Supplementation with branched-chain amino acids attenuates hepatic apoptosis in rats with chronic liver disease

Branched-chain amino acids (BCAA) can function as pharmacologic nutrients for patients with decompensated cirrhosis. However, the effects of BCAA at the early stage of chronic liver disease are not clear. We hypothesized that early BCAA supplementation would attenuate the progression of chronic liver disease. The present study examined the effects of BCAA supplementation on the progression of chronic liver disease in rats caused by injected carbon tetrachloride (CCl₄). Sprague-Dawley rats were fed with a casein diet (control group) or the same diet supplemented with BCAA (BCAA group) for 11 weeks, and all rats were repeatedly injected with CCl₄. Food intake did not significantly differ between control and BCAA groups during the experimental period. Plasma alanine aminotransferase activities gradually increased during the experimental period in both groups but peaked later in the BCAA group. Liver fibrosis was more evident in the control group. Levels of connective tissue growth factor messenger RNA were significantly lower in the livers of rats in the BCAA group than in the control group. Terminal deoxynucleotidyl transferase–mediated deoxyuridine 5-triphosphate nick end labeling assays found considerably more hepatic apoptosis in the control group. Liver cytosolic cytochrome c levels and expression of the proapoptotic Bax protein in the mitochondrial fraction were significantly lower in the BCAA group than in the control group. These results suggest that supplementation with BCAA delays the progression of chronic liver disease caused by CCl₄ in rats by attenuating hepatic apoptosis.     

Naringin Improves Diet-Induced Cardiovascular Dysfunction and Obesity in High Carbohydrate,High Fat Diet-Fed Rats

Obesity, insulin resistance, hypertension and fatty liver, together termed metabolic syndrome, are key risk factors for cardiovascular disease. Chronic feeding of a diet high in saturated fats and simple sugars, such as fructose and glucose, induces these changes in rats. Naturally occurring compounds could be a cost-effective intervention to reverse these changes. Flavonoids are ubiquitous secondary plant metabolites; naringin gives the bitter taste to grapefruit. This study has evaluated the effect of naringin on diet-induced obesity and cardiovascular dysfunction in high carbohydrate, high fat-fed rats. These rats developed increased body weight, glucose intolerance, increased plasma lipid concentrations, hypertension, left ventricular hypertrophy and fibrosis, liver inflammation and steatosis with compromised mitochondrial respiratory chain activity. Dietary supplementation with naringin (approximately 100 mg/kg/day) improved glucose intolerance and liver mitochondrial dysfunction, lowered plasma lipid concentrations and improved the structure and function of the heart and liver without decreasing total body weight. Naringin normalised systolic blood pressure and improved vascular dysfunction and ventricular diastolic dysfunction in high carbohydrate, high fat-fed rats. These beneficial effects of naringin may be mediated by reduced inflammatory cell infiltration, reduced oxidative stress, lowered plasma lipid concentrations and improved liver mitochondrial function in rats.     

Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress

Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product–receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat–high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.     

GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency,Oxidative Stress,Mitochondrial Dysfunction,Abnormalities in Mitophagy and Nutrient Sensing,and Genomic Damage

Determinants of length of life are not well understood, and therefore increasing lifespan is a challenge. Cardinal theories of aging suggest that oxidative stress (OxS) and mitochondrial dysfunction contribute to the aging process, but it is unclear if they could also impact lifespan. Glutathione (GSH), the most abundant intracellular antioxidant, protects cells from OxS and is necessary for maintaining mitochondrial health, but GSH levels decline with aging. Based on published human studies where we found that supplementing glycine and N-acetylcysteine (GlyNAC) improved/corrected GSH deficiency, OxS and mitochondrial dysfunction, we hypothesized that GlyNAC supplementation could increase longevity. We tested our hypothesis by evaluating the effect of supplementing GlyNAC vs. placebo in C57BL/6J mice on (a) length of life; and (b) age-associated GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage in the heart, liver and kidneys. Results showed that mice receiving GlyNAC supplementation (1) lived 24% longer than control mice; (2) improved/corrected impaired GSH synthesis, GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage. These studies provide proof-of-concept that GlyNAC supplementation can increase lifespan and improve multiple age-associated defects. GlyNAC could be a novel and simple nutritional supplement to improve lifespan and healthspan, and warrants additional investigation.     

Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice

Abstract

The present study investigated the relationships among oxidative stress, β-amyloid and cognitive abilities in the APP/PSEN1 double-transgenic mouse model of Alzheimer's disease. In two experiments, long-term dietary supplements were given to aged APP/PSEN1 mice containing vitamin C alone (1 g/kg diet; Experiment 1) or in combination with a high (750 IU/kg diet, Experiments 1 and 2) or lower (400 IU/kg diet, Experiment 2) dose of vitamin E. Oxidative stress, measured by F₄-neuroprostanes or malondialdehyde, was elevated in cortex of control-fed APP/PSEN1 mice and reduced to wild-type levels by vitamin supplementation. High-dose vitamin E with C was less effective at reducing oxidative stress than vitamin C alone or the low vitamin E+C diet combination. The high-dose combination also impaired water maze performance in mice of both genotypes. In Experiment 2, the lower vitamin E+C treatment attenuated spatial memory deficits in APP/PSEN1 mice and improved performance in wild-type mice in the water maze. Amyloid deposition was not reduced by antioxidant supplementation in either experiment.     

Dietary Cocoa Flavanols Enhance Mitochondrial Function in Skeletal Muscle and Modify Whole-Body Metabolism in Healthy Mice

Mitochondrial dysfunction is widely reported in various diseases and contributes to their pathogenesis. We assessed the effect of cocoa flavanols supplementation on mitochondrial function and whole metabolism, and we explored whether the mitochondrial deacetylase sirtuin-3 (Sirt3) is involved or not. We explored the effects of 15 days of CF supplementation in wild type and Sirt3^-/- mice. Whole-body metabolism was assessed by indirect calorimetry, and an oral glucose tolerance test was performed to assess glucose metabolism. Mitochondrial respiratory function was assessed in permeabilised fibres and the pyridine nucleotides content (NAD⁺ and NADH) were quantified. In the wild type, CF supplementation significantly modified whole-body metabolism by promoting carbohydrate use and improved glucose tolerance. CF supplementation induced a significant increase of mitochondrial mass, while significant qualitative adaptation occurred to maintain H₂O₂ production and cellular oxidative stress. CF supplementation induced a significant increase in NAD⁺ and NADH content. All the effects mentioned above were blunted in Sirt3^-/- mice. Collectively, CF supplementation boosted the NAD metabolism that stimulates sirtuins metabolism and improved mitochondrial function, which likely contributed to the observed whole-body metabolism adaptation, with a greater ability to use carbohydrates, at least partially through Sirt3.     

Oxidative stress, mitochondrial respiration, and glycemic control: Clues from chronic supplementation with Cr or As to male wistar rats

Multiple experiments in male Wistar rats were designed to clarify the role of mitochondrial dysfunction in the mechanisms of oxidative stress-related diseases and toxicity-induced pathologies. In this particular report, 21 male Wistar rats were supplemented ad libitum with either As³⁺ or Cr³⁺ salts in drinking water to assess insulin secretion patterns in vivo and in vitro, mitochondrial dysfunction, oxidative stress, liver damage, basal insulin, and glucose tolerance curves, among other parameters. Results were compared with a control group without any metal supplementation. The CrCl₃ supplements were more invasive of metabolism and had a stronger effect on mitochondrial dysfunction than As³⁺, despite that both seem to use similar mechanisms of toxicity; viz.: binding to thiol or -SS- group in enzymes and proteins, and releasing oxidant species during their redox-cycling and metabolic activation processes, e.g., by cytochrome P450 in liver. Results support our aim to prove the influence of oxidative stress-induced mitochondrial dysfunction on glycemic control.     

