Effects of ketogenic diet and ketone monoester supplement on acute alcohol withdrawal symptoms in male mice.

RATIONALE: After alcohol ingestion, the brain partly switches from consumption of glucose to consumption of the alcohol metabolite acetate. In heavy drinkers, the switch persists after abrupt abstinence, leading to the hypothesis that the resting brain may be "starved" when acetate levels suddenly drop during abstinence, despite normal blood glucose, contributing to withdrawal symptoms. We hypothesized that ketone bodies, like acetate, could act as alternative fuels in the brain and alleviate withdrawal symptoms. OBJECTIVES: We previously reported that a ketogenic diet during alcohol exposure reduced acute withdrawal symptoms in rats. Here, our goals were to test whether (1) we could reproduce our findings, in mice and with longer alcohol exposure; (2) ketone bodies alone are sufficient to reduce withdrawal symptoms (clarifying mechanism); (3) introduction of ketogenic diets at abstinence (a clinically more practical implementation) would also be effective. METHODS: Male C57BL/6NTac mice had intermittent alcohol exposure for 3 weeks using liquid diet. Somatic alcohol withdrawal symptoms were measured as handling-induced convulsions; anxiety-like behavior was measured using the light-dark transition test. We tested a ketogenic diet, and a ketone monoester supplement with a regular carbohydrate-containing diet. RESULTS: The regular diet with ketone monoester was sufficient to reduce handling-induced convulsions and anxiety-like behaviors in early withdrawal. Only the ketone monoester reduced handling-induced convulsions when given during abstinence, consistent with faster elevation of blood ketones, relative to ketogenic diet. CONCLUSIONS: These findings support the potential utility of therapeutic ketosis as an adjunctive treatment in early detoxification in alcohol-dependent patients seeking to become abstinent. TRIAL REGISTRATION: clinicaltrials.gov NCT03878225, NCT03255031.

Thiamine and phosphate esters concentrations in whole blood and serum of patients with alcohol use disorder: a relation with cognitive deficits.

Background: In this study, we investigated (1) the effect of chronic and excessive alcohol consumption on whole blood (WB) and serum concentrations of thiamine and its metabolites after supplementation, and (2) the relationship between the perturbations of thiamine metabolism and neuropsychological abilities.Methods: WB and serum samples were collected in patients with Alcohol Use Disorder (AUD) and in healthy control subjects (after oral thiamine supplementation, or without supplementation). Thiamine (Th), thiamine monophosphate (TMP) and thiamine diphosphate (TDP) were quantified. The Brief Evaluation of Alcohol-Related Neuropsychological Impairments (BEARNI) and the Montreal Cognitive Assessment (MoCA) were performed by each AUD participant. Based on the BEARNI score, two groups of AUD patients were studied: AUD patients with no or mild cognitive impairment (AUD COG+), and AUD patients with moderate-to-severe cognitive impairment (AUD COG-).Results: In WB, Th concentrations were significantly higher, and percentages of phosphate esters of thiamine were significantly lower in AUD COG- patients compared to controls. In serum, Th concentrations were significantly higher in AUD COG- patients compared to controls. The percentage of Th in serum was significantly higher in AUD COG- patients compared to AUD COG+ patients, and to the groups of controls. When adjusted on education level, the percentage of Th in serum in AUD patients negatively correlated with the scores at BEARNI and MoCA, and Th concentration in serum negatively correlated with MoCA.Conclusions: These data support an impairment of metabolism and/or distribution of thiamine in AUD patients, and a relationship with the development of alcohol-related cognitive deficits.

Bioresponsive nanostructured systems for sustained naltrexone release and treatment of alcohol use disorder: Development and biological evaluation.

