Up-regulation of BSEP and MRP2 by Calculus Bovis administration in 17α-ethynylestradiol-induced cholestasis: Involvement of PI3K/Akt signaling pathway.

ETHNOPHARMACOLOGY RELEVANCE: Calculus Bovis, also known as Niuhuang, is a rare traditional Chinese medicine that has been widely used in China for 2000 years in pharmacology for sedation, anti-spasm, relieving fever, diminishing inflammation and recovering gallbladder functions. AIM OF THE STUDY: This study aimed to investigate the choleretic potential and molecular responses in rats to Calculus Bovis (CB) administration after 17α-ethynylestradiol (EE)-induced cholestasis. MATERIAL AND METHODS: CB (50 and 100mg/kg per day) was intragastrically (i. g.) given to experimental rats for five consecutive days in coadministration with EE (5mg/kg daily for five days, s.c.). The levels of serum biomarkers were determined biochemically. The histopathology of the liver tissue was evaluated. Expression of bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2) were studied by western blot and immunohistochemical assay. The expression of Akt and phospho-Akt (pAkt) were also measured by western blot. RESULTS: In response to EE, CB treatment significantly prevented an increase in serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT) and total bilirubin (TBIL). CB treatment also repaired tissue lesions caused by EE. Western blots showed that EE significantly decreased the protein expression of BSEP and MRP2. EE also dramatically increased levels of pAkt and decreased levels of Akt. Compared to the EE group, CB treatment increased levels of hepatic BSEP and MRP2 while pAkt levels decreased and Akt levels increased. Immunohistochemistry also indicated that EE decreased the expression of BSEP and MRP2. LY294002 is a selective PI3K inhibitor and showed similar beneficial effects as CB. Decreased expression of BSEP and MRP2 caused by EE were also prevented by LY294002 treatment. CONCLUSION: Calculus Bovis administration can alleviate liver injury and up-regulate the expression of BSEP and MRP2 in 17α-ethynylestradiol-induced cholestasis by a mechanism that may involve inhibiting the activated PI3K/Akt signaling pathway.

Paeonia lactiflora Pall. protects against ANIT-induced cholestasis by activating Nrf2 via PI3K/Akt signaling pathway.

BACKGROUND: Paeonia lactiflora Pall. (PLP), a traditional Chinese herbal medicine, has been used for hepatic disease treatment over thousands of years. In our previous study, PLP was shown to demonstrate therapeutic effect on hepatitis with severe cholestasis. The aim of this study was to evaluate the antioxidative effect of PLP on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis by activating NF-E2-related factor 2 (Nrf2) via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. MATERIALS AND METHODS: Liquid chromatography-mass spectrometry (LC-MS) was performed to identify the main compounds present in PLP. The mechanism of action of PLP and its therapeutic effect on cholestasis, induced by ANIT, were further investigated. Serum indices such as total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), and total bile acid (TBA) were measured, and histopathology of liver was also performed to determine the efficacy of treatment with PLP. Moreover, in order to illustrate the underlying signaling pathway, liver glutathione (GSH) content and mRNA or protein levels of glutamate-cysteine ligase catalytic subunit (GCLc), glutamate-cysteine ligase modulatory subunit (GCLm), Akt, heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (Nqo1), and Nrf2 were further analyzed. In addition, validation of PLP putative target network was also performed in silico. RESULTS: Four major compounds including paeoniflorin, albiflorin, oxypaeoniflorin, and benzoylpaeoniflorin were identified by LC-MS analysis in water extract of PLP. Moreover, PLP could remarkably downregulate serum levels of TBIL, DBIL, AST, ALT, ALP, γ-GT, and TBA, and alleviate the histological damage of liver tissue caused by ANIT. It enhanced antioxidative system by activating PI3K/Akt/Nrf2 pathway through increasing Akt, Nrf2, HO-1, Nqo1, GCLc, and GCLm expression. The putative targets network validation also confirmed the important role of PLP in activating Akt expression. CONCLUSION: The potential mechanism of PLP in alleviating ANIT-induced cholestasis could to be related to the induction of GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. This indicates that PLP might be a potential therapeutic agent for cholestasis.

