Effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone on carbon tetrachloride‐induced hepatic cirrhosis in rats

Aim: The present study was undertaken to evaluate the effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone (HTHQ), a synthesized vitamin E derivative, on carbon tetrachloride (CCl₄)‐induced cirrhosis. Methods: Rats were treated with hypodermic injections of CCl₄ twice a week to induce the hepatic cirrhosis, and given drinking water containing HTHQ or solvent. Primary cultures of rat hepatocytes were performed to evaluate the effects of HTHQ on the expression of inducible nitric oxide synthase (iNOS). Results: Masson's staining of rat livers showed fibrosis around pseudo‐lobules in the CCl₄ group, the lesions being reduced in the CCl₄ HTHQ group. Increases in liver tissue hydroxyproline and α₁(I) collagen, α‐smooth muscle actin and iNOS induced by CCl₄, were also markedly diminished by HTHQ. Furthermore, both HTHQ and vitamin E attenuated interleukin‐1β‐induced iNOS protein expression in cultured hepatocytes, the potency of HTHQ being 10‐times higher than that of vitamin E. Conclusion: HTHQ may inhibit development of hepatic cirrhosis in rats, more potently than vitamin E, by inhibiting the iNOS expression in hepatocytes. Because vitamin E has a radical scavenging action, roles of NO and peroxynitrite will be discussed in the effects of HTHQ on the fibrosis.     

β-hexosaminidase in bile and plasma from patients with cholestasis

Abstract: β-Hexosaminidase (Hex) activity was determined in bile from 18 patients with cholestasis, six patients without cholestasis and in ten normal liver biopsies. The difference in the mean activities in bile from patients with and without cholestasis was not significant. Only about 0.5 promille of total liver Hex activity was lost per day via the bile flow. Gel chromatography showed that enzyme forms present in bile had higher molecular weights than the forms present in liver tissue, indicating that the biliary enzyme was not routed through the lysosomes before release into the bile. In 32 patients with cholestasis, plasma Hex was increased compared to controls, and correlated to bilirubin. The activity was significantly higher in patients with severe cholestasis than in patients with less severe forms of cholestasis, but no significant difference in Hex activity was observed between patients with benign or malignant biliary obstruction. No significant difference was noted between patients with cholestasis for less than 1 week compared to those whose illness had lasted more than 1.5 weeks. The impact of biliary obstruction on plasma Hex is further illustrated by the observation that decompression lowered plasma Hex as well as bilirubin and alkaline phosphatase.     

α‐thalassaemia masked by β gene defects and a new polyadenylation site mutation on the α2‐globin gene

We report three examples of chronic anaemia involving complex combinations of α‐ and β‐globin gene defects. The first case had a potential Hb H disease caused by the classic SEA/RW deletions masked by Hb E [β26(B8)Glu→Lys] in the homozygous state. The second had an unusual Hb H disease caused by compound heterozygosity for two different α2 polyadenylation site mutations masked by a β‐thalassaemia heterozygosity. The third had an intermediate α‐thalassaemia with considerable anaemia caused by an as yet unknown polyadenylation site (AATAAA>AATAAC) mutation in combination with a common RW deletion masked by a common Hb C [β6(A3)Glu→Lys] heterozygosity. Diagnostic methods, genotype/phenotype correlations and the chance of overlooking these combinations during risk assessment in a multiethnic society are discussed.     

Up‐Regulation and Functional Effect of Cardiac β3‐Adrenoreceptors in Alcoholic Monkeys

Background: Recent studies link altered cardiac β‐adrenergic receptor (AR) signaling to the pathology of alcoholic cardiomyopathy (ACM). However, the alteration and functional effect of β₃‐AR activation in ACM are unknown. We tested the hypothesis that chronic alcohol intake causes an up‐regulation of cardiac β₃‐AR, which exacerbates myocyte dysfunction and impairs calcium regulation, thereby directly contributing to the progression of ACM. Methods: We compared myocyte β₃‐ and β₁‐AR expression and myocyte contractile ([Ca²⁺]_i), transient ([Ca²⁺]_iT), and Ca²⁺ current (I_Ca,L) responses to β‐ and β₃‐AR stimulation in myocytes obtained from left ventricle (LV) tissue samples obtained from 10 normal control (C) and 16 monkeys with self‐administered alcohol for 12 months prior to necropsy: 6 moderate (M) and 10 heavy (H) drinkers with group average alcohol intakes of 1.5 ± 0.2 and 3.3 ± 0.2 g/kg/d, respectively. Results: Compared with control myocytes (C), in alcoholic cardiomyocytes, basal cell contraction (dL/dt_max, ?39%, H: 69.8 vs. C: 114.6 μm/s), relaxation (dR/dt_max, ?37%, 58.2 vs. 92.9 μm/s), [Ca²⁺]_iT (?34%, 0.23 vs. 0.35), and I_Ca,L (?25%, 4.8 vs. 6.4pA/pF) were all significantly reduced. Compared with controls, in moderate and heavy drinkers, β₁‐AR protein levels decreased by 23% and 42%, but β₃‐AR protein increased by 46% and 85%, respectively. These changes were associated with altered myocyte functional responses to β‐AR agonist, isoproterenol (ISO), and β₃‐AR agonist, BRL‐37344 (BRL). Compared with controls, in alcoholic myocytes, ISO (10^?8 M) produced significantly smaller increases in dL/dt_max (H: 40% vs. C: 71%), dR/dt_max (37% vs. 52%), [Ca²⁺]_iT (17% vs. 37%), and I_Ca,L (17% vs. 27%), but BRL (10^?8 M) produced a significantly greater decrease in dL/dt_max (H: ?23% vs. C: ?11%), [Ca²⁺]_iT (?30% vs. ?11%), and I_Ca,L (?28% vs. ?17%). Conclusions: Chronic alcohol consumption down‐regulates cardiac β₁‐ and up‐regulates β₃‐ARs, contributing to the abnormal response to catecholamines in ACM. The up‐regulation of cardiac β₃‐AR signaling enhances inhibition of LV myocyte contraction and relaxation and exacerbates the dysfunctional [Ca²⁺]_i regulation and, thus, may precede the development of ACM.     