In this study, microemulsions capable of transforming into nanostructured hexagonal phase gels in vivo upon uptake of biological fluids for naltrexone prolonged release were investigated as a strategy for management of alcohol use disorder (AUD). Microemulsions were prepared using monoolein, tricaprylin, water and propylene glycol; after preliminary characterization, one formulation was selected, which contained 55% of monoolein-tricaprylin (M-55). This microemulsion displayed size below 200 nm and Newtonian rheological behavior. Liquid crystalline gels formed in vitro upon 8 h of contact with water following a second order kinetics. After 120 h, <50% of naltrexone was released in vitro independently on drug loading (5 or 10%). In vivo, gels formed within 24 h of M-55 subcutaneous administration, and persisted locally for over 30 days providing slow release of the fluorescent marker Alexa fluor compared to a solution. Using the conditioned place preference paradigm, a test used to measure drug's rewarding effects, a single dose of M-55 containing 5% naltrexone reduced the time spent in the ethanol-paired compartment by 1.8-fold compared to saline; this effect was similar to that obtained with daily naltrexone injections, demonstrating the formulation efficacy and its ability to reduce dosing frequency. A more robust effect was observed following administration of M-55 containing 10% of naltrexone, which was compatible with aversion. These results support M-55 as a platform for sustained release of drugs that can be further explored for management of AUD to reduce dosing frequency and aid treatment adherence.

Serum and Fecal Oxylipins in Patients with Alcohol-Related Liver Disease.

BACKGROUND: Alcohol-related liver disease is one of the most prevalent chronic liver diseases worldwide. Mechanisms involved in the pathogenesis of alcohol-related liver disease are not well understood. Oxylipins play a crucial role in numerous biological processes and pathological conditions. Nevertheless, oxylipins are not well studied in alcohol-related liver disease. AIMS: (1) To characterize the patterns of bioactive ω-3 and ω-6 polyunsaturated fatty acid metabolites in alcohol use disorder and alcoholic hepatitis patients and (2) to identify associations of serum oxylipins with clinical parameters in patients with alcohol-related liver disease. METHODS: We performed a comprehensive liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis of serum and fecal oxylipins derived from ω-6 arachidonic acid, ω-3 eicosapentaenoic acid, and docosahexaenoic acid in a patient cohort with alcohol-related liver disease. RESULTS: Our results show profound alterations in the serum oxylipin profile of patients with alcohol use disorder and alcoholic hepatitis compared to nonalcoholic controls. Spearman correlation of the oxylipins with clinical parameters shows a link between different serum oxylipins and intestinal permeability, aspartate aminotransferase, bilirubin, albumin, international normalized ratio, platelet count, steatosis, fibrosis and model for end-stage liver disease score. Especially, higher level of serum 20-HETE was significantly associated with decreased albumin, increased hepatic steatosis, polymorphonuclear infiltration, and 90-day mortality. CONCLUSIONS: Patients with alcohol-related liver disease have different oxylipin profiles. Future studies are required to confirm oxylipins as disease biomarker or to connect oxylipins to disease pathogenesis.

Effect of pesticide exposure on the cholinesterase activity of the occupationally exposed tea garden workers of northern part of West Bengal, India.

Context: Pesticide poisoning and related deaths are a global concern, but there is little information about its effect on the occupationally exposed tea garden workers of North Bengal. Objective: This study investigates the level of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the blood of the tea garden workers at risk of exposure to a mixture of pesticides. Materials and methods: The study sample consisted of pesticide exposed workers, non-exposed (control), smokers and alcoholics. AChE and BuChE activity was measured and tested for significance. Results: Results showed that AChE activity was half in the pesticide exposed individuals than controls (p≤ 0.001). BuChE activity was also significantly decreased in the pesticide exposed individuals than controls (p≤ 0.001), while AChE and BuChE activity in smokers and alcoholics were not different from that of controls. However, significantly decreased AChE and BuChE activities were recorded in pesticide exposed workers compared to smokers and alcoholics. Conclusions: The results indicated that the decrease in enzyme activities in tea garden workers was due to mixed pesticides (containing organophosphates) exposure. Age was not found to influence the enzyme activities. However, the gender had little effect on the enzyme activities but the effect was not so prominent.

Copper deficiency caused by excessive alcohol consumption.

