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The Synergistic Hepatoprotective Effect of Curcumin and Ginger Against Carbon Tetrachloride Induced- Liver Fibrosis in Rats
Abstract
The present study aimed to assess the hepatocellular protective activity of the coadministration of curcumin fortified by ginger against carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Five groups were included: control, CCl4, CCl4 treated with curcumin, CCl4 treated with ginger and CCl4 treated with curcumin and ginger. Liver fibrosis was evidenced by significant increase in liver hydroxyproline, the inflammatory cytokine tumor necrosis factor-α (TNF-α) and lipid peroxidation, increased activities of serum aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). Liver enzymes, oxidative status and histological examinations revealed that co-administration of curcumin and ginger significantly arrested progression of hepatic fibrosis induced by CCl4. Elevated activities of serum (AST), (ALT) and (ALP) by CCl4 intoxication were synergistically reduced, while the levels of total protein and albumin were normalized. In addition, the altered levels of malondialdhyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and hydroxyproline in liver tissues of CCl4 hepatotoxied rats were normalized by the oral co-administration of curcumin and ginger. Also, tumor necrosis factor-α (TNF-α) level and catalase (CAT) activity elevated by CCl4 intoxication, were significantly reduced (p<0.05) in liver tissues mainly in the combined treated group. Histological examinations showed that the combined administration of curcumin and ginger returned collagen fiber distribution to almost normal pattern. In conclusion, combined oral administration of both curcumin and ginger are potentially effective in the protection of hepatic fibrosis on the experimental level.
... Curcumin could exert antioxidative effects either directly as a chemical antioxidant due to its ability to scavenge reactive oxygen and nitrogen free radicals or by modulating cellular defenses which themselves exert antioxidant effects [25,26]. Previous studies mentioned that curcumin is a natural antioxidant hepatoprotective agent against hepatotoxicity induced by paracetamol, diethyl nitrosamine, CCl4 models, gentamicin [4,[27][28][29]. Curcumin administration has been reported to prevent hepatic lesions in streptotocin diabetic rats and to protect against oxidative stress in hepatic cell lines [30,31]. ...
... Also, Kadasa et al., [29] found that Curcuma longa significantly lowered the serum levels of ALT, and AST activities in rats treated with diethyl nitrosamine. In addition, Ezz et al., [28] found that curcumin treatment to rats intoxicated with CCl 4 caused significantly reduced serum levels of ALT, AST and ALP activities, and significant elevations in serum total protein and albumin concentrations compared to CCl 4 intoxicated group. Treatment of curcumin reverted the serum protein and albumin levels back to normal in CCl 4 - intoxicated rats, which reflects the well functioning of hepatocytes in protein synthesis [28]. ...
... In addition, Ezz et al., [28] found that curcumin treatment to rats intoxicated with CCl 4 caused significantly reduced serum levels of ALT, AST and ALP activities, and significant elevations in serum total protein and albumin concentrations compared to CCl 4 intoxicated group. Treatment of curcumin reverted the serum protein and albumin levels back to normal in CCl 4 - intoxicated rats, which reflects the well functioning of hepatocytes in protein synthesis [28]. ...
The liver is a vital organ in the body. It plays a major role in metabolism, including ridding the body of substances that would otherwise be injurious if allowed to accumulate, and excretion of xenobiotics from the body. The endogenous antioxidants defenses from reactive oxygen species are strengthened by natural antioxidants and restore the optimal balance by neutralizing reactive species. The present study aims to highlight on hepatotoxic agents, and prevention of hepatic disorders using Curcuma longa, Trigonella foenumgraecum, Allium sativum, Coffea arabica, Petroselinum crispum, Olea europaea leaves, and Mentha piperita. Curcuma longa showed that hepatoprotective effect against hepatotoxicity induced by paracetamol, diethyl nitrosamine, CCl4, and gentamicin. Also, the hepatoprotective effect of Trigonella foenumgraecum seeds has been elucidated against hepatic disorders induced by γ-radiation, monosodium glutamate, ethanol, CCl4, AlCl3, and diabetes. Allium sativum has been used in the treatment of hepatic disorders. The hepatoprotective effect of Allium sativum has been confirmed against oxidative damage and hepatic toxicity of D-galactosamine, lipopolysaccharide, ethanol, and CCl4, which may be due to the presence of organosulfur compounds. Coffea arabica intake has been inversely related to the incidence of liver diseases. Petroselinum crispum showed a hepatoprotective effect against hepatic disorders induced by CCl4 and diabetes, which may be due to their high content of antioxidants. The leaves of Mentha piperita showed a good hepatoprotection against hepatopathy induced arsenic, anti-tuberculosis drugs, and CCl4 which may be due to their high content of phenolics and flavonoids. Olea europaea leaves extract significantly ameliorated pathophysiological changes induced in the liver by diazinon, carbendazim, and γ-irradiation in rats. It can be concluded that administration of Curcuma longa, Trigonella foenumgraecum, Allium sativum, Coffea arabica, Petroselinum crispum, Olea europaea leaves, and Mentha piperita showed a remarkable hepatic protection against hepatotoxic agents, which may be due to its antioxidant properties of these medicinal plants and herbs. So, Human expose to hepatotoxic agents and the patients with hepatic disorders should be advised to take these medicinal plants and herbs.
