Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment.

Hepatocellular carcinoma (HCC) commonly arises from a liver damaged by extensive inflammation and fibrosis. Various factors including cytokines, morphogens, and growth factors are involved in the crosstalk between HCC cells and the stromal microenvironment. Increasing our understanding of how stromal components interact with HCC and the signaling pathways involved could help identify new therapeutic and/or chemopreventive targets. It has become increasingly clear that the cross-talk between tumor cells and host stroma plays a key role in modulating tumor growth. Emerging reports suggest a relationship between HCC and thyroid hormone signaling (dysfunction), raising the possibility that perturbed thyroid hormone (TH) regulation influences the cancer microenvironment and cancer phenotype. This review provides an overview of the role of thyroid hormone and its related pathways in HCC and, specifically, its role in regulating the tumor microenvironment.

Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice.

BACKGROUND: Chronic liver injury triggers a progenitor cell repair response, and liver fibrosis occurs when repair becomes deregulated. Previously, we reported that reactivation of the hedgehog pathway promotes fibrogenic liver repair. Osteopontin (OPN) is a hedgehog-target, and a cytokine that is highly upregulated in fibrotic tissues, and regulates stem-cell fate. Thus, we hypothesised that OPN may modulate liver progenitor cell response, and thereby, modulate fibrotic outcomes. We further evaluated the impact of OPN-neutralisation on murine liver fibrosis. METHODS: Liver progenitors (603B and bipotential mouse oval liver) were treated with OPN-neutralising aptamers in the presence or absence of transforming growth factor (TGF)-ß, to determine if (and how) OPN modulates liver progenitor function. Effects of OPN-neutralisation (using OPN-aptamers or OPN-neutralising antibodies) on liver progenitor cell response and fibrogenesis were assessed in three models of liver fibrosis (carbon tetrachloride, methionine-choline deficient diet, 3,5,-diethoxycarbonyl-1,4-dihydrocollidine diet) by quantitative real time (qRT) PCR, Sirius-Red staining, hydroxyproline assay, and semiquantitative double-immunohistochemistry. Finally, OPN expression and liver progenitor response were corroborated in liver tissues obtained from patients with chronic liver disease. RESULTS: OPN is overexpressed by liver progenitors in humans and mice. In cultured progenitors, OPN enhances viability and wound healing by modulating TGF-ß signalling. In vivo, OPN-neutralisation attenuates the liver progenitor cell response, reverses epithelial-mesenchymal-transition in Sox9+ cells, and abrogates liver fibrogenesis. CONCLUSIONS: OPN upregulation during liver injury is a conserved repair response, and influences liver progenitor cell function. OPN-neutralisation abrogates the liver progenitor cell response and fibrogenesis in mouse models of liver fibrosis.

Sarcoid-associated minimal change disease: a case report.

A patient with sarcoidosis developed minimal change disease presenting as the nephrotic syndrome. We believe this to be the first reported case of minimal change disease associated with sarcoidosis.

In vitro histamine H2-antagonist activity of the novel compound HUK 978.

Histamine stimulated adenylate cyclase from guinea-pig fundic mucosa and 3H-tiotidine binding in guinea-pig cerebral cortex were used to assess the in-vitro histamine H2-activity of the novel H2-antagonist HUK 978. The results showed that HUK 978 was a more potent H2-antagonist than either cimetidine or ranitidine. HUK 978 was also shown to be devoid of activity at the histamine H1-receptor, the muscarinic receptor and the alpha and beta-adrenergic receptors.

Anti-secretory activity of the novel H2-antagonist, HUK 978, in rat, guinea-pig and dog.

The anti-secretory activity of the competitive H2-antagonist HUK 978 was determined in rat, guinea-pig and dog. In all systems examined, HUK 978 was more potent than cimetidine and ranitidine both intravenously and orally. In addition, the compound at approximately equipotent doses as these established H2-antagonists exhibited a significantly longer inhibitory profile following oral and systemic administration. Data from these pharmacological studies and the in vitro investigations previously reported, suggest that HUK 978 is a highly specific H2-antagonist and inhibits acid secretion for longer periods than other competitive compounds.

Inhibition of the rate of 14CO2 production from [14C]ethanol in rats given beta-lactam antibiotics with disulfiram-like effects.

An animal model has been developed to investigate the potentials of various beta-lactam antibiotics for inducing (or producing) disulfiram-like effects. The method, which measures the rate of 14CO2 production in rats after [14C]ethanol administration, is simple to operate and sensitive. On the basis of available clinical information the model appears to be highly predictive for the likely incidence of disulfiram-like side effects in humans. Rats were pretreated intravenously with beta-lactam antibiotics (420 or 500 mg/kg-1) 18 h before ethanol administration or with N-methyl tetrazole thiol (NMTT; 1-methyl-5-mercaptotetrazole) at 96 mg kg-1, 6 h before ethanol administration. The rate of 14CO2 production was decreased to 70 to 80% of control levels by NMTT and the NMTT-containing beta-lactam antibiotics moxalactam, cefamandole, and cefoperazone. Cefotaxime, cephalothin, and cefuroxime which do not contain the NMTT side chain had no significant effect on 14CO2 production. Oral administration of moxalactam (500 mg kg-1) and NMTT (96 mg kg-1) 18 and 6 h, respectively, before ethanol administration significantly decreased 14CO2 production. Intravenous administration of moxalactam (500 mg kg-1) to rats with cannulated bile ducts 18 h before ethanol administration had no statistically significant effect on 14CO2 production, although the rate of 14CO2 production was decreased to 89% of the control level. The effect of dose level and dose interval was also investigated by using moxalactam. The results obtained support the hypothesis that disulfiram-like side effects associated with beta-lactam antibiotics are mediated by NMTT which is released and reabsorbed from the gut after biliary elimination of the parent beta-lactam antibiotic. The time course of inhibition of ethanol metabolism by moxalactam appears to differ from that of disulfiram.