Copper deficiency is a disease that causes cytopaenia and neuropathy and can be treated by copper supplementation. Long-term tube feeding, long-term total parenteral nutrition, intestinal resection and ingestion of zinc are known copper deficiency risk factors; however, alcohol abuse is not. In this case, a 71-year-old man had difficulty waking. He had a history of drinking more than five glasses of spirits daily. He was well until 3 months ago. A month before his visit to our hospital, he could not eat meals but continued drinking. He had macrocytic anaemia on admission. Copper and ceruloplasmin levels were markedly low, and we diagnosed copper deficiency. There were no other known risk factors for copper deficiency. After he began drinking cocoa as a copper supplement, the anaemia ameliorated and he was able to walk. This is the first report showing alcohol abuse as a risk factor for copper deficiency.

Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving.

BACKGROUND: Peripheral immune system cytokines may play an integral role in the underlying sensitized stress response and alcohol craving during early alcohol withdrawal. To date, the nature of these immune changes during early abstinence have not been examined. METHODS: A total of 39 early abstinent, treatment-seeking, alcohol-dependent individuals and 46 socially drinking controls were exposed to three guided imageries: stress, alcohol cue and neutral. These were presented randomly across consecutive days. Plasma measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-10 (IL-10), were collected at baseline, immediately after imagery and at various recovery time-points. Ratings of alcohol craving, negative mood and anxiety were also obtained at the same time-points. RESULTS: The alcohol group demonstrated decreased basal IL-10 compared with controls particularly following exposure to alcohol cue. They also showed a dampened TNFα and TNFR1 response to stress and cue, respectively, and a generalized suppression of IL-6. In the alcohol group, these immune system adaptations occurred alongside significant elevations in anxiety, negative mood and alcohol craving. CONCLUSIONS: Findings demonstrate that broad immunosuppression is still observed in alcohol-dependent individuals after 3 weeks of abstinence and may be linked to motivation for alcohol.

Thiamine deficiency, oxidative metabolic pathways and ethanol-induced neurotoxicity: how poor nutrition contributes to the alcoholic syndrome, as Marchiafava-Bignami disease.

Ethanol is an important risk factor for the occurrence of several brain disorders that depend on the amount, period and frequency of its consumption. Chronic use of ethanol often leads to the development of neurodegenerative syndromes, which cause morphological and functional impairments such as foetal alcohol syndrome in newborns exposed to ethanol during pregnancy, Wernicke-Korsakoff Syndrome and, more rarely, Marchiafava-Bignami disease (MBD). MBD is characterized by primary degeneration of the corpus callosum, without inflammation and is associated with oxidative stress and hypovitaminosis, as well as altered mental status, to mention dementia, seizures, depression and so on. This review discusses MBD and poor nutrition as a risk factor for the development of such alcoholic syndrome, with focus on diagnosis, pathogenic aspects, signs and symptoms, as well as therapeutic perspectives. On the basis of the inclusion/exclusion criteria adopted, the performed search in scientific databases (Pubmed, Scielo and Google Scholar) resulted in 100 studies that are being presented and discussed in the present work. Review, case-control and cohort studies on alcoholism-associated hypovitaminosis, oxidative stress, MBD and ethanol metabolism pathways were admitted as relevant. We highlight that MBD is a poorly described, diagnosed, insidious and progressive condition, for which evidence suggests a synergism between ethanol-induced neurotoxic effects and hypovitaminosis B. Present treatment consists of vitamin B1(thiamine) supplementation. Nonetheless, other strategies such as the inclusion of antidepressants or steroidal anti-inflammatories as add-on therapies have been employed as an attempt to improve the damage. Indeed, both the diagnosis and treatment are difficult, and death occurs within few years.

Association of plasma calcium concentrations with alcohol craving: New data on potential pathways.