Danning tablets attenuates α-naphthylisothiocyanate-induced cholestasis by modulating the expression of transporters and metabolic enzymes.

BACKGROUND: The Danning tablets (DNts) is commonly prescribed in China as a cholagogic formula. Our previous studies showed that DNts exerted the protective effect on α-naphthylisothiocyanate (ANIT)-induced liver injury with cholestasis in a dose-dependent mannar. However, the detailed molecular mechanisms of DNts against ANIT-induced cholestasis are still not fully explored. METHODS: Danning tablet (3 g/kg body weight/day) was administered orally to experimental rats for seven days before they were treated with ANIT (60 mg/kg daily via gastrogavage) which caused cholestasis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (T-Bil), direct bilirubin (D-Bil) and total bile acid (TBA) were measured to evaluate the protective effect of Danning tablet at 12, 24 and 48h after ANIT treatment. Meanwhile, total bilirubin or total bile acid in the bile, urine and liver were also measured at 48h after ANIT treatment. Furthermore, the hepatic or renal mRNA and protein levels of metabolic enzymes and transports were investigated to elucidate the protective mechanisms of Danning tablet against ANIT-induced cholestasis. RESULTS: In this study, we found that DNts significantly attenuated translocation of multidrug resistance-associated protein 2 (Mrp2) from the canalicular membrane into an intracellular and up-regulated the hepatic mRNA and protein expressions of metabolic enzymes including cytochrome P450 2b1(Cyp2b1) and uridine diphosphate-5¢- glucuronosyltransferase (Ugt1a1)) and transporters including bile salt export pump (Bsep) and multidrug resistance protein 2 (Mdr2)) as well as renal organic solute transporter beta (Ostß), accompanied by further increase in urinary and biliary excretion of bile acid and bilirubin. CONCLUSIONS: DNts might promote bile acid and bilirubin elimination by regulating the expressions of hepatic and renal transporters as well as hepatic metabolic enzymes.

The effects of hyperbaric oxygen application against cholestatic oxidative stress and hepatic damage after bile duct ligation in rats.

BACKGROUND: The aim of this study was to evaluate the preventive and therapeutic potential of hyperbaric oxygen therapy (HBO) on the liver tissue against bile duct ligation (BDL)-induced oxidative damage and fibrosis in rats. MATERIALS AND METHODS: We divided 32 adult male Sprague Dawley rats into four groups: sham, sham plus HBO, BDL, and BDL plus HBO; each group contained eight animals. We placed the sham plus HBO and BDL plus HBO groups in an experimental hyperbaric chamber in which we administered pure oxygen at 2.5 atmospheres absolute 100% oxygen for 90 min on 14 consecutive days. RESULTS: The application of BDL clearly increased the tissue malondialdehyde level, myeloperoxidase activity, and hydroxyproline content and decreased the antioxidant enzymes (superoxide dismutase and catalase activities) and glutathione level. Hyperbaric oxygen therapy treatment significantly decreased the elevated tissue malondialdehyde level, myeloperoxidase activity, and hydroxyproline content and increased the reduced superoxide dismutase and catalase activities and glutathione level in the tissues. The changes demonstrating the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated bile ducts into lobules, mononuclear cells, and neutrophil infiltration into the widened portal areas were observed in BDL group. Treatment of BDL with HBO attenuated alterations in liver histology. Alpha smooth muscle actin, cytokeratin-positive ductular proliferation, and the activity of terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling in the BDL decreased with HBO treatment. CONCLUSIONS: The data indicate that HBO attenuates BDL-induced oxidative injury, hepatocytes damage, bile duct proliferation, and fibrosis. The hepatoprotective effect of HBO is associated with antioxidative potential.

Antioxidant enzyme activities in hepatic tissue from children with chronic cholestatic liver disease.