... Today, medicinal plants play an important role in pharmacology and medicine, it is estimated that about 80% of the world population relies on botanical preparations as medicine to meet their health needs because of their properties and lesser side effects (Ogbera et al., 2010;Shirin and Prakash, 2010;Ezz et al., 2011;Sakr et al., 2011). Herbs and spices are generally considered safe and proved to be effective against various human ailments (Uz et al., 2009). ...
... The ginger extract increased body weight when treated along with dimethylhidrazine (Dias et al., 2006). Moreover, Ezz et al. (2011) found that the coadministration of ginger to rat against carbon tetrachloride (CCl4)-induced liver fibrosis increased in total body weight by 1.0-fold compared to CCl4 group. Ginger powder that added to standard diet at 5% as constituents of fiber after administration of gentamicin (100 mg/kg/day) to rats increased total body weight by 1.2-fold as compared to gentamicin group (Abd El-Ghany et al., 2012). ...
... The co-administration of GAE with KBrO 3 increased the level of total proteins and the same effect of ginger on protein content had been reported for other xenobiotics (Atta et al., 2010;Ezz et al., 2011;EL-Shenawy et al., 2011;Hamed et al., 2012;Abd El-Ghany et al., 2012). Treatment the mice with ginger reverted the serum protein levels back to normal, which reflects the well functioning of hepatocytes in protein synthesis (Ezz et al., 2011). ...
Toxicological studies have shown that KBrO3 affects the nutritional quality of bread and can be generated free oxygen radicals which cause oxidative stress. The present study aimed to clarify the possible role played by the ginger aqueous extract (GAE) in decreasing the negative effects of KBrO3 in the male mice. Forty albino mice were divided into; group I was normal control, group II was treated with GAE, group III was injected i.p. with of KBrO3 and group IV was treated with GAE followed by KBrO3 for 30 days. KBrO3 was found to significant increased the serum activities of ALP and LDH, serum uric acid and creatinine levels as well as arginase activity. Results showed an elevation of NO and LPO levels for liver and kidney tissue of KBrO3-treated mice. Elicit a significant decrease in the activities of liver SOD, CAT and GPx as well as the liver GSH level by KBrO3 treatment. Pre-treatment the mice with GAE prior to KBrO3-treatment significantly decreased the adverse harmful effects of KBrO3 exposure on the liver and kidney tissues and improved the antioxidant parameters. Ginger with antioxidant abilities lower incidence of various human morbidities. Current research reveals the different potential applications of natural antioxidant in prevention or control of disease.
... The present study shows that co-administration of gentamicin and curcumin significantly decreased the elevations in the serum ALT, AST, ALP, and Ɣ-GT activities and increased the levels of serum total proteins and albumin a compared with gentamicin treated group. Curcumin is a natural antioxidant hepatoprotective agent against hepatotoxicity induced by paracetamol, diethyl nitrosamine, CCl 4 models [37,41,51]. This results are run in parallel with the results of Kadasa et al., [41] who reported that curcumin significantly lowered the serum levels of ALT, and ALT activities in rats treated with diethyl nitrosamine. ...