Recently, calcium was suggested to be the active moiety of acamprosate. We examined plasma calcium concentrations in association with severity of alcohol dependence and its interaction with regulating pathways and alcohol craving in alcohol-dependent patients. 47 inpatient alcohol-dependent patients undergoing detoxification treatment underwent laboratory testing, including calcium, sodium, liver enzymes as well as serum concentrations of calcitonin, parathyroid hormone and vitamin D. The psychometric dimension of craving was analyzed with the Obsessive Compulsive Drinking Scale (OCDS). The severity of withdrawal was measured with the Alcohol Dependence Scale (ADS) and with the Alcohol Dependence Scale for high-risk sample (ADS-HR). The main findings of our investigation are: a) a negative correlation of plasma calcium concentrations with alcohol craving in different dimensions of the OCDS; b) a negative correlation of plasma calcium concentrations with breath alcohol concentration; c) lowered calcitonin concentration in the high-risk sample of alcoholics; d) lowered plasma vitamin D concentrations in all alcoholic subjects. Our study adds further support for lowered plasma calcium concentrations in patients with high alcohol intake and especially in patients with increased craving as a risk factor for relapse. Lowered calcitonin concentrations in the high-risk sample and lowered vitamin D concentrations may mediate these effects. Calcium supplementation could be a useful intervention for decreasing craving and relapse in alcohol-dependent subjects.

Effects of Sex, Drinking History, and Omega-3 and Omega-6 Fatty Acids Dysregulation on the Onset of Liver Injury in Very Heavy Drinking Alcohol-Dependent Patients.

BACKGROUND: Heavy alcohol consumption frequently causes liver inflammation/injury, and certain fatty acids (FAs) may be involved in this liver pathology. In this study, we evaluated the association of heavy drinking and the changes in the FA levels involved in the ω-6 (pro-inflammatory) and ω-3 (anti-inflammatory) state in alcohol-dependent (AD) patients who had no clinical manifestations of liver injury. We aimed to identify sex-based differences in patients with mild or no biochemical evidence of liver injury induced by heavy drinking. METHODS: A total of 114 heavy drinking AD female and male patients aged 21 to 65 years without clinical manifestations of liver injury, who were admitted to an alcohol dependence treatment program, were grouped by the alanine aminotransferase (ALT) levels: ≤40 IU/l, as no liver injury (GR.1), and >40 IU/l, as mild liver injury (GR.2). Patients were actively drinking until the day of admission. Comprehensive metabolic panel, comprehensive FA panel, and drinking history data were evaluated. RESULTS: Elevated ALT and aspartate aminotransferase (AST) showed close association with markers of heavy alcohol intake. In the patients with mild biochemical liver injury (GR.2), females showed significantly higher AST level than males. Significant association of AST and total drinks in past 90 days (TD90) in females, and AST and heavy drinking days in past 90 days (HDD90) in males was observed. The ω-6:ω-3 ratio showed a significant pro-inflammatory response only in females with mild liver injury (GR.2) when adjusted by drinking history marker, TD90. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were increased in males with liver injury, while females did not show any comparable rise in EPA; and DHA levels were lower. CONCLUSIONS: Measures of heavy drinking, TD90 and HDD90, predicted changes in liver injury. Changes in the ω-3 and ω-6 FA levels and the ω-6:ω-3 ratio showed a pro-inflammatory shift in patients with biochemical liver injury with a significant effect in females. Changes in FAs involved in the inflammatory state may represent one mechanism for liver inflammation/injury in response to heavy alcohol drinking.

Moderate alcohol consumption in chronic form enhances the synthesis of cholesterol and C-21 steroid hormones, while treatment with Tinospora cordifolia modulate these events in men.