BACKGROUND/AIM: To study the oxidative stress status in children with cholestatic chronic liver disease by determining activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) in liver tissue. MATERIALS AND METHODS: A total of 34 children suffering from cholestatic chronic liver disease were studied. They were selected from the Hepatology Clinic, Cairo University, and compared with seven children who happened to have incidental normal liver biopsy. The patients were divided into three groups: extrahepatic biliary atresia (n=13), neonatal hepatitis (n=15) and paucity of intrahepatic bile ducts (n=6); GPx, SOD and CAT levels were measured in fresh liver tissue using ELISA. RESULTS: In the cholestatic patients, a significant increase was found in mean levels of SOD, GPx and CAT in hepatic tissue compared to control children. The three enzymes significantly increased in the extrahepatic biliary atresia group, whereas in the groups of neonatal hepatitis and paucity of intrahepatic bile ducts, only GPx and CAT enzymes were significantly increased. CONCLUSION: Oxidative stress could play a role in the pathogenesis of cholestatic chronic liver diseases. These preliminary results are encouraging to conduct more extensive clinical studies using adjuvant antioxidant therapy.

Ascorbic acid supplementation has a cytoprotective effect on secondary biliary cirrhosis: experimental study in young rats.

OBJECTIVE: To test whether ascorbic acid supplementation has any cytoprotective effect on a model of secondary biliary cirrhosis in young rats. METHODS: We studied 40 Wistar rats weaned at the 21st postnatal day. Each group of 10 was subjected to one of the following four treatments, until 49th postnatal day, when they suffered euthanasia: 1) LC-double ligature and resection of the common bile duct and daily administration of ascorbic acid [100 mg/g of body weight (bw)]; 2) LA-double ligature and resection of the common bile duct and daily administration of aqueous vehicle (1 mL/g bw); 3) SC-sham operation and daily administration of ascorbic acid (100 mg/g bw); 4) SA-double ligature and resection of the common bile duct and daily administration of aqueous vehicle (1 mL/g bw). The rats were weighed daily. On the 27th day after the operation they received an intra-peritoneal injection of 1.5 mg/g bw of sodium pentobarbital, and the pentobarbital sleeping time was measured. Blood was collected for serum alanine aminotransferase and aspartate aminotransferase activity measurements, serum albumin and globulin concentrations, and the liver was assessed for liver water and fat content. Data were submitted to two-way ANOVA and paired comparisons between groups were tested using the SNK method. Significance level was set at 0.05. RESULTS: Ascorbic acid supplementation attenuated the effects of cholestasis: decreased the pentobarbital sleeping time, serum globulin, and the liver fat content. CONCLUSIONS: Our results corroborate the hypothesis that ascorbic acid supplementation has a cytoprotective effect in secondary biliary cirrhosis.

Suplementação com ácido ascórbico tem efeito citoprotetor na cirrose biliar secundária: estudo experimental em ratos jovens / Ascorbic acid supplementation has a cytoprotective effect on secondary biliary cirrhosis: experimental study in young rats

OBJETIVO: Testar se a suplementação com ácido ascórbico tem algum afeito citoprotetor em um modelo de cirrose biliar secundária em ratos jovens. MÉTODOS: Foram estudados 40 ratos Wistar desmamados no 21º dia pós-natal. Cada grupo de 10 foi submetido a um dos seguintes quatro tratamentos, até o 49º dia pós-natal, quando foram submetidos a eutanásia: 1) LC - ligadura dupla e ressecção do ducto biliar comum e administração diária de ácido ascórbico [100 mg/g de peso corporal (pc)]; 2) LA - ligadura dupla e ressecção do ducto biliar comum e administração diária de veículo aquoso (1 mL/g pc); 3) SC - operação simulada e administração diária de ácido ascórbico (100 mg/g pc); 4) SA - ligadura dupla e ressecção do ducto biliar comum e administração diária de veículo aquoso (1 mL/g pc). Os ratos eram pesados diariamente. No 27º dia pós-operatório, eles receberam injeção intraperitoneal de 1,5 mg/g pc de pentobarbital sódico, e o tempo de sono induzido pelo pentobarbital foi medido. Coletou-se sangue para determinação de atividade sérica de alanina aminotransferase e de aspartato aminotransferase, níveis de albumina e globulina séricas, e o fígado foi analisado quanto à conteúdo de água e gordura. Os dados foram submetidos à ANOVA two-way, e comparações pareadas entre grupos foram testadas com o método de SNK. O nível de significância foi estabelecido em 0,05. RESULTADOS: A suplementação com ácido ascórbico atenuou os efeitos da colestase: reduziu o tempo de anestesia pelo pentobarbital, globulina sérica e o conteúdo de gordura no fígado. CONCLUSÕES: Nossos resultados corroboram a hipótese de que a suplementação com ácido ascórbico tem um efeito citoprotetor na cirrose biliar secundária.

