Effect of saffron supplementation on liver enzymes: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Possible protective effects of saffron (Crocus sativus L) have been reported in several randomized clinical trials (RCTs). Current systematic review was performed to summarize the efficacy of saffron intake on liver enzymes. METHODS: An electronic database search was conducted on PubMed/Medline, Scopus, Web of Science, and Cochrane for RCTs comparing effect of saffron and placebo on liver enzymes from inception to July 2021. There was no restriction in language of included studies and we calculated the standardized mean difference (SMD) and 95% Confidence Intervals (CI) for each variable. Random-effect model was used to calculate effect size. RESULTS: Eight studies (n = 463 participants) were included in the systematic review. The saffron intake was associated with a statistically significant decrease in aspartate aminotransferase (AST) (SMD: -0.18; 95% CI: -0.34, -0.02; I2 = 0%) in comparison to placebo intake. Our results also indicated that saffron consumption did not have a significant effect on alanine aminotransferase (ALT) (SMD: -0.14; 95% CI: -0.36, 0.09; I2 = 47.0%) and alkaline phosphatase (ALP) levels (SMD: 0.14; 95% CI: -0.18, 0.46; I2 = 42.9%) compared to placebo. CONCLUSIONS: Saffron intake showed beneficial impacts on circulating AST levels. However, larger well-designed RCTs are still needed to clarify the effect of saffron intake on these and other liver enzymes.

Pimpinella anisum Essential Oil Nanoemulsion Toxicity against Tribolium castaneum? Shedding Light on Its Interactions with Aspartate Aminotransferase and Alanine Aminotransferase by Molecular Docking.

The insecticidal activity is the result of a series of complex interactions between toxic substances as ligands and insect's enzymes as targets. Actually, synthetic insecticides used in pest control programs are harmful to the environment and may affect non-target organisms; thus, the use of natural products as pest control agents can be very attractive. In the present work, the toxic effect of aniseed (Pimpinella anisum L.) essential oil (EO) and its nanoemulsion (NE) against the red flour beetle Tribolium castaneum, has been evaluated. To assess the EO mode of action, the impact of sub-lethal concentrations of aniseed EO and NE was evaluated on enzymatic and macromolecular parameters of the beetles, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, total lipids and glucose. Finally, a molecular docking study was conducted to predict the mode of action of the major EO and NE components namely E-anethole, Limonene, alpha-himalachalene, trans-Verbenol and Linalool at binding site of the enzymes AST and ALT. Herein, the binding location of the main compounds in both proteins are discussed suggesting the possible interactions between the considered enzymes and ligands. The obtained results open new horizons to understand the evolution and response of insect-plant compounds interactions and their effect predicted at the molecular levels and side effects of both animal and human.

Characterizations and hepatoprotective effect of polysaccharides from Mesona blumes against tetrachloride-induced acute liver injury in mice.

Mesona blumes polysaccharide (MBP), a primary active component extracted from Mesona blumes, has a number of bioactivities. Nevertheless, hepatoprotective activity of MBP has been rarely reported. The purpose of this study is to investigate hepatoprotective effects of MBP on acute liver injury in mice. Results indicated that the MBP could remarkably decrease the increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum caused by tetrachloride (CCl4) treatment (P < 0.05). Medium and high dose of MBP treatment (200 mg/kg body weight, 300 mg/kg body weight) not only prominently enhanced the levels of antioxidant enzymes (superoxide dismutase, SOD) and non-enzyme antioxidants (glutathione, GSH) compared with CCl4-induced, but also dramatically decreased lipid peroxidation levels of liver tissues (P < 0.05). In addition, medium and high doses of MBP significantly enhanced the serum levels of IL-1ß and TNF-α (P < 0.05). This study showed that MBP had hepatoprotective activity against acute liver injury caused by CCl4.

The synergy of diammonium glycyrrhizinate remarkably reduces the toxicity of oxymatrine in ICR mice.

Most traditional Chinese medicine prescription dosages are imprecise. This study analyzes the toxicities and adverse effects of a combination the active ingredients of licorice and Kushen medicine: oxymatrine (OMT) and diammonium glycyrrhizinate (DG). The median lethal dose (LD50) and mortality were analyzed in single-dose OMT (or DG) intraperitoneally injected mice with or without combination DG (or OMT). Body weight changes as well as levels of serum sodium and potassium, alanine transaminase (ALT), aspartate transaminase (AST), creatinine, and urea were measured in mice treated with a daily dose of OMT and/or DG for 14days. This study showed that the LD50 of OMT for males and females were 347.44 and 429.15mg/kg, respectively. The LD50 of DG were 525.10 and 997.26mg/kg for males and females, respectively. DG significantly decreased the mice LD50-induced mortality of the OMT, however OMT did not succeed in reducing the LD50-induced mortality rate of DG. The combination of OMT and DG obviously attenuated the changes of the body weight, serum sodium, and potassium induced by DG or OMT alone. These results suggested that toxicity and adverse effects of the OMT was significantly attenuated by DG. The OMT neutralized the adverse effects of the DG, but not the toxicity.