Chronic and heavy alcohol consumption disrupts lipid metabolism and hormonal balance including testosterone levels. However, studies doubt the relationship between moderate alcohol intake and sex hormone levels. Therefore, the aim of the present investigation was to establish the direct impact of chronic and moderate alcohol intake on cholesterol homeostasis and steroid hormone synthesis. Asymptomatic chronic and moderate alcoholics (n=12) without chronic liver disease and healthy volunteers (n=14) were selected for the study. Furthermore, effects of standardized water extract of Tinospora cordifolia (Willd) Mier. (Menispermaceae) (TCJ), a well reported anti-alcoholic herbal drug, on urinary steroids was studied. This study included four groups, i.e. a) healthy; b) healthy+TCJ; c) alcoholic; d) alcoholic+TCJ. The blood and urine samples from each group were collected on day 0 and 14 of the post-treatment with TCJ and analyzed. Alcoholic blood samples showed the significantly higher values of traditional biomarkers γ-GT and MCV along with cholesterol, LDL, TGL and urinary methylglucuronide compared to healthy. Qualitative analysis of steroids showed that moderate alcohol intake in a chronic manner increased the cholesterol synthesis and directed its flow toward C-21 steroids; shown by increased levels of corticosterone (2.456 fold) and cortisol (3.7 fold). Moreover, alcohol intake also increased the synthesis of estradiol and clearance rate of other steroids through the formation of glucuronides. Therefore, it decreased the synthesis and increased the clearance rate of testosterone (T) and androstenedione (A). Quantitative analysis confirmed decreased T/A ratio from 2.31 to 1.59 in plasma and 2.47 to 1.51 in urine samples of alcoholics. TCJ intervention normalized the levels of steroids and significantly improved the T:A ratio to 2.0 and 2.12 in plasma and urine. The study revealed that TCJ modulated lipid metabolism by inhibiting cholesterol and glucuronides synthesis.

[Effect of improper diets on blood viscosity in SD rats in high-salt and fat diet and alcohol abuse simulation model].

OBJECTIVE: To observe the effect of composite factors, like long-term high-salt & fat diet and alcohol abuse on blood viscosity and blood pressure in rats, and compare with a model induced by high molecular dextran, in order to build a chronic hyperviscosity aminal model which is similar to human hyperviscosity in clinic and lay a foundation for efficacy evaluation on traditional Chinese medicines. METHOD: Male SD rats were randomly divided into the normal group, the high molecular dextran (HMD) group and the high salt & fat and alcohol (HSFA) group. The HMD group was given normal diet and water for 23 day and then 10% HMD through tail vein for 5 days. The HSFA group was fed with high salt and high fat diets every day and alcohol for 20 h x d(-1) for 13 weeks. After the modeling, whole blood viscosity and plasma viscosity were measured in the 5th, 8th and 11th week. Blood pressure was measured in the 5d, 7h, and 10th week. Red cell count (RBC) and hematocrit (HCT) were measured in the 11th week. PAgT, Fb, ET-1, NO, PGI, TXA2 contents of the normal group and the HSFA group were measured in the 13th week, and IECa21 content was measured with flow cytometry. Result: After the modeling, the HMD group was in good conditions with glossy hairs and active behaviors. The HSFA group was depressed with withered hairs and less activities. During the 5th-11th weeks, the HMD group and the HSFA group showed higher values in high and low shear whole blood viscosity (WBV) than the normal control group. The plasma viscosity (PV) of HMD rats was significantly increased only in the 5th week, and that of HSFA rats significantly increased in the 8"' and 11th week, particularly in the 11'h week. In the 111h week, the HSFA group showed significant increases in RBC and HCT. After the modeling, the blood pressure of HMD rats showed no significant changes, but the blood pressure of HSFA rats significantly increased during 7' and 101h weeks, particularly in the 10"' week. In the 13th week, PAgT, IECa2+, Fb, ET-1 of HSFA rats significantly increased, but with decreases in NO and PGI2. CONCLUSION: Long-term high salt & fat and alcohol diets can cause abnormal blood viscosity in rats. WBV significantly increased since the 5th week in rats, and PV increased since the 8th week. The mechanism for increasing BV may be: (1) increases in RBC, HCT, and IECa2+, (2) PAgT increase, (3) Fb content increase, or (4) TXA2/PGI2, ET-1/NO imbalance. Although the modeling time with the method is longer than that with the HMD method, the model is more stable and moderate, and could lead to abnormal increases in WBV and PV; Whereas the HMD method only induced transient increase in plasma viscosity and abnormal increase in SBP. The model is more similar to traditional Chinese medicine syndromes and pathogenesis, with higher value for studies on efficacy of traditional Chinese medicines.