Switching to Regular Diet Partially Resolves Liver Fibrosis Induced by High-Fat,High-Cholesterol Diet in Mice

The globally prevalent disease, non-alcoholic steatohepatitis (NASH), is characterized by a steatotic and inflammatory liver. In NASH patients, tissue repair mechanisms, activated by the presence of chronic liver damage, lead to the progressive onset of hepatic fibrosis. This scar symptom is a key prognostic risk factor for liver-related morbidity and mortality. Conflicting reports discuss the efficiency of dietary interventions on the reversibility of advanced fibrosis established during NASH. In the present study, the effect of dietary interventions was investigated in the outcome of the fibrosis settled in livers of C57BL/6J mice on a high-fat, high-cholesterol diet (HFHCD) for 5 or 12 consecutive weeks. Various clinico-pathological investigations, including a histological analysis of the liver, measurement of plasma transaminases, steatosis and fibrosis, were performed. To assess the effectiveness of the dietary intervention on established symptoms, diseased mice were returned to a standard diet (SD) for 4 or 12 weeks. This food management resulted in a drastic reduction in steatosis, liver injuries, inflammatory markers, hepatomegaly and oxidative stress and a gradual improvement in the fibrotic state of the liver tissue. In conclusion, our results demonstrated that dietary intervention can partially reverse liver fibrosis induced by HFHCD feeding.     

Preconditioning with Short-Term Dietary Restriction Attenuates Cardiac Oxidative Stress and Hypertrophy Induced by Chronic Pressure Overload

Left ventricular (LV) hypertrophy and associated heart failure are becoming a more prevalent and critical public health issue with the aging of society, and are exacerbated by reactive oxygen species (ROS). Dietary restriction (DR) markedly inhibits senescent changes; however, prolonged DR is difficult. We herein investigated whether preconditioning with short-term DR attenuates chronic pressure overload-induced cardiac hypertrophy and associated oxidative stress. Male c57BL6 mice were randomly divided into an ad libitum (AL) diet or 40% restricted diet (DR preconditioning, DRPC) group for 2 weeks prior to ascending aortic constriction (AAC), and all mice were fed ad libitum after AAC surgery. Two weeks after surgery, pressure overload by AAC increased LV wall thickness in association with LV diastolic dysfunction and promoted myocyte hypertrophy and cardiac fibrosis in the AL+AAC group. Oxidative stress in cardiac tissue and mitochondria also increased in the AL+AAC group in association with increments in cardiac NADPH oxidase-derived and mitochondrial ROS production. LV hypertrophy and associated cardiac dysfunction and oxidative stress were significantly attenuated in the DRPC+AAC group. Moreover, less severe mitochondrial oxidative damage in the DRPC+AAC group was associated with the suppression of mitochondrial permeability transition and cardiac apoptosis. These results indicate that chronic pressure overload-induced cardiac hypertrophy in association with cardiac and mitochondrial oxidative damage were attenuated by preconditioning with short-term DR.     

Vascular endothelial dysfunction, oxidative stress--a new topic within the referral section of Orvosi Hetilap

The author describes some of the numerous domains regarding the new topic called "Vascular endothelial dysfunction, oxidative stress". The endothelium is responsible for the constancy and integrity of the milieu interieur by producing various substances. Endothelial dysfunction occurs when there is imbalance between vasodilators and vasoconstrictors, growth factors and their inhibitors, proinflammatory and antiinflammatory agents, prothrombotic and fibrinolytic activities. The reason for this imbalance may be response to vascular endothelial or intimal injury caused by mechanical, physical, chemical, microbiological, immunologic, genetic damage or any of their combination. Endothelial dysfunction occurring on the huge inner surface of the vessels (the endothelium) is responsible for the triggering of atherosclerosis, which is a chronic vascular disease. All the risk factors of vascular pathology are leading to chronic (cardio)vascular diseases by causing endothelial dysfunction. Decreased endogenous antioxidative capacity leads to oxidative stress by free radical reactions of physiological oxidative metabolic processes, ending as the ultimate reason for endothelial dysfunction induced by risk factors. The therapeutic and preventive effects of causal antioxidant treatments having intracellular and mitochondrial effects (statins, angiotensin-converting-enzyme inhibitors, angiotensin-receptor-blockers, acetylsalicylic acid, and third generation beta-blockers) should be emphasized. It is also important to underline the physiological-pathophysiological-therapeutic consubstantiality and systemic nature of human vasculature and to emphasize the preventive-therapeutic significance of the vascular consequence cascade. And finally, there has been large process in the assessment of oxidative stress and consecutive endothelial dysfunction which revolutionized our clinical point of view.     

