A closer look at alcohol-induced changes in the ghrelin system: novel insights from preclinical and clinical data.

Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, that is, the effects of alcohol on the ghrelin system, remains to be fully established. To further characterize this relationship, we examined (1) ghrelin levels via secondary analysis of human laboratory alcohol administration experiments with heavy-drinking participants; (2) expression of ghrelin, ghrelin receptor, and ghrelin-O-acyltransferase (GOAT) genes (GHRL, GHSR, and MBOAT4, respectively) in post-mortem brain tissue from individuals with alcohol use disorder (AUD) versus controls; (3) ghrelin levels in Ghsr knockout and wild-type rats following intraperitoneal (i.p.) alcohol administration; (4) effect of alcohol on ghrelin secretion from gastric mucosa cells ex vivo and GOAT enzymatic activity in vitro; and (5) ghrelin levels in rats following i.p. alcohol administration versus a calorically equivalent non-alcoholic sucrose solution. Acyl- and total-ghrelin levels decreased following acute alcohol administration in humans, but AUD was not associated with changes in central expression of ghrelin system genes in post-mortem tissue. In rats, alcohol decreased acyl-ghrelin, but not des-acyl-ghrelin, in both Ghsr knockout and wild-type rats. No dose-dependent effects of alcohol were observed on acyl-ghrelin secretion from gastric mucosa cells or on GOAT acylation activity. Lastly, alcohol and sucrose produced distinct effects on ghrelin in rats despite equivalent caloric value. Our findings suggest that alcohol acutely decreases peripheral ghrelin concentrations in vivo, but not in proportion to alcohol's caloric value or through direct interaction with ghrelin-secreting gastric mucosal cells, the ghrelin receptor, or the GOAT enzyme.

Sensitivity analysis of key factors influencing compression-induced deformation of waste rocks for backfilling to reduce environmental pollution.

As solid wastes are generated during coal mining, waste rocks can be backfilled into goaf so as to reduce geological hazards and environmental damage caused by coal mining; however, under different stress regimes, the sensitivities of factors influencing compression-induced deformation (CID) of waste rocks for backfilling (WRBs) are different. In order to control the compression-induced deformation of waste rocks for backfilling more efficiently, compression characteristics of waste rocks for backfilling under four different stress levels were tested by using a homemade loading test system for granular materials based on an orthogonal experiment. The influences of lithology, particle size distribution (PSD), lateral stress, and number of lateral loading cycles on compression-induced deformation of waste rocks for backfilling and sensitivities ranks of the four factors were analysed. The test results showed that: (1) under an axial stress of less than 10 MPa, lateral stress was considered the main factor influencing compression-induced deformation of waste rocks for backfilling; when the axial stress ranged from 10 to 20 MPa, particle size distribution was the main influencing factor; (2) under four different axial stress levels, the optimal combination of influencing factors is sandstone, a particle size distribution from 0 to 10 mm, 3 MPa lateral stress, and 7 lateral loading cycles; (3) to control the compression-induced deformation of waste rocks for backfilling, it was necessary to optimise the lateral stress under an axial stress of less than 10 MPa; while the axial stress was between 10 and 20 MPa, it was essential to optimise the particle size distribution.

Recycling of crushed waste rock as backfilling material in coal mine: effects of particle size on compaction behaviours.

Crushed waste rocks can be used as materials for backfilling goafs, so as to achieve the simultaneous goals of processing solid waste and controlling surface subsidence; however, particle size distribution directly affects the compaction of crushed waste rocks. Therefore, by employing a self-designed bidirectional loading test system for granular materials, this study tested compaction characteristics of crushed waste rocks with four different particle size distributions. Moreover, this research tested the changes of parameters in lateral and axial loading of crushed waste rocks and analysed the influence of particle size distribution on lateral strain, axial strain, porosity, lateral stress, and lateral pressure coefficient during compaction. The test results show that (1) particle size distribution affects porosity, strain, and lateral pressure coefficient of crushed waste rocks under lateral and axial loading. (2) For the samples under particle size distribution ranging from 0 to 10 mm, the initial porosity is low and deformations are small under axial loading, so that particles can make contact and bear effective stress in grain-grain contact. Therefore, more stress is transferred to the lateral direction. (3) After compaction, the curves of the samples of crushed waste rocks under four particle size distributions all shift upwards in comparison with those before compaction, indicating that particles are crushed and the proportion of small particles constantly increases. (4) A reasonable particle size distribution can significantly improve stress characteristics, reduce crushing of particles in the samples, and increase the stiffness of the samples, so as to achieve better compaction effects.

In vitro effect of genistein on DNA damage in leukocytes from mucopolysaccharidosis IVA patients.

Mucopolysaccharidosis IVA is a lysosomal storage disorder leading to an increase in glycosaminoglycans storage. Genistein is an isoflavone capable to inhibit glycosaminoglycans production. The objective of this study was to analyze the in vitro effect of different concentrations of genistein on DNA injury in mucopolysaccharidosis IVA patients. The lower concentration tested (10 µM) showed a significant increase on DNA injury in vitro, although higher concentrations (30 µM and 50 µM) showed higher DNA damage.