OBJECTIVE: To test whether ascorbic acid supplementation has any cytoprotective effect on a model of secondary biliary cirrhosis in young rats. METHODS: We studied 40 Wistar rats weaned at the 21st postnatal day. Each group of 10 was subjected to one of the following four treatments, until 49th postnatal day, when they suffered euthanasia: 1) LC-double ligature and resection of the common bile duct and daily administration of ascorbic acid [100 mg/g of body weight (bw)]; 2) LA-double ligature and resection of the common bile duct and daily administration of aqueous vehicle (1 mL/g bw); 3) SC-sham operation and daily administration of ascorbic acid (100 mg/g bw); 4) SA-double ligature and resection of the common bile duct and daily administration of aqueous vehicle (1 mL/g bw). The rats were weighed daily. On the 27th day after the operation they received an intra-peritoneal injection of 1.5 mg/g bw of sodium pentobarbital, and the pentobarbital sleeping time was measured. Blood was collected for serum alanine aminotransferase and aspartate aminotransferase activity measurements, serum albumin and globulin concentrations, and the liver was assessed for liver water and fat content. Data were submitted to two-way ANOVA and paired comparisons between groups were tested using the SNK method. Significance level was set at 0.05. RESULTS: Ascorbic acid supplementation attenuated the effects of cholestasis: decreased the pentobarbital sleeping time, serum globulin, and the liver fat content. CONCLUSIONS: Our results corroborate the hypothesis that ascorbic acid supplementation has a cytoprotective effect in secondary biliary cirrhosis.

[Metabolic changes in rat brain histaminergic neurons in dynamics of subhepatic cholestasis].

The aim of the study was the estimation of metabolic changes in rat brain histaminergic neurons in dynamics of subhepatic cholestasis. The investigation was carried out in male Wistar rats using the quantitative histochemical methods. It was found that cholestasis induced significant changes in the activity of dehydrogenases of succinate, lactate, glucose-6-phosphate, NADH and NADPH, as well as of acid phosphatase and type B monoamine oxidase in hypothalamic histaminergic neurons. These changes depended on the duration of cholestasis and had the dynamic, undulating pattern. They were demonstrated already after 5 days of cholestasis, reached their maximum by 10-20 days, were decreased at 45 days and disappeared after 90 days.

Effect of betaine supplementation on changes in hepatic metabolism of sulfur-containing amino acids and experimental cholestasis induced by alpha-naphthylisothiocyanate.

Alterations in the hepatic metabolism of sulfur amino acids in experimental cholestasis induced by alpha-naphthylisothiocyanate (ANIT) (100 mg/kg, po) were monitored in male mice for 1 week. We also examined the effects of betaine supplementation (1% in drinking water) for 2 weeks on the hepatotoxicity and changes in the sulfur amino acid metabolism induced by ANIT treatment. Acute ANIT challenge elevated the serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) activities, and total bilirubin contents from 5 h after the treatment, reaching a peak at t = 48-72 h. Hepatic S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels were decreased significantly in a manner almost inversely proportional to the changes in serum parameters measured to determine the ANIT-induced toxicity. Hepatic glutathione and cysteine levels were elevated at t = 120 h after the treatment. Betaine supplementation blocked or significantly attenuated induction of the hepatotoxicity by ANIT. The decrease in SAM and SAH levels was also inhibited by betaine intake. The results indicate that betaine supplementation may antagonize the induction of experimental cholestasis and changes in the metabolism of sulfur amino acids associated with ANIT treatment. The underlying mechanism and pharmacological significance of its action are discussed.