... i/p) once daily for seven days produced significant elevation of serum ALT with significant hypoprotienemia and hypoalbumenemia due to damaging of the hepatic cells. Also, Ezz et al., [37] found that curcumin treatment to rats intoxicated with CCl 4 caused significantly reduced serum levels of ALT, AST and ALP activities, and significant elevations in serum total protein and albumin concentrations compared to CCl4 intoxicated grouop. Treatment of curcumin reverted the serum protein and albumin levels back to normal in CCl 4 -intoxicated rats , which reflects the well functioning of hepatocytes in protein synthesis [37]. ...
... Also, Ezz et al., [37] found that curcumin treatment to rats intoxicated with CCl 4 caused significantly reduced serum levels of ALT, AST and ALP activities, and significant elevations in serum total protein and albumin concentrations compared to CCl4 intoxicated grouop. Treatment of curcumin reverted the serum protein and albumin levels back to normal in CCl 4 -intoxicated rats , which reflects the well functioning of hepatocytes in protein synthesis [37]. ...
Gentamicin induced hepatotoxicity in experimental animals were reported by many investigators. Natural antioxidants strengthen the endogenous antioxidants defenses from reactive oxygen species and restore the optimal balance by neutralizing the reactive species. The present work aimed to evaluate the effectiveness of Curcuma longa (Cur), and Rosmarinus officinalis (Ros) as a natural source of antioxidants to minimize the harmful effects of gentamicin (GM) induced hepatotoxicity in Guinea pigs. Guinea pigs were divided into five groups. The first group (control) was injected intraperitoneal with saline. The 2nd group was injected intraperitoneal with gentamicin at a dose of 100 mg/kg body weight /day. The 3th , 4th , and 5th groups were injected intraperitoneal with gentamicin (100 mg/kg b. wt /day) concurrently with curcumin, rosemary, and curcumin with rosemary at the doses of 200 mg, 220 mg, and 200 mg with 220 mg /kg body weight /day respectively orally by gavage for 10 days. Liver function was assessed by measuring serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ- glutamyltransferase activities (γ-GT), total proteins, albumin, and globulin concentrations, A/G ratio, and histopathological changes of liver were examined. GM -induced hepatotoxicity was evidenced by increase in serum levels of AST, ALT, ALP and γGT; a decrease in serum total proteins, albumin, and globulin concentrations; and a significant alteration in hepatic architecture. Co-administration of Cur and/or Ros with GM prevented severe alterations of biochemical parameters and disruptions of liver structure, which may be due to its antioxidant property. it can be concluded that, gentamicin had adverse effects on the liver. Curcumin and rosemary administration showed a remarkable amelioration of these abnormalities in gentamicin treated male Guinea pigs, which may be due to its antioxidant property. So, the patients should be advised to take curcumin and rosemary in combination while they are treated by gentamicin. Further studies are necessary to elucidate exact mechanism of hepato-protection and potential usefulness of curcumin and rosemary as a protective agent against gentamicin induced hepatotoxicity in clinical trials.
... [3] Considering hazards of treatment failure, drug resistance and high costs associated with current hepatic and renal therapy, there is an interest in study of natural compounds with free radicals scavenging capacity. [4] Hepatotoxicity Implies chemical-driven liver damage induced by certain medicinal agents and other chemical agents. [5] Drug-induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failure. ...
... About 0.5 gm of each liver was homogenized by ultrasonic homogenizer in 5 ml ice-cold phosphate buffered saline (PBS) to obtain ultimately10% (w/v) whole liver homogenate. [4] The homogenate was centrifuged at 3000 rpm for 15 min and the resultant supernatant was stored at (-20°C) until used for determination of reduced Glutathione (GSH), Malondialdehyde (MDA), Superoxide dismutase (SOD) and Hydroxyproline concentration. ...
An experimental study was conducted to evaluate the protective effects of an antioxidant (Hesperidin) on carbon tetrachloride-induced hepatic toxicity. This effect was evaluated through assessment of liver functions as well as histopathological changes in livers of rats exposed to Hesperidin prior to carbon tetrachloride. Thirty two male albino rats were distributed to four equal groups each of 8 rats. Group I (Negative control). Group II (Positive control group: received vehicle (Carboxymethyl Cellulose) for 10 days and were challenged with CCl4 2 ml/kg/SC (40% v/v in olive oil) on 8 th day. Group III (HDN: 100 mg/kg): rats received HDN continuously for 8 days. On 8 th day, they received CCl4 2ml/kg/SC in olive oil. HDN was further continued for 2 more days. Group IV (HDN: 200 mg/kg): rats received HDN continuously for 8 days. On 8 th day, they received CCl4 2ml/kg/SC in olive oil. HDN was further continued for 2 more days. After ten days of treatment, liver enzymes, oxidant parameters as malondialdehyde and antioxidant parameters as glutathione and superoxide dismutase were assessed. Histopathological examination of the liver tissues was conducted. Hesperidin in the dose of 100 and 200 mg/kg produced a significant decrease in the levels of liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and oxidant parameters as malondialdehyde. Antioxidant parameters as glutathione and superoxide dismutase also have shown significant increase. These findings were confirmed by histopathology. Hesperidin in a dose of 100 and 200 mg/kg offers dose-dependent significant protection against hepatotoxicity produced by CCl4 in albino rats.