Polydatin administration improves serum biochemical parameters and oxidative stress markers during chronic alcoholism: a pilot study.

AIM: Polydatin, a hydroxystilbene derived from the rhizome of Polygonum cuspidatum, elicits hepatoprotective and neuroprotective effects through its anti-oxidant properties. The present study aimed to determine the effects of oral administration of polydatin in alcoholic patients in order to improve liver biochemical parameters, serum oxidative stress and mental state. We enrolled 20 chronic alcoholic patients hospitalized for rehabilitative therapy. The patients were divided into two groups receiving the following treatment regimes for two weeks: administration of an anti-oxidant nutritional supplement containing glutathione and vitamin C (group 1), or glutathione, vitamin C and polydatin (group 2). RESULTS: The results of the present study show that elevated plasma aspartate aminotransferase and alanine aminotransferase levels in patients after two weeks of alcohol withdrawal were significantly reduced by polydatin (group 2), when compared to group 1. Polydatin also significantly reduced lipid peroxidation levels. Finally, our preliminary data resulting from the analysis of the Mini-Mental Status suggest that polydatin improves cognitive performance. CONCLUSION: Daily dietary administration of polydatin should be considered for prevention and treatment of liver disease and cognitive impairment in alcoholic patients.

Change in psychiatric symptomatology after benfotiamine treatment in males is related to lifetime alcoholism severity.

BACKGROUND: Severe alcoholism can be associated with significant nutritional and vitamin deficiency, especially vitamin B1 (thiamine) which is associated with neurological deficits impacting mood and cognition. Alcohol consumption was reduced among female but not male alcoholics after supplementation with the high potency thiamine analog benfotiamine (BF). We examined the relationship between lifetime alcoholism severity, psychiatric symptoms and response to BF among the alcohol dependent men from this cohort. METHODS: Eighty-five adult men (mean age=48±8 years) meeting DSM-IV-TR criteria for a current alcohol use disorder who were abstinent <30days participated in a randomized, double-blind, placebo-controlled trial of 600mg BF vs placebo (PL) for 6 months. Psychometric testing included a derived Lifetime Alcoholism Severity Score (AS), Symptom Checklist 90R (SCL-90R), and the Barratt Impulsivity Scale (BIS) at baseline and at 6 months. RESULTS: Baseline SCL-90-R scale scores for men with high alcoholism severity (AS≥24; N=46 HAS) were significantly greater than for men with low alcoholism severity (AS<24; N=39 LAS), but BIS scores did not differ. MANOVA modeling at follow-up (N=50 completed subjects) identified a significant treatment effect (F=2.5, df=10, p<0.03) and treatment×alcoholism severity level interaction (F=2.5, dfnum=10, dfden=30, p<0.03) indicating reduced SCL-90-R scores among BF treated, HAS males. Above normal plasma thiamine levels at follow-up predicted reduced depression scores in a BF-treated subset (F=3.2, p<0.09, N=26). CONCLUSION: BF appears to reduce psychiatric distress and may facilitate recovery in severely affected males with a lifetime alcohol use disorder and should be considered for adjuvant therapy in alcohol rehabilitation. TRIAL REGISTRATION: #NCT00680121 High Dose Vitamin B1 to Reduce Abusive Alcohol Use.

Detection of new human metabolic urinary markers in chronic alcoholism and their reversal by aqueous extract of Tinospora cordifolia stem.