Inhibition study of alanine aminotransferase enzyme using sequential online capillary electrophoresis analysis.

We report the study of several inhibitors on alanine aminotransferase (ALT) enzyme using sequential online capillary electrophoresis (CE) assay. Using metal ions (Na(+) and Mg(2+)) as example inhibitors, we show that evolution of the ALT inhibition reaction can be achieved by automatically and simultaneously monitoring the substrate consumption and product formation as a function of reaction time. The inhibition mechanism and kinetic constants of ALT inhibition with succinic acid and two traditional Chinese medicines were derived from the sequential online CE assay. Our study could provide valuable information about the inhibition reactions of ALT enzyme.

Effects of dietary supplementation with vitamin C and vitamin E and their combination on growth performance, some biochemical parameters, and oxidative stress induced by copper toxicity in broilers.

This study investigated effects of dietary supplementation with vitamin C, vitamin E on performance, biochemical parameters, and oxidative stress induced by copper toxicity in broilers. A total of 240, 1-day-old, broilers were assigned to eight groups with three replicates of 10 chicks each. The groups were fed on the following diets: control (basal diet), vitamin C (250 mg/kg diet), vitamin E (250 mg/kg diet), vitamin C + vitamin E (250 mg/kg + 250 mg/kg diet), and copper (300 mg/kg diet) alone or in combination with the corresponding vitamins. At the 6th week, the body weights of broilers were decreased in copper, copper + vitamin E, and copper + vitamin C + vitamin E groups compared to control. The feed conversion ratio was poor in copper group. Plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase activities, iron, copper concentrations, and erythrocyte malondialdehyde were increased; plasma vitamin A and C concentrations and erythrocyte superoxide dismutase were decreased in copper group compared to control. Glutathione peroxidase, vitamin C, and iron levels were increased; aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and copper levels were decreased in copper + vitamin C group, while superoxide dismutase, glutathione peroxidase, and vitamin E concentrations were increased; aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were decreased in copper with vitamin E group compared to copper group. The vitamin C concentrations were increased; copper, uric acid, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and malondialdehyde were decreased in copper + vitamin C + vitamin E group compared to copper group. To conclude, copper caused oxidative stress in broilers. The combination of vitamin C and vitamin E addition might alleviate the harmful effects of copper as demonstrated by decreased lipid peroxidation and hepatic enzymes.

Protective role of Aralia elata polysaccharide on mercury(II)-induced cardiovascular oxidative injury in rats.

Mercury(II) is a highly toxic environmental pollutant leading to oxidative stress in animals and human beings. In this study we aimed to investigate the possible protective effect of a water-soluble polysaccharide (AEP-w1) from the root bark of Aralia elata against experimental mercury(II)-induced cardiovascular oxidative injury in rat model. The results showed that delayed AEP-w1 supplement to HgCl2-treated mice not only decreased serum lactate dehydrogenase (LDH) and tumor necrosis factor-α (TNF-α) levels, but also increased serum nitric oxide (NO) metabolite levels and antioxidant capacity. Moreover, AEP-w1 administration to HgCl2-treated mice significantly decreased malondialdehyde (MDA) level and myeloperoxidase (MPO) activity and increased superoxide dismutase (SOD) and catalase (CAT) activities, along with glutathione (GSH) level in rat cardiac tissue. In addition, elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine (Cr) levels in the saline-treated Hg group were also reversed by AEP-w1 treatment. Therefore, the present study demonstrates that alleviation of HgCl2-induced oxidative injury in rat by AEP-w1 contributes to better understanding of its beneficial effect against cardiovascular diseases.

Rutin and quercetin, bioactive compounds from tartary buckwheat, prevent liver inflammatory injury.