... [3] Considering hazards of treatment failure, drug resistance and high costs associated with current hepatic and renal therapy, there is an interest in study of natural compounds with free radicals scavenging capacity. [4] Hepatotoxicity Implies chemical-driven liver damage induced by certain medicinal agents and other chemical agents. [5] Drug-induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failure. ...
... About 0.5 gm of each liver was homogenized by ultrasonic homogenizer in 5 ml ice-cold phosphate buffered saline (PBS) to obtain ultimately10% (w/v) whole liver homogenate. [4] The homogenate was centrifuged at 3000 rpm for 15 min and the resultant supernatant was stored at (-20°C) until used for determination of reduced Glutathione (GSH), Malondialdehyde (MDA), Superoxide dismutase (SOD) and Hydroxyproline concentration. Determination of liver function: Commercial kit Purchased from ...
Abstract:
An experimental study was conducted to evaluate the protective effects of an antioxidant (Hesperidin) on carbon tetrachloride-induced hepatic toxicity. This effect was evaluated through assessment of liver functions as well as histopathological changes in livers of rats exposed to Hesperidin prior to carbon tetrachloride. Thirty two male albino rats were distributed to four equal groups each of 8 rats. Group I(Negative control). Group II (Positive control group: received vehicle (Carboxymethyl Cellulose) for 10 days and were challenged with CCl4 2 ml/kg/SC (40% v/v in olive oil) on 8th day. Group III (HDN: 100
mg/kg): rats received HDN continuously for 8 days. On 8th day, they received CCl4 2ml/kg/SC in olive oil.
HDN was further continued for 2 more days. Group IV (HDN: 200 mg/kg): rats received HDN continuously for 8 days. On 8th day, they received CCl4 2ml/kg/SC in olive oil. HDN was further continued for 2 more days. After ten days of treatment, liver enzymes, oxidant parameters as malondialdehyde and antioxidant parameters as glutathione and superoxide dismutase were assessed. Histopathological examination of the liver tissues was conducted.
Hesperidin in the dose of 100 and 200 mg/kg produced a significant decrease in the levels of liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and oxidant parameters as malondialdehyde. Antioxidant parameters as glutathione and superoxide dismutase also have shown significant increase. These findings were confirmed by histopathology. Hesperidin in a dose of 100 and 200 mg/kg offers dose-dependent significant protection against hepatotoxicity produced by CCl4 in albino rats.Abstract:
An experimental study was conducted to evaluate the protective effects of an antioxidant (Hesperidin) on carbon tetrachloride-induced hepatic toxicity. This effect was evaluated through assessment of liver
functions as well as histopathological changes in livers of rats exposed to Hesperidin prior to carbon tetrachloride. Thirty two male albino rats were distributed to four equal groups each of 8 rats. Group I (Negative control). Group II (Positive control group: received vehicle (Carboxymethyl Cellulose) for 10 days and were challenged with CCl4 2 ml/kg/SC (40% v/v in olive oil) on 8th day. Group III (HDN: 100
mg/kg): rats received HDN continuously for 8 days. On 8th day, they received CCl4 2ml/kg/SC in olive oil.
HDN was further continued for 2 more days. Group IV (HDN: 200 mg/kg): rats received HDN continuously for 8 days. On 8th day, they received CCl4 2ml/kg/SC in olive oil. HDN was further continued for 2 more days. After ten days of treatment, liver enzymes, oxidant parameters as malondialdehyde and antioxidant parameters as glutathione and superoxide dismutase were assessed. Histopathological examination of the liver tissues was conducted.