The impact of hepatic xanthine oxidase and xanthine dehydrogenase activities on liver function in chronic cholestasis.

Activities of hepatic xanthine oxidase (XO) and xanthine dehydrogenase (XD), serum liver enzymes, and reduced glutathione (GSH) were determined in livers of chronic cholestatic rats. The common bile duct was ligated (CBDL) and rats were randomized to either an untreated group or to treatment with allopurinol, a competitive XO inhibitor, or received a tungsten-supplemented diet to inactivate XO and XD, or received antioxidants vitamin C and vitamin E. One group underwent only sham laparotomy. After 4 weeks, in untreated CBDL animals serum aspartate aminotransferase and bilirubin concentrations were significantly elevated and hepatic GSH was significantly decreased when compared with the sham-operated group. Histochemical and enzymatic determinations of XD and XO showed a significant increase in hepatic XO activity after CBDL. Treatment with allopurinol and a tungsten-supplemented, molybdenum-free diet significantly attenuated serum liver enzymes, hepatic XO activity, and improved hepatic GSH levels, whereas vitamins C and E had a positive effect only on hepatic GSH levels. Our results support the hypothesis that cholestasis-induced hepatocellular injury is partially triggered by oxidative processes derived from increased hepatic XO activity. Inhibition and inactivation of XO exerts a hepatocellular protective effect in chronic cholestasis.

A tungsten supplemented diet attenuates bacterial translocation in chronic portal hypertensive and cholestatic rats: role of xanthine dehydrogenase and xanthine oxidase.

BACKGROUND: Bacterial translocation (BT) plays a major role in the pathophysiological process of spontaneous infections in portal hypertension (PH) and cholestatic jaundice. The major mechanisms promoting BT in experimental animal models are the disruption of the intestinal ecological equilibrium and disruption of the intestinal mucosal barrier. The enzymes xanthine dehydrogenase (XD) and xanthine oxidase (XO) are often implicated as a significant source of oxidants which have a major impact on the impairment of intestinal barrier function. AIM: To investigate the incidence of BT in rats with PH and obstructive jaundice, and to evaluate the impact of XD and XO. METHODS: Animals were subjected to sham laparotomy (SL), PH by calibrated stenosis of the portal vein, and common bile duct ligation (CBDL). They were fed either a standard pellet diet or a tungsten supplemented molybdenum-free diet. Four weeks after the operative procedure, intestinal colonisation and BT to portal vein, vena cava, mesenteric lymph nodes, liver, and spleen were determined. Intestinal XD and XO activity were measured enzymatically and histochemically. RESULTS: Significant (p<0.01) intestinal bacterial overgrowth was present in all PH and CBDL groups compared with the SL group. In normally fed animals after SL, BT occurred in 12%. In PH and after CBDL, the rate of BT increased significantly (p<0.05) to 28% and 54% respectively. In the jejunum of normally fed animals subjected to PH or CBDL, a significant increase in XO was observed (p<0.01). Animals fed a tungsten supplemented diet showed a significant attenuation of BT to 14% in PH and 22% after CBDL (p<0. 05). Tungsten treatment completely suppressed jejunal XD and XO activities. CONCLUSIONS: Significant intestinal bacterial overgrowth, BT, and XD to XO conversion occurred in PH and after CBDL. XD and XO inactivation by a tungsten supplemented molybdenum-free diet significantly reduced the incidence of BT without affecting intestinal bacterial overgrowth. These data strongly support the hypothesis that increased XD to XO conversion may contribute to intestinal barrier failure in PH and after CBDL.