<Emphasis Type="Italic">Sasa veitchii</Emphasis> extract protects against carbon tetrachloride-induced hepatic fibrosis in mice

Background

The current study aimed to investigate the hepatoprotective effects of Sasa veitchii extract (SE) on carbon tetrachloride (CCl₄)-induced liver fibrosis in mice.

Methods

Male C57BL/6J mice were intraperitoneally injected with CCl₄ dissolved in olive oil (1 g/kg) twice per week for 8 weeks. SE (0.1 mL) was administered orally once per day throughout the study, and body weight was measured weekly. Seventy-two hours after the final CCl₄ injection, mice were euthanized and plasma samples were collected. The liver and kidneys were collected and weighed.

Results

CCl₄ administration increased liver weight, decreased body weight, elevated plasma alanine aminotransferase, and aspartate aminotransferase and increased liver oxidative stress (malondialdehyde and glutathione). These increases were attenuated by SE treatment. Overexpression of tumor necrosis factor-α was also reversed following SE treatment. Furthermore, CCl₄-induced increases in α-smooth muscle actin, a marker for hepatic fibrosis, were attenuated in mice treated with SE. Moreover, SE inhibited CCl₄-induced nuclear translocation of hepatic nuclear factor kappa B (NF-κB) p65 and phosphorylation of mitogen-activated protein kinase (MAPK).

Conclusion

These results suggested that SE prevented CCl₄-induced hepatic fibrosis by inhibiting the MAPK and NF-κB signaling pathways.

     

Acetyl-l-carnitine and lipoic acid improve mitochondrial abnormalities and serum levels of liver enzymes in a mouse model of nonalcoholic fatty liver disease

Mitochondrial abnormalities are suggested to be associated with the development of nonalcoholic fatty liver. Liver mitochondrial content and function have been shown to improve in oral feeding of acetyl-l-carnitine (ALC) to rodents. Carnitine is involved in the transport of acyl-coenzyme A across the mitochondrial membrane to be used in mitochondrial β-oxidation. We hypothesized that oral administration ALC with the antioxidant lipoic acid (ALC + LA) would benefit nonalcoholic fatty liver. To test our hypothesis, we fed Balb/C mice a standard diet (SF) or SF with ALC + LA or high-fat diet (HF) or HF with ALC + LA for 6 months. Acetyl-l-carnitine and LA were dissolved at 0.2:0.1% (wt/vol) in drinking water, and mice were allowed free access to food and water. Along with physical parameters, insulin resistance (blood glucose, insulin, glucose tolerance), liver function (alanine transaminase [ALT], aspartate transaminase [AST]), liver histology (hematoxylin and eosin), oxidative stress (malondialdehyde), and mitochondrial abnormalities (carbamoyl phosphate synthase 1 and electron microscopy) were done. Compared with SF, HF had higher body, liver, liver-to-body weight ratio, white adipose tissue, ALT, AST, liver fat, oxidative stress, and insulin resistance. Coadministration of ALC + LA to HF animals significantly improved the mitochondrial marker carbamoyl phosphate synthase 1 and the size of the mitochondria in liver. Alanine transaminase and AST levels were decreased. In a nonalcoholic fatty liver mice model, ALC + LA combination improved liver mitochondrial content, size, serum ALT, and AST without significant changes in oxidative stress, insulin resistance, and liver fat accumulation.     