Metabolism of cefotaxime: a review.

Cefotaxime (CTX) sodium is a potent semisynthetic cephalosporin antibiotic that has an unusually broad spectrum of antibacterial activity. This paper discusses the metabolism of 14C-CTX in rats, dogs, and humans as well as in vitro studies in cells of rats and rabbits. Excretion of radioactivity was similar in the three species, with greater than 80% of the dose being recovered in urine. About one-third of the administered dose was eliminated unchanged. Desacetylcefotaxime. (des-CTX) was the major metabolite. Ordinarily, only the two products, both having antibacterial activity, were found in plasma. Also found in dog and human urine were two other metabolites, M2 and M3, both inactive. These metabolites were, however, found in the plasma and bile of nephrectomized rats. The metabolic pathway follows the route: CTX----des-CTX----des-CTX lactone----metabolites M2 and M3. All reactions probably occur in the liver. Differences in metabolism between the species are quantitative rather than qualitative.

Disposition of cefotaxime in rat, dog and man.

The excretory pathway for the elimination of 14C-cefotaxime (14C-HR 756) was found to be the same for rat, dog and man with elimination into the urine being the most important route, accounting for greater than 80% of the dosed radioactivity. The amounts of unchanged cefotaxime eliminated in the urine ranged from 20-32% in rat and dog to 56% in man. The major metabolite in each species was the microbiologically active desacetyl cefotaxime, which was present in both plasma and urine. Two further metabolites, recently identified as the stereoisomeric forms of the opened beta-lactam ring form of desacetyl cefotaxime lactone were also found in the urine of dog and man.

Whole body autoradiographic and quantitative tissue distribution studies with 14C-cefotaxime in the rat.

The absorption, distribution and elimination of radioactivity following intravenous (i.v.) or intramuscular (i.m.) administration of 14C-cefotaxime (14C-HR 756) to the rat has been examined by qualitative and quantitative techniques. After i.v. and i.m. doses to male albino animals radioactivity was extensively distributed throughout the body and rapidly eliminated with a predominant half-life of approximately 30 to 40 min. Maximum plasma levels for the i.m. dose were reached within 20 min and approximately 85% of the dose was recovered from the urine (74%) and faeces (11%) within 8 h after dosing. In all quantitative studies 100 +/- 5% of the dose was recovered within 24 h. Whole body autoradiography studies showed good distribution of radioactivity from the blood into the tissues including lung, liver, kidney, heart, bone marrow and the gastrointestinal tract. Lowest levels were seen in the eye and brain. There was limited placental transfer of radioactivity in 14-day pregnant animals although by day 18 of the gestation period radioactivity was detected in the foetus but distribution into individual organs and tissues could not be seen. There was no evidence to show that retention of radioactivity in pigmented tissues had occurred nor was there any suggestion of accumulation of radioactivity in any organ or tissue as a consequence of multiple dosing with 14C-cefotaxime.

Cefotaxime: sites and pathway of metabolic conversion.

This paper examines the metabolism of 14C-cefotaxime (14C-HR 756) in the rat and attempts to identify the metabolic events in this and other species. In rat desacetyl cefotaxime is usually the major excretion product and sole metabolite of cefotaxime. However, when renal elimination of this metabolite is prevented by bilateral nephrectomy, two further metabolites, the stereoisomeric opened beta-lactam ring forms of desacetyl cefotaxime lactone, are also produced. These metabolites are found in the urine of man and dogs dosed with cefotaxime. It is suggested that generation of these metabolites is dependent on formation of the lactone form of the desacetyl metabolite. Evidence is also presented showing that these metabolic conversions occur in the liver.

Metabolism of cefotaxime in animals and humans.

The metabolism of [14C]cefotaxime was studied in vivo in rats, dogs, and humans and in vitro in cells of rats and rabbits. Excretion of radioactivity was similar in all species, and greater than 80% of the dose was recovered in the urine. Approximately one-third of the dose was eliminated unchanged, and the major metabolite was desacetylcefotaxime. Under normal circumstances these two products, both with antibacterial activity, were the only materials detected in the plasma. Two further metabolites, designated M2 and M3, (formerly known as UP1 and UP2, respectively, were observed in canine and human urine. Although M2 and M3 were not present in the plasma of normal animals, they were found in the plasma and bile of nephrectomized rats. Extensive studies have shown that the metabolic pathway follows the route: cefotaxime leads to desacetylcefotaxime leads to desacetylcefotaxime lactone leads to M metabolites. The rate-limiting step is the formation of desacetylcefotaxime lactone. All of these reactions take place in the liver. It is concluded that species differences in the metabolism of cefotaxime are more likely to be quantitative than qualitative and that both rat and dog are suitable species for toxicity studies.