Hesperidin in the dose of 100 and 200 mg/kg produced a significant decrease in the levels of liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and oxidant parameters as malondialdehyde. Antioxidant parameters as glutathione and superoxide dismutase also have shown significant increase. These findings were confirmed by histopathology. Hesperidin in a dose of 100 and 200 mg/kg offers dose-dependent significant protection against hepatotoxicity produced by CCl4 in albino rats.Abstract:
An experimental study was conducted to evaluate the protective effects of an antioxidant (Hesperidin) on carbon tetrachloride-induced hepatic toxicity. This effect was evaluated through assessment of liver
functions as well as histopathological changes in livers of rats exposed to Hesperidin prior to carbon tetrachloride. Thirty two male albino rats were distributed to four equal groups each of 8 rats. Group I (Negative control). Group II (Positive control group: received vehicle (Carboxymethyl Cellulose) for 10 days and were challenged with CCl4 2 ml/kg/SC (40% v/v in olive oil) on 8th day. Group III (HDN: 100
mg/kg): rats received HDN continuously for 8 days. On 8th day, they received CCl4 2ml/kg/SC in olive oil.
HDN was further continued for 2 more days. Group IV (HDN: 200 mg/kg): rats received HDN continuously for 8 days. On 8th day, they received CCl4 2ml/kg/SC in olive oil. HDN was further continued for 2 more days. After ten days of treatment, liver enzymes, oxidant parameters as malondialdehyde and antioxidant parameters as glutathione and superoxide dismutase were assessed. Histopathological examination of the liver tissues was conducted.
Hesperidin in the dose of 100 and 200 mg/kg produced a significant decrease in the levels of liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and oxidant parameters as malondialdehyde. Antioxidant parameters as glutathione and superoxide dismutase also have shown significant increase. These findings were confirmed by histopathology. Hesperidin in a dose of 100 and 200 mg/kg offers dose-dependent significant protection against hepatotoxicity produced by CCl4 in albino rats.Abstract:
An experimental study was conducted to evaluate the protective effects of an antioxidant (Hesperidin) on carbon tetrachloride-induced hepatic toxicity. This effect was evaluated through assessment of liver
functions as well as histopathological changes in livers of rats exposed to Hesperidin prior to carbon tetrachloride. Thirty two male albino rats were distributed to four equal groups each of 8 rats. Group I (Negative control). Group II (Positive control group: received vehicle (Carboxymethyl Cellulose) for 10 days and were challenged with CCl4 2 ml/kg/SC (40% v/v in olive oil) on 8th day. Group III (HDN: 100
mg/kg): rats received HDN continuously for 8 days. On 8th day, they received CCl4 2ml/kg/SC in olive oil.
HDN was further continued for 2 more days. Group IV (HDN: 200 mg/kg): rats received HDN continuously for 8 days. On 8th day, they received CCl4 2ml/kg/SC in olive oil. HDN was further continued for 2 more days. After ten days of treatment, liver enzymes, oxidant parameters as malondialdehyde and antioxidant parameters as glutathione and superoxide dismutase were assessed. Histopathological examination of the liver tissues was conducted.
Hesperidin in the dose of 100 and 200 mg/kg produced a significant decrease in the levels of liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and oxidant parameters as malondialdehyde. Antioxidant parameters as glutathione and superoxide dismutase also have shown significant increase. These findings were confirmed by histopathology. Hesperidin in a dose of 100 and 200 mg/kg offers dose-dependent significant protection against hepatotoxicity produced by CCl4 in albino rats.
... Furthermore, in this study, we noted a CCl 4 infiltration of inflammatory cells in liver. Ezz et al. (2011) found similar results. According to these authors, TNFα amount increases due to CCl 4 administration. ...