Menhaden oil decreases high-fat diet-induced markers of hepatic damage, steatosis, inflammation, and fibrosis in obese Ldlr-/- mice

The frequency of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with obesity in the United States. NASH is progressive and characterized by hepatic damage, inflammation, fibrosis, and oxidative stress. Because C20-22 (n-3) PUFA are established regulators of lipid metabolism and inflammation, we tested the hypothesis that C20-22 (n-3) PUFA in menhaden oil (MO) prevent high-fat (HF) diet-induced fatty liver disease in mice. Wild-type (WT) and Ldlr(-/-) C57BL/6J mice were fed the following diets for 12 wk: nonpurified (NP), HF with lard (60% of energy from fat), HF-high-cholesterol with olive oil (HFHC-OO; 54.4% of energy from fat, 0.5% cholesterol), or HFHC-OO supplemented with MO (HFHC-MO). When compared with the NP diet, the HF and HFHC-OO diets induced hepatosteatosis and hepatic damage [elevated plasma alanine aminotransferase (ALT) and aspartate aminotransferases] and elevated hepatic expression of markers of inflammation (monocyte chemoattractant protein-1), fibrosis (procollagen 1α1), and oxidative stress (heme oxygenase-1) (P ≤ 0.05). Hepatic damage (i.e., ALT) correlated (r = 0.74, P < 0.05) with quantitatively higher (>140%, P < 0.05) hepatic cholesterol in Ldlr(-/-) mice fed the HFHC-OO diet than WT mice fed the HF or HFHC-OO diets. Plasma and hepatic markers of liver damage, steatosis, inflammation, and fibrosis, but not oxidative stress, were lower in WT and Ldlr(-/-) mice fed the HFHC-MO diet compared with the HFHC-OO diet (P < 0.05). In conclusion, MO [C20-22 (n-3) PUFA at 2% of energy] decreases many, but not all, HF diet-induced markers of fatty liver disease in mice.     

Vitamin D3 improves lipophagy-associated renal lipid metabolism and tissue damage in diabetic mice

Oxidative stress and abnormal lipid metabolism in diabetes can trigger renal lipotoxicity, extending to diabetic nephropathy. Vitamin D₃ has been known to be involved in lipid metabolism as well as insulin secretion or inflammation. Therefore, we hypothesized that vitamin D₃ supplementation attenuated hyperglycemia-induced renal damage in diabetic mice. Diabetes was induced by a 40% kJ high-fat diet with 30 mg/kg body weight of streptozotocin by intraperitoneal injection twice in male C57BL/6J mice. Among diabetic mice (fasting blood glucose > 140 mg/dL), mice were supplemented with 300 ng/kg body weight of vitamin D₃ dissolved in olive oil for 12 weeks. Normal control and diabetic control mice were orally administrated with olive oil as a vehicle. Normal control mice were fed with an AIN-93G diet during the experiment. Vitamin D₃ supplementation in diabetic mice improved glucose intolerance and kidney function, demonstrated by diminishing glomerular areas. Vitamin D₃ supplementation in diabetic mice significantly reduced triglycerides and low-density lipoprotein cholesterol in plasma as well as triglycerides and total cholesterol in the kidney. Furthermore, vitamin D₃ supplementation attenuated lipid synthesis, oxidative stress, and apoptosis, accompanied by activation of β-oxidation, antioxidant defense enzymes, and autophagy in diabetic mice. In conclusion, vitamin D₃ supplementation ameliorates hyperglycemia-induced renal damage through the regulation of lipid metabolisms, oxidative stress, apoptosis, and autophagy in diabetes. Vitamin D₃ could be a promising nutrient to weaken diabetic nephropathy.     