Tartary buckwheat (Fagopyrum tataricum) is a healthy and nutritionally important food item. In this study, we investigated the hepatoprotective effects of 75% ethanol extracts from tartary buckwheat (EEB) against ethanol- and carbon tetrachloride (CCl(4))-induced liver damage. EEB were administered to C57BL/6 mice (ethanol induction) and Sprague-Dawley (SD) rats (CCl(4) induction) for 4 and 8 consecutive weeks, respectively. The major active compounds, rutin and quercetin, were also administered to ethanol- and CCl(4)-induced animals. EEB inhibited increase in serum aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) levels in the ethanol- and CCl(4)-induced animals; similar effects were found after rutin and quercetin administration. Moreover, EEB elevated the antioxidant enzyme activities, including those of catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and superoxide dismutase (SOD), and inhibited the levels of hepatic inflammation in the ethanol- and CCl(4)-treated animals. This study suggests that EEB exerts hepatoprotection via promoting anti-oxidative and anti-inflammatory properties against oxidative liver damage.

Effects of alanine aminotransferase inhibition on the intermediary metabolism in Sparus aurata through dietary amino-oxyacetate supplementation.

In liver, through the reaction catalysed by alanine aminotransferase (ALT), alanine becomes an effective precursor for gluconeogenesis. In the present study amino-oxyacetate (AOA) was used to evaluate its effect on liver ALT activity of the carnivorous fish Sparus aurata. Moreover, the derived metabolic effects on metabolites and other key enzymes of glycolysis, gluconeogenesis and the pentose phosphate pathway were also studied. A dose-effect-dependent inhibition of AOA on hepatic cytosolic and mitochondrial ALT activity was observed in vitro. In vivo, AOA behaved as an inhibitor of hepatic cytosolic ALT activity. A long-term exposure to AOA increased pyruvate kinase activity in the liver irrespective of the composition of the diet supplied to fish. 1H NMR studies showed that inclusion of AOA to the diet decreased the hepatic levels of alanine, glutamate and glycogen. Moreover, 2H NMR analysis indicated a higher renewal rate for alanine in the liver of fish fed with a high-carbohydrate/low-protein diet, while AOA decreased alanine 2H-enrichment irrespective of the diet. The present study indicates that AOA-dependent inhibition of the cytosolic ALT activity could help to increase the use of dietary carbohydrate nutrients.

Protective effect of Acanthopanax gracilistylus-extracted Acankoreanogenin A on mice with fulminant hepatitis.

The release of pro-inflammatory cytokines in both acute (IL-1ß and TNF-α) and chronic [high mobility group box 1 protein (HMGB1)] phases, is thought to play important roles in the development of fulminant hepatitis (FH). Triterpenoid Acankoreanogenin A (AA) which is extracted from the leaves of the Acanthopanax gracilistylus W.W. Smith (AGS) has shown its inhibiting effect on TNF-α, IL-1ß and HMGB1 release in vitro in our preliminary experiments. In present study, we investigated the effect of AA on mice with fulminant hepatitis in vivo. Fulminant hepatitis mice model was established by intraperitoneally injecting galactosamine (GalN) and lipopolysaccharide (LPS). The levels of serum of TNF-α, IL-1ß, ALT, AST and HMGB1 from AA-treated mice were measured at different time points. Our results demonstrated that pre-treatment of mice with AA markedly reduced the serum levels of TNF-α, IL-1ß, HMGB1, ALT and AST with the improvement in histological features. And the survival rate from AA-treated fulminant hepatitis mice was increased. Furthermore, delayed administration of AA after peak occurrence of the early pro-inflammatory cytokines still endowed significant protection against GalN/LPS-induced lethality. The post-treatment of AA could significantly attenuate the release of HMGB1, but not the TNF-α and IL-1ß. These results indicate that AA inhibits the systemic release of pro-inflammatory cytokine HMGB1, and dose-dependently rescue the mice from lethal GalN/LPS-induced fulminant hepatitis, which suggests this component as a candidate therapy for fulminant hepatitis.

Curcumin limits the fibrogenic evolution of experimental steatohepatitis.

Nonalcoholic steatohepatitis is characterized by the association of steatosis with hepatic cell injury, lobular inflammation and fibrosis. Curcumin is known for its antioxidant, anti-inflammatory and antifibrotic properties. The aim of this study was to test whether the administration of curcumin limits fibrogenic evolution in a murine model of nonalcoholic steatohepatitis. Male C57BL/6 mice were divided into four groups and fed a diet deficient in methionine and choline (MCD) or the same diet supplemented with methionine and choline for as long as 10 weeks. Curcumin (25 microg per mouse) or its vehicle (DMSO) was administered intraperitoneally every other day. Fibrosis was assessed by Sirius red staining and histomorphometry. Intrahepatic gene expression was measured by quantitative PCR. Hepatic oxidative stress was evaluated by staining for 8-OH deoxyguanosine. Myofibroblastic hepatic stellate cells (HSCs) were isolated from normal human liver tissue. The increase in serum ALT caused by the MCD diet was significantly reduced by curcumin after 4 weeks. Administration of the MCD diet was associated with histological steatosis and necro-inflammation, and this latter was significantly reduced in mice receiving curcumin. Curcumin also inhibited the generation of hepatic oxidative stress. Fibrosis was evident after 8 or 10 weeks of MCD diet and was also significantly reduced by curcumin. Curcumin decreased the intrahepatic gene expression of monocyte chemoattractant protein-1, CD11b, procollagen type I and tissue inhibitor of metalloprotease (TIMP)-1, together with protein levels of alpha-smooth muscle-actin, a marker of fibrogenic cells. In addition, curcumin reduced the generation of reactive oxygen species in cultured HSCs and inhibited the secretion of TIMP-1 both in basal conditions and after the induction of oxidative stress. In conclusion, curcumin administration effectively limits the development and progression of fibrosis in mice with experimental steatohepatitis, and reduces TIMP-1 secretion and oxidative stress in cultured stellate cells.