Abstract The aim of the present study was to investigate the extraction and the characterization of a novel heteropolysaccharide from Tunisian halophyte Lobularia maritima (LmPS). We were also interested in its antioxidant, anti‐inflammatory, and hepatoprotective effects on carbon tetrachloride (CCl4)‐induced liver injury in rats. LmPS physicochemical properties were evaluated by thin‐layer chromatography (TLC), high‐performance liquid chromatography (HPLC), thermogravimetric analysis (TGA), and UV absorption. According to TLC and HPLC results, LmPS was a heteropolysaccharide composed of glucose, galactose, and xylose. Its molecular weight was 130.62 kDa. This heteropolysaccharide was characterized by a significant antioxidant potential and was efficient against oxidative stress and CCL4‐induced hepatotoxicity in rat Wistar models (n = 8) treated with a single dose of LmPS 250 mg/kg of body weight. This was evidenced by a significant increase in serum marker enzymes specially aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH). The cytokines released after stimulation of rats with LmPS showed high anti‐inflammatory profiles with an increased rate of interleukine‐10 (IL‐10) with 0.03 pg/mL compared to animals treated only with CCl4. On the contrary, we noticed a decrease of the other cytokines (tumor necrosis factor α: TNF‐α, interleukine‐6: IL‐6, transforming growth factor beta 1: TGF‐β1) with average concentration values of
... ALT, AST activities are thought as the very particular indicator of hepatic damage. They are mainly located in hepatic cell cytoplasm therefore the hepatic injured cells enhanced cellular penetration and cause immediate release of these enzymes into circulation (Ezz et al., 2015;Ramaiah, 2007). ALP formed in bile canalcular cells, it increased in a condition of blockage or inflammation of biliary ducts. ...
Present study was designed to evaluate the effects of coffee on liver function tests and liver antioxidant enzymes in thioacetamide induced liver cirrhosis in rats. Experimental study period was consisted of eighteen weeks divided into two phases. Therefore 24 rats were distributed randomly into four groups (n=6). Group I served as control. In phase I, group II and III received thioacetamide (200mg/kg body weight intraperitoneally twice a week) and group IV received saline for 12 weeks. In phase II, group II received saline while group III and IV received an oral dose of coffee (0.4mg/Kg b.w) daily for 6 weeks. At the end of the study period rats were sacrificed and blood was collected to get serum and liver was homogenized for the determination of antioxidant enzymes. Marked increase in serum total and direct bilirubin, ALT, AST whereas reduced ALP was observed in test group. The reduced tissue SOD activity and increased tissue catalase and tissue MDA activity were also observed in test group. However, coffee consumption in group III in phase II significantly restored liver biomarkers and the tissue antioxidant enzymes SOD, catalase and MDA activities. In conclusion, thioacetamide induced liver cirrhosis can be prevented by coffee supplementation.
... In rats treated with DOX, we found significant increase in heart tissue MDA levels suggesting increased lipid peroxidation. Cardiac tissue damage may be due to increased oxidative stress and depletion of antioxidants [30]. ...
Rhizomes of the plant Curcuma longa, has been traditionally used in medicine and culinary practices in India. It possesses various pharmacological effect viz antioxidant, hepatoprotective, anti-inflammatory, anti-thrombosis and anti-apoptotic. The study was undertaken to assess the effect of curcumin and curcumin loaded mesoporoussilica nanoparticles (MSNs) against doxorubicin (DOX)-induced myocardial toxicity in rats. Further, the study also included the bioavailability estimation of curcumin delivered alone and delivered via mesoporous technology. Cardiotoxicity was produced by cumulative administration of DOX (2.5 mg/kg for two weeks). Curcumin and curcumin loaded mesoporous nanoparticles (MSNs) each 200 mg/kg, po was administered as pretreatment for two weeks and then for two alternate weeks with DOX. The repeated administration of DOX induced cardiomyopathy associated with an antioxidant deficit and increased level of cardiotoxic biomarkers. Pretreatment with curcumin (alone and via MSNs) significantly protected myocardium from the toxic effects of DOX by significantly decreased the elevated level of malondialdehyde (MDA) and increased the reduced level of GSH, SOD and CAT in cardiac tissue. MSNs based delivery was found superior compared to Curcumin delivered alone. Moreover, the results of bioavailability assessment in rats clearly indicated higher Cmax and AUC values in rats when Curcumin was administered via MSNs indicating superior bioavailability. The bioavailability of curcumin loaded MSNs, biochemical and histopathology reports support the good cardioprotective effect of curcumin which could be attributed to its increased bioavaibility lead to good antioxidant and anti-inflammatory activity.
... Oxidative stress, resulting from an imbalance in the generation of free radicals and antioxidant defense molecules, affects biological macromolecules causing their structural alterations that lead to cell damage and its death, [31,32]. Certain drugs may induce oxidative stress by forming drug-derived radicals that can not only deplete the antioxidant defenses but can also react directly with biomolecules [33]. ...