Chinese Tea Alleviates CCl4-Induced Liver Injury through the NF-κBorNrf2Signaling Pathway in C57BL-6J Mice

Liver injury is a life-threatening condition that is usually caused by excessive alcohol consumption, improperdiet, and stressful lifestyle and can even progress to liver cancer. Tea is a popular beverage with proven health benefits and is known to exert a protective effect on the liver, intestines, and stomach. In this study, we analyzed the therapeutic effects of six kinds of tea on carbon tetrachloride (CCl₄)-induced liver injury in a mouse model. The mice were injected with 10 mL/kg 5% CCl₄ to induce liver injury and then given oral gavage of green tea, yellow tea, oolong tea, white tea, black tea, and dark tea, respectively. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, and the expression levels of inflammation and oxidative stress-related proteins in the liver tissues were quantified. All six kinds of tea partly reduced the liver index, restored the size of the enlarged liver in the CCl₄ model, and decreased the serum levels of ALT and AST. Furthermore, the highly fermented dark tea significantly reduced the expression levels of NF-κB and the downstream inflammatory factors, whereas the unfermented green tea inhibited oxidative stress by activating the antioxidant Nrf2 pathway. Taken together, tea can protect against liver inflammation, and unfermented tea can improve antioxidant levels. Further studies are needed on the bioactive components of tea to develop drugs against liver injury.     

Linoleic acid-rich fats reduce atherosclerosis development beyond its oxidative and inflammatory stress-increasing effect in apolipoprotein E-deficient mice in comparison with saturated fatty acid-rich fats

The relative benefit of replacing saturated fatty acid with linoleic acids is still being debated because a linoleic acid-enriched diet increases oxidative and inflammatory stresses, although it is associated with a reduction in serum cholesterol levels. The present study was conducted to evaluate the effect of dietary supplementation of linoleic acid-rich (HL) fat, compared with a saturated fatty acid-rich (SF) fat on atherosclerotic lesion areas, serum and liver cholesterol levels, oxidative stress (urinary isoprostanes and serum malondialdehayde) and inflammatory stress (expression of aortic monocyte chemoattractant protein-1; MCP-1) in apo E-deficient mice. Male and female apo E-deficient mice (8 weeks old; seven to eight per group) were fed an AIN-76-based diet containing SF fat (50 g palm oil and 50 g lard/kg) or HL fat (100 g high-linoleic safflower-seed oil/kg) for 9 weeks. Compared with the SF diet, the HL diet lowered atherosclerosis (P<0.05). It reduced serum total cholesterol levels (P<0.05), increased HDL-cholesterol levels (P<0.05) and lowered liver esterified cholesterol levels (P<0.01). The HL diet-fed mice showed increased expression of MCP-1 mRNA (P<0.05), serum levels of malondialdehayde (P<0.05) and urinary excretion of 2,3-dinor-5,6-dihydro-8-iso-prostaglandin F2alpha; P<0.05). These results suggest that having biomarkers in vivo for oxidative stress and inflammatory status of endothelial cells does not necessarily indicate predisposition to an increased lesion area in the aortic root in apo E-deficient mice fed an HL or SF diet.     

High-Fat Diet Augments the Effect of Alcohol on Skeletal Muscle Mitochondrial Dysfunction in Mice

Previous studies have shown that chronic heavy alcohol consumption and consumption of a high-fat (HF) diet can independently contribute to skeletal muscle oxidative stress and mitochondrial dysfunction, yet the concurrent effect of these risk factors remains unclear. We aimed to assess the effect of alcohol and different dietary compositions on mitochondrial activity and oxidative stress markers. Male and female mice were randomized to an alcohol (EtOH)-free HF diet, a HF + EtOH diet, or a low-Fat (LF) + EtOH diet for 6 weeks. At the end of the study, electron transport chain complex activity and expression as well as antioxidant activity and expression, were measured in skeletal muscles. Complex I and III activity were diminished in muscles of mice fed a HF + EtOH diet relative to the EtOH-free HF diet. Lipid peroxidation was elevated, and antioxidant activity was diminished, in muscles of mice fed a HF + EtOH diet as well. Consumption of a HF diet may exacerbate the negative effects of alcohol on skeletal muscle mitochondrial health and oxidative stress.     