Green tea modulates reserpine toxicity in animal models.

Reserpine, a natural product extracted from Rauwolfia serpintina or Rauwolfia vomitoria, is a known dopamine depleter that inhibits several neurotransmitters. Reserpine has been used clinically to control hypertension, schizophrenia, insomnia and insanity. The use of this drug, however, has been limited because of its side effects which include oxidative damage to organs, including the liver. Green tea catechins are potent antioxidants that have the potential to counteract reserpine induced oxidative stress. This study investigated the merits of administering green tea concurrently with reserpine to prevent oxidative hepatic damage in Sprague-Dawely (SD) rats. Reserpine was found to cause hepatic damage, with elevated levels of oxidative stress markers, such as Thiobarbituric Acid Reactive Substances (TBARS), transaminases and cholesterol. Reserpine also induced hepatic ultra-structural damage in the cytoplasmic membrane, nuclear envelope, endoplasmic reticulum (rER), ribosomal stripping and mitochondria. Electron microscopy examination showed revival of liver cells as a result of green tea extract administration to experimental rats.

Curcumin attenuates diet-induced hypercholesterolemia in rats.

BACKGROUND: Curcumin (a component of turmeric) has long been used as a spice and food-coloring agent. In experimental animals, curcumin has shown anti-diabetic, anti-inflammatory, cytotoxic and anti-oxidant properties. MATERIAL/METHODS: The possible hypolipidemic effect of curcumin was investigated in rats fed a high-cholesterol diet (HCD). The lipid profile and activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were assessed in serum, as well as anti-oxidant parameters in liver tissues. RESULTS: Feeding the animals a high cholesterol diet (HCD) for 7 consecutive days (1 ml 100 g(-1)) resulted in marked hypercholesterolemia, increased serum level of low-density lipoprotein cholesterol (LDL-C), but a decreased serum high-density lipoprotein cholesterol (HDL-C). Curcumin admixed with the diet (0.5% w/w) decreased serum total cholesterol (TC) by about 21% and LDL-C by 42.5%, but it increased serum HDL by 50%. The atherogenic indices (LDL-C/HDL-C and TC/HDL-C) were reduced by 52% and 35%, respectively. Curcumin also decreased the enzyme activities of serum AST and ALT, which were increased in HCD animals. CONCLUSIONS: Curcumin showed an obvious hypocholesterolemic effect that could be due to an effect on cholesterol absorption, degradation or elimination, but not due to an anti-oxidant mechanism. This could be supported by the finding in our study that neither HCD nor curcumin-admixed HCD had any effects on the liver content of glutathione (GSH) or superoxide dismutase (SOD) activity. Thus one could argue that ingestion of curcumin-containing spices in the diet, especially one rich in fats, could have a lipid-lowering effect.

Oleanolic acid nanosuspensions: preparation, in-vitro characterization and enhanced hepatoprotective effect.

Oleanolic acid is a naturally derived triterpene used clinically in the treatment of hepatitis in China, but its poor solubility often leads to poor bioavailability. In the present study, oleanolic acid nanosuspensions were prepared by the nanoprecipitation method and then systematically characterized. The average particle size of the obtained nanosuspensions was 284.9 nm, with a polydispersity index of 0.216. Transmission electron microscopy and atomic force microscopy showed that the drug existed as spherical or near-spherical nanoparticles in the nanosuspensions. Differential scanning calorimetry and X-ray diffraction studies indicated that oleanolic acid was present in an amorphous state in the lyophilized nanosuspensions. At 25 degrees C, the saturation solubility of oleanolic acid was increased by about 6 times after nanoation (25.72 microg mL(-1) vs 4.37 microg mL(-1)). In the in-vitro drug release experiments, the lyophilized nanosuspensions showed a faster drug dissolution rate than that of the coarse drug powder (approx. 90% vs 15% during the first 20 min), and nearly 95% of the oleanolic acid was released by 120 min. As evidenced by the lower serum alanine aminotransferase activity and liver malondialdehyde content, pre-treatment with oleanolic acid nanosuspensions significantly enhanced the hepatoprotective effect of oleanolic acid against carbon tetrachloride-induced liver injury.

