver --- p.A-l / Appendix II Embryology --- p.A-2 / "Appendix III Percentages of occurrence of the different types of coeliac axis, by Michels' study" --- p.A-3 / "Appendix IV Percentages of occurrence of the different types of the hepatic arterial blood supply, by Michels' study" --- p.A-4 / Appendix V No. of deaths from malignant liver cancer in Hong Kong froml984 to1993 --- p.A-5 / Appendix VI Flow chart for HCC management in PWH of Hong Kong --- p.A-6 / Appendix VII Comparison with Michels' study --- p.A-7 / Appendix VIII Comparison of the group with HCC and the group without HCC --- p.A-8 / Appendix IX Comparison of the male and female group --- p.A-9

Background: Hepatic ischemia reperfusion injury (IRI) results from the interruption and then reinstatement of the liver’s blood supply. IRI involves both an ischemic and an immune-mediated reperfusion phase of tissue injury; similar inflammatory events are seen in other forms of acute (sterile) liver injury (ALI), including paracetamol toxicity. Hypothesis Irrespective of the primary insult, common pathways exist in the pathophysiology of the lymphocyte-mediated secondary liver injury. Natural mechanisms exist to limit lymphocyte function and these pathways can be targeted therapeutically by immunomodulatory agents. Aims: 1. To assess the relative importance of different lymphocyte subsets in IRI. 2. To correlate observations in IRI with other models of ALI. 3. To identify possible pharmacological targets. Materials and Methods Three experimental murine models of acute liver injury were utilised to test this hypothesis: murine model of warm hepatic IRI, concanavalin A (con A) hepatitis and paracetamol-induced liver injury. These models were interrogated with a combination of (transgenic and knockout) mouse lines, in vivo antibody depletion and small molecule inhibition. Injury was evaluated primarily in terms of the biochemical marker of liver injury alanine aminotransferase (ALT). Data were correlated with human tissue where possible. Results: T cells (CD3εKO vs WT p=0.010), but not other lymphocyte populations (B cells, NK cells, or other innate lymphoid cells), play a central role in warm hepatic IRI. Programmed Death Receptor-1 (PD-1) is a negative regulator of pro-inflammatory cytokine production by T cells and the absence of PD-1 was associated with significantly worse hepatic IRI (p=0.034), con A hepatitis (p=0.00020) and paracetamol-induced liver injury (p=0.0050). Interferon-γ (IFNγ) and T-box expressed in T cells (T-bet) are important mediators of hepatic IRI (p=0.017) and paracetamol induced liver injury (p=0.0007). The absence of IL-6 was associated with significant protection in paracetamol induced liver injury (p=0.006). The infiltrates within the recipient liver of patients transplanted following paracetamol overdose stain positively for PD-1, IFNγ and T-bet. The Janus family of kinases (JAK) play an important role in the common pathways of cytokine signal transduction. In vivo use of a selective JAK1/JAK2 inhibitor is protective in hepatic IRI (p=0.0014), con A hepatitis (p=0.019) and paracetamol-induced liver injury (p=0.0045). Conclusions: Common pathways appear to exist in the immune-mediated secondary phase of injury in ALI. Targeting these pathways will complement existing (cytoprotective) treatment strategies.