Peripheral T cell receptors αβ and γδ in patients with Hodgkin's lymphoma

Antigen recognition by T cells is determined by an antigen specific T cell receptor (TCR). Two heterodimeric TCR structures associated with CD3 have been defined: TCR αβ and TCR γδ. TCR αβ and its function are well described but the role of TCR γδ in normal and lymphoproliferative disorders is not well established. In newly diagnosed or relapsed/refractory Hodgkin's disease (HD), a disease associated with defective T cell functions and increased sIL-2R, We determined levels of seven TCR αβ variable regions [βV5(a), βV5(b), βV6(a), βV12(a), αβV(a), αV2(a)] and TCR γδ by using monoclonal antibodies (MCA). TCR γδ levels did not show any difference, but several variable regions of the TCR αβ differed when groups are compared with each other and the control group.     

Amyloid‐β neurotoxicity in organotypic culture is attenuated by melatonin: involvement of GSK‐3β, tau and neuroinflammation

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by accumulation of extracellular deposits of amyloid‐β (Aβ) peptide in brain regions that are important for memory and cognition. The buildup of Aβ aggregates in the AD is followed by the formation of intracellular neurofibrillary tangles and activation of neuroinflammatory reactions. The present study investigated whether melatonin possesses a neuroprotective effect against Aβ‐induced toxicity. For this purpose, organotypic hippocampal slices were cultured and exposed to 25 μm of Aβ_25–35 in the absence or in the presence of melatonin (25, 50, or 100 μm ). In addition, the authors have investigated the involvement of GSK‐3β, tau protein, astroglial, and microglial activation, and cytokine levels in the melatonin protection against Aβ‐induced neurotoxicity. Melatonin prevented the cell damage in hippocampus induced by the exposure to Aβ_25–35. In addition, melatonin significantly reduced the activation of GSK‐3β, the phosphorylation of tau protein, the glial activation and the Aβ‐induced increase of TNF‐α and IL‐6 levels. On the basis of these findings, we speculate that melatonin may provide an effective therapeutic strategy for AD, by attenuating Aβ‐induced phosphorylation of tau protein, and preventing GSK‐3β activation and neuroinflammation.     

Effect of Heparin on Conformation of the β2‐Microglobulin Molecule

Heparin, one of the essential molecules called glycosaminoglycans (GAGs), is the anticoagulant that is commonly used in regular hemodialysis, during which dialysis‐related amyloidosis (DRA) may develop. The pathogenic protein, i.e. precursor protein, in DRA is β₂‐microglobulin (β₂m). Recent studies defined amyloidosis as a protein misfolding disease of precursor proteins including β₂m. Because the analytic technique capillary electrophoresis can identify molecular variants of the folded β₂m, i.e. conformational variants, we utilized it to investigate the effect of heparin on β₂m conformation and thus determined whether heparin can promote DRA development by inducing a conformational change in the amyloidogenic β₂m molecule. Heparin had a slight but significant effect on intermediate β₂m conformation but no effect on native β₂m conformation and on conversion of native to intermediate β₂m. Our findings thus suggest a possible association of β₂m with GAGs containing a sulfate moiety, including heparin, in HD patients.     

δβ -Thalassaemia in Two Yugoslavian Families

Members of two Yugoslavian families were found to have δβ-thalassaemia. Interaction of β-thalassaemia with δβ-thalassaemia occurred in two young children producing a clinical condition which is somewhat less severe than that of homozygous β-thalassaemia. Results from biosynthetic analyses indicate that the degree of globin chain imbalance in double heterozygotes for β- and δβ-thalassaemia is similar to that in homozygous β-thalassaemia. Fetal haemoglobin of all heterozygotes contained ^Gγ and ^Aγ chains in an average ratio of about 2:3 whereas that in the two double heterozygotes had ^Gγ and ^Aγ chains in a ratio of 3:2.