Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures

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Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents.

Hepatic fibrosis and cirrhosis are common findings in humans with hemochromatosis. In this study we investigated the molecular pathways of iron-induced hepatic fibrosis and evaluated the anti-fibrogenic effect of vitamin E. Male gerbils were treated with iron-dextran and fed a standard diet or a alpha-tocopherol enriched diet (250 mg/Kg diet). In gerbils on the standard diet at 6 wk after dosing with iron, in situ hybridization analysis documented a dramatic increase of signal for collagen mRNA around iron foci onto liver fat storing cells (FSC), as identified by immunocytochemistry with desmin antibody. After 4 mo, micronodular cirrhosis developed in these animals, with nonparenchymal cells surrounding hepatocyte nodules and expressing high level of TGF beta mRNA. In this group, in vivo labeling with [3H]-thymidine showed a marked proliferation of nonparenchymal cells, including FSC. In iron-dosed gerbils on the vitamin E-enriched diet for 4 mo, in spite of a severe liver iron burden, a normal lobular architecture was found, with a dramatic decrease of collagen mRNA accumulation and collagen deposition. At the molecular level, a total suppression of nonparenchymal cell proliferation was appreciable, although expression of collagen and TGF beta mRNAs was still present into microscopic iron-filled nonparenchymal cell aggregates scattered throughout the hepatic lobule. In conclusion, our study shows that anti-oxidant treatment during experimental hepatic fibrosis arrests fibrogenesis and completely prevents iron induced hepatic cirrhosis mainly through inhibition of nonparenchymal cell proliferation induced by iron

Carotenoids and liposoluble vitamins in liver cirrhosis

The role played by carotenoids, retinol and tocopherol in quencing oxidative cellular damage and combatting tumor growth is well documented, but little is known about their activity in human liver cirrhosis (LC), where oxidative damage and tumoral complications are common-place. We investigated 59 patients with LC of different etiology on admission to hospital and compared them with 32 healthy controls, matched for age and sex. Nutritional (cutaneous skinfolds, creatinine-height index) and serum parameters were determined; of these, alpha- and beta-carotene, cryptoxanthin, lycopene, retinol and alpha-tocopherol were detected by an high-performance liquid chromatographic (HPLC) technique, devised in our laboratory, which afforded an accurate and simultaneous resolution of all six compounds. The results point to a significant reduction in almost all the vitamin factors in LC, as well as in total serum lipids. In consequence, the ratio tocopherol/total serum lipids remains almost unchanged: 2.45 +/- 0.08 (m +/- se) in controls and 2.34 +/- 0.16 in patients. The effects of age, sex, nutritional habits, alcohol, malnutrition and the severity of the disease were also evaluated in relation to the vitamin-factor levels. It is suggested that the reduced levels observed in LC patients are due to a number of factors including portal hypertension and lymphatic circulation impairment, and it is concluded that thorough screening and improved diet are beneficial in the follow-up of LC

Pharmacokinetics of tia profenic acid in headache attacks - a preliminary report

This preliminary study examined the pharmacokinetics of 300 mg of tiaprofenic acid, in single oral dose, in 7 migraine patients during and out of migraine attacks. Plasma concentration of tiaprofenic acid was determined by HPLC analysis. The absorption phase did not differe between in and out migraine attacks. also other pharmacokinetic parameters evaluated were not affected by headache attacks as well. We conclude that tiaprofenic acid absorption and metabolism are not affected by migraine attacks

Hepatic tocopherol content in primary hepatocellular carcinoma and liver metastases