Hepatoprotective effect of Himoliv, a polyherbal formulation in rats.

The effect of Himoliv (HV) was evaluated in carbon tetrachloride or paracetamol induced hepatotoxicity in rats. Liver necrosis was produced by administering single dose of either carbon tetrachloride (CCl4, 1 ml/kg, 50% v/v with olive oil, s.c.) or paracetamol (PC, 1 g/kg, p.o.). The liver damage was evidenced by elevated levels of serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) and serum alkaline phosphatase (ALP) and hepatic thiobarbituric acid reacting substances (TBARS) and superoxide dismutase (SOD). HV pretreatment (0.5 and 1.0 ml/kg, p.o.) significantly (P < 0.001) reduced CCl4 or PC-induced elevations of the levels of SGOT, SGPT, ALP and TBARS, while the reduced concentration of SOD due to CCl4 or PC was reversed. Silymarin (25 mg/ kg, p.o.), a known hepatoprotective drug showed similar results.

Enzyme inactivation by metal-catalyzed oxidation of coenzyme Q1.

Ubiquinol-1 in aerated aqueous solution inactivates several enzymes--alanine aminotransferase, alkaline phosphatase, Na+/K(+)-ATPase, creatine kinase and glutamine synthetase--but not isocitrate dehydrogenase and malate dehydrogenase. Ubiquinone-1 and/or H2O2 do not affect the activity of alkaline phosphatase and glutamine synthetase chosen as model enzymes. Dioxygen and transition metal ions, even if in trace amounts, are essential for the enzyme inactivation, which indeed does not occur under argon atmosphere or in the presence of metal chelators. Supplementation with redox-active metal ions (Fe3+ or Cu2+), moreover, potentiates alkaline phosphatase inactivation. Since catalase and peroxidase protect while superoxide dismutase does not, hydrogen peroxide rather than superoxide anion seems to be involved in the inactivation mechanism through which oxygen active species (hydroxyl radical or any other equivalent species) are produced via a modified Haber-Weiss cycle, triggered by metal-catalyzed oxidation of ubiquinol-1. The lack of efficiency of radical scavengers and the almost complete protection afforded by enzyme substrates and metal cofactors indicate a 'site-specific' radical attack as responsible for the oxidative damage.

Effect of tannin-rich leaves of oak (Quercus incana) on various microbial enzyme activities of the bovine rumen.

1. The objective of the present experiment was to study the effects of oak (Quercus incana) leaves rich in tannins on various enzyme activities of the bovine rumen. 2. The procedure employed was incubation of tannin-rich, very-low-tannin or virtually tannin-free leaves in nylon-gauze bags in the rumen, and determination of enzyme activities in microbes tightly bound to the solid matrix and in microbes loosely plus tightly attached to the solid matrix. 3. The activities of urease (EC 3.5.1.5), carboxymethylcellulose, glutamate dehydrogenase (EC 1.4.1.2) and alanine aminotransferase (glutamic-pyruvic transaminase) (EC 2.6.1.2) were significantly lower in the tannin-rich group, whereas the activities of glutamate ammonia ligase (glutamine synthetase) (EC 6.3.1.2; both gamma-glutamyltransferase (EC 2.3.2.2) and the forward reaction) were higher in the tannin-rich group. These changes were more marked in micro-organisms tightly bound to the solid matrix than in the more complex microbial compartment. 4. The protein, DNA and RNA contents, and protein: RNA ratio, were significantly lower in the tannin-rich group, whereas no difference was observed for protein: DNA between the groups. 5. Effects of tannin-containing extracts of oak leaves on various rumen enzymes in vitro showed a trend similar to that observed in nylon-gauze bags, suggesting that the changes observed in various compartments were due to the tannins of oak leaves.

Antihepatotoxic actions of tannins.

The antihepatotoxic effects of tannin analogues were examined utilizing carbon tetrachloride- and galactosamine-induced cytotoxicity in primary cultured rat hepatocytes. Most tannins showed significant antihepatotoxic effects in these two assay systems. Hydrolyzable tannins generally exhibited an intense enzyme inhibitory action on glutamic-pyruvic transaminase while condensed tannins exerted a much less inhibitory action, although variations were observed depending on structure. Structure-activity relationships are discussed.