Supplementation with a Specific Combination of Metabolic Cofactors Ameliorates Non-Alcoholic Fatty Liver Disease,Hepatic Fibrosis,and Insulin Resistance in Mice

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD⁺) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1α1) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.     

Fatty liver in the intensive care unit

PURPOSE OF REVIEW: Non-alcoholic steatohepatitis is a liver disease characterized by steatosis and steatohepatitis in subjects whose alcohol consumption is negligible. The primary form is associated with insulin resistance whereas secondary non-alcoholic steatohepatitis occurs notably during total parenteral nutrition or in patients in the intensive care unit. This review is mainly focused on recent developments in the understanding of the pathogenesis of this disease. RECENT FINDING: Pathogenesis involves the direct role of fatty acids in liver injury, oxidative stress, cytokines, genetic susceptibility or mitochondrial dysfunction. An increased delivery of free fatty acids to the liver contributes to the first hit, originating liver steatosis. The process may undergo a second hit, characterized by inflammation and hepatocellular degeneration. Mitochondrial dysfunction plays a key role by leading to abnormal generation of reactive oxygen species, which cause lipid peroxidation. The peroxidation products and cytokines favor progression from steatohepatitis to fibrosis. Fatty liver disease may also be encountered in the intensive care unit in patients receiving parenteral nutrition. However, an adapted glucose-lipid ratio as source of non-protein calories prevents the development of fatty liver. Moreover, recent evidence suggests the importance of the type of lipid infused (structured lipid emulsion or fish oils). The acute phase response associated with severe disease can also lead to the development of fatty liver in spite of adequate nutritional support. SUMMARY: The pathogenesis of non-alcoholic steatohepatitis is multifactorial, but there is growing evidence that mitochondrial dysfunction always plays a key role. Adapted nutrition may prevent in part fatty liver in the intensive care unit.     

Standardized Bacopa monnieri extract ameliorates acute paraquat-induced oxidative stress,and neurotoxicity in prepubertal mice brain

Objectives: Bacopa monnieri (BM), an ayurvedic medicinal plant, has attracted considerable interest owing to its diverse neuropharmacological properties. Epidemiological studies have shown significant correlation between paraquat (PQ) exposure and increased risk for Parkinson's disease in humans. In this study, we examined the propensity of standardized extract of BM to attenuate acute PQ-induced oxidative stress, mitochondrial dysfunctions, and neurotoxicity in the different brain regions of prepubertal mice.

Methods: To test this hypothesis, prepubertal mice provided orally with standardized BM extract (200?mg/kg body weight/day for 4 weeks) were challenged with an acute dose (15?mg/kg body weight, intraperitoneally) of PQ after 3 hours of last dose of extract. Mice were sacrificed after 48 hours of PQ injection, and different brain regions were isolated and subjected to biochemical determinations/quantification of central monoamine (dopamine, DA) levels (by high-performance liquid chromatography).

Results: Oral supplementation of BM for 4 weeks resulted in significant reduction in the basal levels of oxidative markers such as reactive oxygen species (ROS), malondialdehyde (MDA), and hydroperoxides (HP) in various brain regions. PQ at the administered dose elicited marked oxidative stress within 48 hours in various brain regions of mice. However, BM prophylaxis significantly improved oxidative homeostasis by restoring PQ-induced ROS, MDA, and HP levels and also by attenuating mitochondrial dysfunction. Interestingly, BM supplementation restored the activities of cholinergic enzymes along with the restoration of striatal DA levels among the PQ-treated mice.

Discussion: Based on these findings, we infer that BM prophylaxis renders the brain resistant to PQ-mediated oxidative perturbations and thus may be better exploited as a preventive approach to protect against oxidative-mediated neuronal dysfunctions.