[The action of Essentiale and its combination with cordiamine and vitamin E on the processes of xenobiotic biotransformation and lipid peroxidation and on liver structure in rats with cholestasis]. / Deistvie essentsiale, ego kombinatsii s kordiaminom i vitaminom E na protsessy biotransformatsii ksenobiotikov, perekisnogo okisleniia lipidov i struktury pecheni krys s kholestazom.

Intensive regeneration of cholangia and cholangioles, fibrosis, microglobular cirrhosis, vacuolar and granular dystrophy, and necrosis of hepatocytes were found in the liver of rats 36 days after ligation of the common bile duct. Lipid peroxidation was activated, the activity of the mono-oxidase system was inhibited in maintained function of glucuro- and glutathione transferase. Essentiale (per os in starch mucilage, 1 ml/kg. for 35 days) increased the activity of cytosol glutathione-S-transferase and normalized the decreased blood plasma antioxidant activity. Combination of essentiale with cordiamin (nikethamide) and viatmin E (50 mg/kg for 35 days) considerably activated the mono-oxigenase, glucoro- and glutathione transferase systems of the liver: the free-radical processes became less intense. The structure of the liver improves insignificantly in both methods of treatment.

Hypothalamic nitric oxide synthase is depressed in cholestatic rats.

We examined hypothalamic nitric oxide synthase (NOS) levels and release as well as steady-state mRNA levels in rats with cholestasis due to bile duct resection (BDR) and in sham-resected control rats. BDR rats had a significant reduction in hypothalamic NOS-containing neurons in the hypothalamic paraventricular nucleus as determined by NADPH-diaphorase staining, compared with sham-resected controls. In addition, NOS activity, measured indirectly by determining nitrite release from hypothalamic explants, was significantly lower in BDR rats compared with sham-resected animals. Hypothalamic steady-state NOS mRNA levels [brain constitutive NOS (bNOS)] were determined by semiquantitative reverse transcription-polymerase chain reaction and were found to be increased 1.5-fold in BDR rats compared with sham rats. In summary, BDR rats have diminished hypothalamic NOS levels and activity coupled with enhanced steady-state bNOS mRNA levels, suggesting that depressed hypothalamic NOS protein levels are due to posttranscriptional defects.

A controlled trial of choleretic and hepatoprotective actions of Livzon and dehydrocholic acid in a model of obstructive jaundice in albino rats.

The authors have tried to examine the hepatoprotective and cholerectic action of a new indigenised drug, Livzon (Hind Chemicals Ltd., Kanpur, India) and compared its action to Decholin (casella-Riedel Pharma GmbH, Frankfurt, Germany), a known hepatoprotective and choleretic agent. Albino rats were chosen as the experimental animals. Obstructive jaundice was created by ligating the common bile ducts after taking liver biopsies. The animals were divided into three groups: (i) Control group-no drug was given, (ii) Livzon trial group, (iii) Decholin group. The animals were reoperated, liver biopsies were taken and histologically examined. The study confirmed the hepatoprotective and choleretic actions of Livzon and Decholin. However, Decholin was more of a choleretic, the Livzon was more hepatoprotective.

Complications associated with total parenteral nutrition in infants with short bowel syndrome.

The use of total parenteral nutrition (TPN) in five out of six infants with short bowel syndrome (SBS) adaptation permitted enteral nutrition. The duration of TPN depended on the extent of the resection, whether it was proximal or distal, and the adaptation of the residual gut. Residual bowel measuring 10 cm required prolonged TPN in the sixth infant and was not compatible with survival. Catheter-related complications were infection, malposition and dislodgement of the catheter. Metabolic complications were easily controlled by regulating the concentration of the infusate and the rate of the infusion. Osteopenia was common in prolonged TPN and was corrected with vitamin D supplementation. Cholestasis was the most common complication. It was demonstrated with elevation of gamma-glutamyl-transpeptidase levels which became evident as early as six weeks after the introduction of TPN. Serum bilirubin and transaminase elevations were later manifestations. One infant died of hepatic decompensation. Late morphological manifestations were those of cholestatic changes with fibrosis. The biochemical abnormalities of cholestasis were reversible provided TPN was discontinued at an early stage.