A nutrição é um dos principais fatores que afetam a eficiência reprodutiva por influenciar o crescimento, maturação e capacidade ovulatória do folículo bem como o perfil e estado metabólico do animal, gerando cenários que prejudicam ou corroboram o desenvolvimento e estabelecimento da prenhez. Diferentes fontes energéticas utilizadas na nutrição são capazes de alterar os padrões de fermentação ruminal e causar respostas endócrinas distintas. A partir disso, os objetivos desse estudo foram avaliar de que forma duas fontes energéticas da dieta influenciam a produção embrionária, a expressão gênica de enzimas hepáticas que metabolizam progesterona (P4) e a insulinemia. Em um delineamento em crossover, 22 vacas holandesas não lactantes e não gestantes foram distribuídas em dois grupos: um recebendo milho e outro polpa cítrica como fonte de energia da dieta. A quantidade de alimento fornecida foi de 1,3% do peso corporal em matéria seca por dia. O estudo foi composto por dois períodos de 71 dias de duração e em cada um deles foram realizadas duas superovulações (aos 35 e aos 70 dias) e uma biópsia hepática (aos 71 dias). Amostras sanguíneas foram colhidas imediatamente antes do fornecimento do alimento e 4 horas após, em dias pré-determinados, para dosagem de glicose, insulina e P4. Ao final do estudo as vacas passaram por teste de tolerância à glicose (TTG). Foi quantificada a expressão gênica de enzimas que metabolizam a P4 por RT-qPCR. A análise estatística foi realizada por meio de regressão logística pelo Proc MIXED do SAS 9.3. Os dados de expressão gênica foram avaliados por meio de delta CT. Imediatamente antes do fornecimento do alimento, a insulina circulante foi maior para o grupo milho (P < 0,01) e a P4 circulante foi maior para o grupo polpa cítrica (P < 0,01). Quatro horas após a alimentação, a P4 foi igual entre os tratamentos. A relação da P4 circulante na hora 4 e 0 foi maior para o grupo milho (P < 0,01). Tanto a glicose basal como o Homa-IR (Homeostasis model assessment of insulin resistance) foram maiores para o grupo milho. No TTG, o grupo milho apresentou maior pico de glicose no momento 5 minutos, maior taxa de decaimento da glicose (P = 0,01) e menor tempo de meia vida da glicose (P = 0,05). Não houve efeito de tratamento na resposta superestimulatoria, superovulatória, produção de embriões e na expressão gênica das enzimas que metabolizam a P4, mas as superovulações realizadas aos 70 dias produziram embriões de qualidade inferior em relação às realizadas aos 35 dias, independente de tratamento. Conclui-se que, embora tenha sido possível alterar a insulina circulante através da dieta, a quantidade e qualidade de embriões produzidos não foram alteradas. O aumento pós-prandial da P4 circulante não foi relacionado a menor expressão gênica das enzimas hepáticas que metabolizam a P4. / Nutrition is one of the main factors affecting reproductive efficiency by influencing the growth, maturation and ovulatory capacity of the follicle and metabolic status of the animal, leading to scenarios that impair or corroborate the development and establishment of pregnancy. Different energy sources in the composition of the diet can alter ruminal fermentation patterns and cause different endocrine responses. The objectives of this study were to evaluate how two different energy sources in the diet can influence embryo production, gene expression of liver enzymes that metabolize progesterone (P4) and circulating insulin. In a crossover design, 22 non-lactating and non-pregnant Holstein cows were allocated into two groups: one receiving corn and other receiving citrus pulp as the energy supply of the diet. The amount of feed provided was 1.3% of body weight of dry matter per day. The study consisted of two 71-days periods and cows were superovulated twice on each period (at 35 and 70 days). Liver biopsy was performed after 71 days from the beginning of each replicate. Blood was sampled immediately before feeding and 4 hours later, at predetermined days, for measurement of glucose, insulin and P4. At the end of the study cows underwent a glucose tolerance test (GTT). Gene expression of liver enzymes that metabolize P4 was quantified by RT-qPCR. Statistical analysis was performed using logistic regression of Proc Mixed of SAS 9.3. Gene expression data were evaluated using delta CT. Immediately before feeding, the circulating insulin was greater for the corn group (P < 0.01) and circulating P4 was greater for the citrus pulp group (P < 0.01). Four hours after feeding, circulating P4 was similar. The relationship of circulating P4 between hour 4 and 0 was greater for the corn group (P < 0.01). Both basal circulating glucose and HOMA-IR (Homeostasis model assessment of insulin resistance) were greater for the corn group. The corn group had also greater glucose peak at the time 5 minutes of the GTT, greater glucose rate of decay (P = 0.01) and a shorter half-life of glucose (P = 0.05). There was no treatment effect on superstimulatory and superovulatory response, on embryo production and on gene expression of liver enzymes that metabolize P4. However, superovulations performed at 70 days produced lower embryo quality compared to those performed at 35 days, regardless of treatment. In conclusion, although it was possible to change circulating insulin by feeding different diets, the quantity and quality of embryos produced were not affected by the diets. The postprandial increase in circulating P4 was not associated with altered gene expression of hepatic enzymes that metabolize P4.

No description available.

Tissue slices can be made from organs, such as liver, kidney, brain, and heart, and from various species including humans, dogs, non-human primates, rats and mice. It has been demonstrated that human and rat liver slices are viable for up to 2 days, and liver slices have been extensively used as an in vitro method to study hepatic drug metabolism and toxicity in humans. The objective of this study was to determine the utility of canine hepatic slices as an in vitro model for studying drug metabolism and hepatotoxicity in dogs. Canine hepatic slices were incubated in media containing various drugs to determine the hepatotoxicity of the agents and the ability of the slices to metabolize the drugs. The toxicity of phenobarbital, primidone, lidocaine and carprofen to canine hepatic slices was assessed by determining changes in supernatant concentrations of potassium ions and adenosine triphosphate (ATP); histologic lesions were determined as necrosis, extent of vacuolation and severity of vacuolation. Xenobiotic drug metabolizing enzymatic activity was investigated by determining the metabolism of lidocaine to monoethylglycinexylidide (MEGX), and administration of phenobarbital plus primidone was used as a positive control for hepatotoxicity in dogs. The function of drug-metabolizing enzymes was demonstrated by the successful metabolism of lidocaine to MEGX. Carprofen, a drug which causes idiosyncratic hepatic disease in dogs, did not show any hepatotoxicity at concentrations of 10, 50 and 100 µg/ml using potassium ion levels, ATP concentrations and histology as indicators of hepatotoxicity. Slices incubated in media without drug showed no toxicity over 24 hours based on potassium ion and ATP supernatant concentrations while significant increases in histologic lesions were noted at 8, 12 and 24 hours. Canine hepatic slices were a useful model for examining drug metabolism and toxicity for up to 24 hours.