AIMS: We have studied urine metabolic signature of chronic alcoholism (CA) before and after treatment with an Ayurvedic drug Tinospora cordifolia aqueous extract (TCE). METHODS: Urinary metabolites of chronic alcoholics and apparently healthy subjects were profiled using HPLC-Q-TOF-MS. Discrimination models from the initial data sets were able to correctly assign the unknown samples to the CA, treated or healthy groups in validation sets with r(2) > 0.98. RESULTS: Metabolic signature in CA patients include changed tryptophan, fatty acids and pyrimidines metabolism. Several novel biomarkers of alcoholism were observed in urine for the first time which includes, 5-hydroxyindole, phenylacetic acid, picolinic acid, quinaldic acid, histidine, cystathionine, riboflavin, tetrahydrobiopterin and chenodeoxyglycocholic acid, in addition to previously reported biomarkers. Treatment of CA with TCE reverted the levels of most of the biomarkers except tetrahydrobiopterin levels. CONCLUSIONS: These results suggested that the measurement of these urine metabolites could be used as a non-invasive diagnostic method for the detection of CA. As TCE treatment significantly reversed the affected pathways without any side effect. Overall, the present data depicts that TCE may be used either alone or adjunct in reducing alcohol-induced disorders.

Protective effect of corn peptides against alcoholic liver injury in men with chronic alcohol consumption: a randomized double-blind placebo-controlled study.

BACKGROUND: Corn peptides (CPs) are a novel food prepared from corn gluten meal, which is a main by-product of the corn starch industry. Recently, significant beneficial effects of CPs on early alcoholic liver injury in rats and on acute alcoholic injury in mice were observed. To our knowledge, the present study is the first report showing that CPs supplementation has beneficial effects on lipid profile, oxidative stress and alcoholic liver injury in men with chronic alcohol consumption. METHODS: A 9-week, randomized, double-blind, placebo-controlled study was conducted between September 2011 and August 2012 to assess the hepatoprotective effect of CPs. A total of 161 men were randomized to receive CPs (n=53), whey protein (n=54), or corn starch placebo (n=54) at the same dose of 2 g twice daily. 146 participants completed the study. Serum lipid profile, serum markers of liver injury, oxidative stress and inflammation, and fatty liver based on the results of abdominal ultrasonography were assessed at the beginning and end of the intervention. RESULTS: CPs supplementation (4 g/d) for 9 weeks significantly lowered serum levels or activities of total cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase, malondialdehyde and tumor necrosis factor-α, and significantly increased serum activities of superoxide dismutase and glutathione peroxidase, but the same dose of whey protein and corn starch (placebo) did not demonstrate these effects. CONCLUSIONS: Our results indicate that CPs may have protective effects on alcohol-induced liver damage via modulation of lipid metabolism and oxidative stress. CPs may potentially be used as a functional food for the management of alcoholic liver disease in subjects with chronic alcohol consumption.

Peripheral systems: neuropathy.

Long-term, excessive consumption of alcoholic beverages produces a peripheral neuropathy with symptoms of decreased superficial sensation, hyperalgesia, and weakness. Alcoholic neuropathy is characterized by axonal degeneration with reduced density of both small and large fibers and axonal sprouting. Electrophysiologic studies reveal a marked reduction in the amplitude of sensory potentials and moderate slowing of nerve conduction, mainly in the lower extremities. Dietary deficiency of vitamins, which are often associated with chronic alcoholism, can contribute to the pathogenesis. Recent studies using animal models have identified several mechanisms by which ethanol impacts peripheral nerve function. Ethanol can exert direct neurotoxic effects on peripheral nerves via its metabolite acetaldehyde and by enhancing oxidative stress. Ethanol activation of protein kinase Cε signaling in primary afferent nociceptors plays an important role in lowering nociceptive threshold. Further, ethanol causes cytoskeletal dysfunction and inhibits both anterograde and retrograde axonal transport. Alcoholic neuropathy is potentially reversible and treatments include abstinence from alcoholic beverages and consumption of a nutritionally balanced diet supplemented with B vitamins. However, response to these treatment strategies can be variable, which underscores the need for novel therapeutic strategies. In this review, we provide an overview of the clinical findings and insights on molecular mechanisms from animal models.

Zn(II)-curcumin protects against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism.