[The antioxidant action of dalargin on the liver in experimental acute cholestasis]. / Antioksidantnoe deistvie dalargina na pechen' v usloviiakh ostrogo kholestaza v éksperimente.

Experiments were conducted on 182 rats with acute cholestasis to study the effect of intra-abdominal dalargin injection (10 mcg/kg) with the serotonin antagonist ketanserine (150 mg/kg) on xanthine oxidase (XO) activity and level of lipid peroxidation in the hepatic tissue and on the activity of the hepatospecific enzymes histidase and urokaninase in hepatic tissue and blood serum 1, 3, and 5 hours after the injection. Dalargin reduced XO activity by 32-37% in different periods after the injection, dalargin in combination with ketanserine--by 37-48%. Dalargin reduced the level of lipid peroxidation by 29-35%, and when combined with ketanserine--by 37-49%. The administration of dalargin reveals a distinct tendency towards reduction of the release of the hepatospecific enzymes histidase and urokanase into the blood and increase of their activity in the hepatic tissue. Dalargin with ketanserine produces a similar effect but of a higher degree. These data allow us to speak of the hepatoprotective effect of dalargin, which is potentiated by its injection together with ketanserine. It was found that dalargin (50 mcg/kg, intraperitoneally) increases the leu-enkephalin content in the hepatic tissue more than 3.5 fold one hour after injection.

[Abnormal lipoprotein (LP-X) in the first months of life with particular reference to obstructive jaundice (author's transl)]. / Das abnorme Lipoprotein (LP-X) in den ersten Lebensmonaten unter Berücksichtigung der Cholestase

Abnormal lipoprotein (LP-X) represents a specific parameter for the presence of obstructive jaundice in the adult. Since LP-X has also been detected in the serum of newborn infants, both full-term and premature, and in early infancy, in the absence of clinical evidence of obstructive jaundice, extensive investigations were undertaken in infants during the neonatal period to clarify this phenomenon. The present study reports the data obtained in over 2000 sera from over 370 infants (mature newborn and premature newborn and young infants), tested more or less continuously by means of the Rapidophor method, initially on a qualitative, and subsequently, on a semi-quantitative basis. LP-X appears within the first fortnight in newborn infants, irrespective of the mode of feeding. The LP-X concentration was correlated to the birth weight. Premature infants displaying signs of immaturity possessed markedly higher LP-X levels than mature newborn infants. LP-X was not correlated to the alkaline phosphatase level, nor to the gammaglutamyl transferase activity; the bilirubin level, likewise, had no connection with the LP-X concentration. Patients with proven obstructive jaundice showed distinctly higher LP-X concentrations (greater than 56 mg/100 ml), whereby the rise in LP-X level in some cases preceded the appearance of the clinical manifestations of obstructive jaundice. The following hypotheses are advanced in order to explain the presence of LP-X during the neonatal period and are discussed on the basis of clinical observations in adults, the physiological conditions in the newborn infant and the results of the present study: The liver, which occupies the central position amongst metabolic organs, also in the case of the lipoproteins, is at a physiological stage of organic and functional maturation during this early period of life. Under these circumstances, a pseudo-obstructive mechanism on the basis of insufficient excretion of biliary lipoproteins, in conjunction with a simultaneous "physiological" deficiency of lecithin: cholesterol acyl transferase could lead to the appearance of LP-X in the serum. Catabolism of the resultant LP-X cannot take place owing to an inadequate activity of lipoprotein lipase. Functional immaturity can be presumed in the case of both enzyme systems during the neonatal period. On attainment of a degree of maturity compatible with the appropriate neonatal stage, the LP-X values become negative between the 7th and the 16th week of life. It is conceivable that the appearance of LP-X in the newborn infant can be ascribed to LP-X1, since the "physiological" LP-X concentrations in the neonatal period (values of up to 20 mg/100 ml) are distinctly lower than the values found in obstructive jaundice. LP-X determination can be rated as a useful supplementary investigation in the differential diagnosis of extrahepatic biliary atresia during the first weeks or months of life...