Investigation of oxidative stress parameters in treated phenylketonuric patients.

Phenylketonuria (PKU) is the most frequent disturbance of amino acid metabolism being caused by severe deficiency of phenylalanine hydroxylase activity. Untreated PKU patients present severe mental retardation whose pathophysiology is not completely estabilished. Despite the low-Phe diet, a considerable number of phenylketonuric patients present a mild to moderate psychomotor delay and decreased cognitive functions. In the present study we evaluated various parameters of oxidative stress namely thiobarbituric acid-reactive species (TBA-RS), total antioxidant reactivity (TAR) and activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in two groups of treated PKU patients, one with well controlled and the other with high Phe blood levels in order to investigate whether blood Phe concentrations could be correlated with the extend of oxidative stress. We initially verified a marked increase of TBA-RS, and a decrease of TAR in plasma, as well as a reduction of erythrocyte GSH-Px activity which were similar in both groups of PKU patients, when compared to controls of similar ages. In contrast, CAT and SOD activities were not altered in PKU patients. These results show that oxidative stress occurs in PKU patients and that this pathogenic process is probably not directly correlated to Phe blood levels.

Oxidative stress in patients with phenylketonuria.

Phenylketonuria (PKU) is an autossomal recessive disease caused by phenylalanine-4-hydroxylase deficiency, which is a liver-specific enzyme that catalyzes the hydroxylation of l-phenylalanine (Phe) to l-tyrosine (Tyr). The deficiency of this enzyme leads to the accumulation of Phe in the tissues and plasma of patients. The clinical characterization of this disease is mental retardation and other neurological features. The mechanisms of brain damage are poorly understood. Oxidative stress is observed in some inborn errors of intermediary metabolism owing to the accumulation of toxic metabolites leading to excessive free radical production and may be a result of restricted diets on the antioxidant status. In the present study we evaluated various oxidative stress parameters, namely thiobarbituric acid-reactive species (TBA-RS) and total antioxidant reactivity (TAR) in the plasma of PKU patients. The activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were also measured in erythrocytes from these patients. It was observed that phenylketonuric patients present a significant increase of plasma TBA-RS measurement, indicating a stimulation of lipoperoxidation, as well as a decrease of plasma TAR, reflecting a deficient capacity to rapidly handle an increase of reactive species. The results also showed a decrease of erythrocyte GSH-Px activity. Therefore, it is presumed that oxidative stress is involved in the pathophysiology of the tissue damage found in PKU.

Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers.

RATIONALE: Although numerous studies have documented that nicotine can function as an effective reinforcer of intravenous self-administration behavior in animals, it has not been clearly shown to maintain intravenous self-administration behavior above vehicle placebo levels in humans. OBJECTIVES: To compare the reinforcing effectiveness of nicotine versus saline placebo in human research volunteers responding under fixed-ratio (FR) schedules of intravenous drug self-administration while systematically increasing response requirements. METHODS: Eight male cigarette smokers resided in an inpatient research unit. During 3-h sessions, intravenous injections of nicotine and saline were available concurrently and were contingent on responding (pulling a lever). Nicotine dose (0.75, 1.5, 3.0 mg/injection), time out (TO) value after each injection (1-20 min) and FR response requirement (10-1600) were varied in different subjects over consecutive sessions. RESULTS: Number of nicotine injections/session significantly decreased as dose/injection increased and the number of self-administered nicotine injections was significantly greater than the number of self-administered saline injections across conditions. When FR value was progressively increased over sessions, response rates for nicotine, but not saline, injections increased, with maximal rates at the highest FR values. Rates of responding and injections/session were markedly and significantly higher for nicotine than for saline at FR values of 200 and above. Subjects rated effects of nicotine as both significantly more positive and more negative than saline placebo, with positive ratings significantly higher than negative ratings. CONCLUSIONS: Nicotine functioned as a prototypic drug of abuse, serving as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Subjects adjusted their responding to response requirements in a way that maintained relatively constant levels of nicotine injections per session.

Evidence that oxidative stress is increased in patients with X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a hereditary disorder of peroxisomal metabolism biochemically characterized by the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in different tissues and in biological fluids. The disease is clinically characterized by central and peripheral demyelination and adrenal insufficiency, which is closely related to the increased concentrations of these fatty acids. However, the mechanisms underlying the brain damage in X-ALD are poorly known. Considering that free radical generation is involved in various neurodegenerative disorders, like Parkinson disease, multiple sclerosis and Alzheimer's disease, in the present study we evaluated various oxidative stress parameters, namely chemiluminescence, thiobarbituric acid reactive species (TBA-RS), total radical-trapping antioxidant potential (TRAP), and total antioxidant reactivity (TAR) in plasma of X-ALD patients, as well as the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in erythrocytes and fibroblasts from these patients. It was verified a significant increase of plasma chemiluminescence and TBA-RS, reflecting induction of lipid peroxidation, as well as a decrease of plasma TAR, indicating a deficient capacity to rapidly handle an increase of reactive species. We also observed a significant increase of erythrocytes GPx activity and of catalase and SOD activities in fibroblasts from the patients studied. It is therefore proposed that oxidative stress may be involved in pathophysiology of X-ALD.