Curcumin can chelate metal ions, forming metallocomplexes. We compared the effects of Zn(II)-curcumin with curcumin against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism. Oral administration of Zn(II)-curcumin dose-dependently prevented the ethanol-induced elevation of serum malondialdehyde (MDA) content and reductions in glutathione level and superoxide dismutase (SOD) activity. Zn(II)-curcumin also inhibited ethanol-induced liver injury. Additionally, Zn(II)-curcumin dose-dependently inhibited hemorheological abnormalities, including the ethanol-induced elevation of whole blood viscosity, plasma viscosity, blood viscosity at corrected hematocrit (45%), erythrocyte aggregation index, erythrocyte rigidity index and hematocrit. Compared to curcumin at the same dose, Zn(II)-curcumin more effectively elevated SOD activity, ameliorated liver injury and improved hemorheological variables. These results suggest that Zn(II)-curcumin protected the rats from ethanol-induced liver injury and hemorheological abnormalities via the synergistic effect of curcumin and zinc.

Nutritional intake and status in persons with alcohol dependency: data from an outpatient treatment programme.

PURPOSE: Malnutrition increases the risk of developing alcohol-related complications. The aim of this study was to describe nutrient intake, nutritional status and nutrition-related complications in a Danish population of outpatients with alcohol dependency. METHODS: This was a cross-sectional study with a 6-month follow-up enrolling persons with alcohol dependency (n = 80) admitted to a hospital-based outpatient clinic. Body mass index, the waist-to-hip ratio and handgrip strength (HGS) were measured, a 7-day food diary was collected, and biochemical testing was conducted. Dual-energy X-ray absorptiometry was performed to determine body composition and bone mineral density (BMD). RESULTS: In total, 64% of the patients with alcohol dependency had vitamin D insufficiency (25-OH-vit D <50 nmol/l). Compared with surveys of the general population, the patients with alcohol dependency had lower energy intake (p = 0.008), s-zinc levels (p < 0.001), s-magnesium levels (p = 0.02), Z-scores for BMD (lumbar spine, p = 0.03; total hip, p = 0.009) and HGS (p < 0.001). Osteopenia was observed in 52% of individuals, and overt osteoporosis was noted in 7%. Comparing baseline data with data from the follow-up (n = 30), we found a decrease in s-CRP (p = 0.002) and s-alanine amino transferase (p = 0.01) levels and an increase in s-parathyroid hormone levels (p = 0.02). CONCLUSIONS: Patients with alcohol dependency have an altered nutritional status and risk of complications, as evidenced by osteopenia/osteoporosis and reduced muscle strength. Treatment at an outpatient clinic improved the variables related to liver function, but no change was observed in nutritional status over time. These findings suggest that specific screening and targeted treatment regimens for nutritional deficits could be beneficial.

Serum selenium levels and oxidative balance as differential markers in hepatic damage caused by alcohol.

AIMS: Antioxidant system abnormalities have been associated with ethanol consumption. This study examines the effects of chronic ethanol consumption on oxidative balance, including selenium (Se) levels in alcoholic patients with or without liver disease, and if these measurements could be indicative of liver disease. MAIN METHODS: Serum Se levels, antioxidant enzymes' activities, malondialdehyde (MDA) and protein carbonyl (PC) were determined in three groups of patients: alcoholics without liver disease, alcoholics with liver disease, and non-alcoholics with liver disease; and in healthy volunteers. KEY FINDINGS: Serum Se levels were lower in alcoholic patients and in patients affected by liver disease and especially lower in the alcoholic liver disease group. These values were correlated with the activity of glutathione peroxidase (GPx), the antioxidant selenoprotein. The antioxidant activities of the glutathione reductase (GR) and superoxide dismutase (SOD) were also lower in the three non-healthy groups. However, GR activity decreased and SOD activity increased in the non-alcoholic liver disease group versus alcoholic groups. Higher concentrations of PC in serum were found in non-healthy groups and were higher in alcoholic patients who also showed higher MDA levels. The highest MDA and PC levels were found in the alcoholic liver disease group. SIGNIFICANCE: We conclude that serum Se levels are drastically decreased in alcoholic liver disease patients, showing that this element has a direct correlation with GPx activity, and lipid oxidation, suggesting that the serum Se/MDA ratio could be an indicator of hepatic damage caused by alcohol consumption, and pointing to Se as a possible antioxidant therapy.