The high incidence of hepatocellular carcinoma (HCC) in cirrhosis, where previous studies have indicated a severe reduction in several antioxidant vitamin factors, prompted us to compare plasma Liposoluble vitamins with tocopherol content in healthy and neoplastic liver tissue in humans. This, with a view to a more positive preventive dietary approach, given the conflicting results obtained by liposoluble vitamin dietary supplementation in different malignancies, Eleven patients with cirrhosis, 18 patients affected by cirrhosis with HCC, and 10 patients with liver metastases (LM) from digestive tract adenocarcinomas were compared with controls who had undergone perlaparoscopic cholecistectomy. Plasma alpha- and beta-carotene, retinol and tocopherol, together with liver tocopherol, from both nonmalignant portions and malignant nodules of the same organ, were determined by high-performance liquid chromatography following a well-assessed technique, The results confirm a trend towards a reduction in circulating carotenoids and tocopherol in cirrhosis and in patients affected by cirrhosis with HCC. Tocopherol content in liver tissue is significantly decreased in cirrhosis (0.26 +/- 0.03 mu mol/g prot., mean + SEM, P <.001) and in cirrhotic areas of the HCC group (0.31 + 0.02, P <.002), with respect to its content in liver specimens of healthy controls (0.46 + 0.03) and in healthy areas of the same organ in patients with LM (0.41 + 0.03). Tocopherol concentration is further reduced by 50% in malignant liver nodules of HCC, with respect to surrounding cirrhotic tissue, whereas in metastatic liver nodules from digestive neoplasms the tocopherol content is almost twice that of healthy surrounding areas. This unpredictable tocopherol behavior in liver specimens, of secondary as opposed to primary malignancies of the liver, affords further insight into the conflicting effects of liposoluble vitamins employed in the chemopreventive treatment of different malignant diseases, where hepatic tocopherol concentration show opposite trends: halved in primary HCC and doubled in LM of digestive adenocarcinomas, with respect to healthy controls

Plasma nitric oxide production during acute hyperhomocysteinemia in atherosclerotic patients and controls

The work deals with the different production of nitric oxide by vascular endothelium during hyoerhomocysteinemia induced by oral methionine load in patiemts affected by diffuse atherosclerosis and in sex amd age -matched control

Regulation of transferrin, transferrin receptor, and ferritin genes in human duodenum

To gain insights at the molecular level into the expression of iron-regulated genes [transferrin (Tf), transferrin receptor (TfR), and ferritin H and L subunits] in human intestinal areas relevant to iron absorption, the steady-state levels of specific messenger RNAs (mRNAs) were analyzed in gastric and duodenal samples obtained from 6 normal subjects, or 10 patients with anemia, 14 patients with untreated iron overload, and 8 patients with various gastrointestinal disorders. No Tf mRNA was detected in human gastroduodenal tissue, confirming earlier findings in the rat. In normal subjects, although higher levels of ferritin H- and L-subunit mRNAs were consistently found in duodenal than in gastric samples, no differences in the content of TfR transcripts were detected. However, a dramatic increase in TfR mRNA levels was specifically found in duodenal samples from subjects with mild iron deficiency but severe anemia. This response of the TfR gene is presumably secondary to decreased cellular iron content due to its accelerated transfer into the bloodstream, as also indicated by the low levels of ferritin subunit mRNAs found in the same tissue samples, and is not linked to faster growth rate of mucosal cells because no changes in duodenal expression of histone, a growth-related gene, were detected. In patients with secondary iron overload, a down-regulation of duodenal TfR gene expression and a concomitant increase in ferritin mRNA content were documented. On the contrary, a lack of TfR gene down-regulation and an abnormally low accumulation of ferritin H- and L-subunit mRNAs were detected in the duodenums of subjects with idiopathic hemochromatosis. Whether these molecular abnormalities in idiopathic hemochromatosis are relevant to the metabolic defect(s) of the disease is presently unknown

Decrease in plasma tryptophan after a tryptophan-free amino acid solution. A comparison between cirrhotic and control subjects

In healthy subjects the administration of an amino acid mixture devoid of tryptophan causes a marked decrease of plasma tryptophan. This is because amino acid mixtures induce protein synthesis and tryptophan in blood is incorporated into newly synthesized proteins. We hypothesized that a tryptophan-free mixture could differently affect plasma tryptophan levels in subjects with an impaired protein synthesis such as chronic liver patients. We studied tryptophan levels after a tryptophan-free amino acid solution in controls and cirrhotics fasting 12 hours. Plasma total tryptophan fell to 91% of the initial level 60 minutes after the administration of the diet, to 71% after 120 \u2032, and to 50% after 210\u2032 in controls. In cirrhotics the solution caused a decrease of plasma tryptophan that began significantly later than in controls, the delay being proportional to the severity of the disease. Cirrhotics were subdivided into two groups in accordance to the Pugh modification of the Child-Turcotte criteria. Total plasma tryptophan was 100% of base line levels after 60\u2032, 88% after 120\u2032, and 65% after 210\u2032 in less severe clinical condition; total plasma tryptophan was 102% of base line levels after 60\u2032, 98% after 120\u2032, and 75% after 210\u2032 in more severe clinical condition