Abstract: The present study aimed to evaluate the effectiveness of curcumin, and Rosemary as a natural source of antioxidants to minimize the harmful effects of gentamicin induced dyslipidemia in Guinea pigs. Guinea pigs were divided into five groups. The first group (control) was injected intraperitoneal with saline. The 2nd group was injected intraperitoneal with gentamicin at a dose of 100 mg/kg body weight /day. The 3th , 4th , and 5th groups were injected intraperitoneal with gentamicin (100 mg/kg b. wt /day) concurrently with curcumin, rosemary, and curcumin with rosemary at the doses of 200 mg, 220 mg, and 200 mg with 220 mg /kg body weight /day respectively orally by gavage for 10 days. Blood samples were obtained for assessment of serum cholesterol, triglycerides, high density lipids, low density lipids, and very low density lipids concentrations. Gentamicin treatment induced dyslipidemia. Guinea pigs that injected intraperitonally with gentamicin at a dose of 100 mg/kg body weight daily for 10 days had significantly (p<0.05) increase the concentrations of serum cholesterol, triglycerides, low density lipids cholesterol, very low density lipids cholesterol concentrations, and the atherogenic ratios based on lipid profile parameters (Castelli’s Risk Index I, Castelli’s Risk Index II, Atherogenic Coefficient and Atherogenic Index of Plasma) and decreased the serum high density lipids cholesterol concentration. Co-administration of rosemary and/or curcumin with gentamicin significantly improved of all lipid profile parameters, and atherogenic ratios parameters. It can be concluded that, gentamicin had adverse effects on lipid profile parameters, and the atherogenic ratios parameters. Rosemary and/or curcumin supplementation showed a remarkable amelioration of these abnormalities in gentamicin treated male Guinea pigs. It is recommended that the use of gentamicin must be limited and use of rosemary and curcumin as antioxidants to prevent the dyslipidemia. Further studies are necessary to elucidate exact mechanism of protection of hyperlipidemia, atherogenic and potential usefulness of rosemary and curcumin as a protective agent against gentamicin induced dyslipidemia and atherogenic in clinical trials.
... At the end of study, livers were immediately removed and weighed. Each liver was cut longitudinally into two halves; one half was fixed in 10% phosphatebuffered formalin for histological examination, while the other half was stored at -70 °C for biochemical analysis (Magda et al., 2011). ...
Objective: Lamotrigine is an antiepileptic drug, widely used in the treatment of epilepsy; long-term use of this drug can cause hepatotoxicity. Zingiber officinale Roscoe (ginger) possesses antioxidant properties. In present research, the effect ofhydroalcoholic extract of ginger (HEG) on the liver of lamotrigine-treated epileptic rats was investigated
Material and Methods: Forty-eight female Wistar rats were selected and allocated to 8 groups of 6 each. Group 1: Negative controls were treated with normal saline. Group 2: Positive controls were treated with lamotrigine (LTG) (10 mg/kg) daily by gavages for 4 consecutive weeks. Epilepsy was induced in treatment groups by i.p. injection of pentylenetetrazol (PTZ) (40 mg/kg). Group 3: Epileptic group received normal saline (10 ml/kg). Group 4: Epileptic group was treated with LTG (10 mg/kg). Groups 5 and 6: Epileptic groups received HEG (50 and 100 mg/kg). Groups 7 and 8: Epileptic groups received LTG and HEG (50 and 100 mg/kg). At the end of 28 days, blood samples were drawn and their livers were processed for light microscopy.
Results: The mean values of TG, CHOL, AST, and ALT activity significantly rose (p<0.01) in groups 2, 3, and 4, while in rats treated with HEG (groups 5, 6, 7, and 8), the levels of liver enzymes significantly decreased (p<0.05) compared with epileptic group treated with lamotrigine (group 4). Histopathological changes of liver samples were comparable with respective control.
Conclusion: These results suggest that hydroalcoholic extract of ginger improves liver function in lamotrigine-induced hepatotoxicity.
The current study explorated the hepatoprotective and immunomodulatory effects of Linalool (Lin) against carbon tetrachloride (CCl4)‐induced toxicity in mice. Four study groups (n = 8 each) were used: (1) a negative control group; (2) a toxicity control group (single dose of CCl4 administered at day 14 as 1ml/kg of CCL4 in 1% olive oil. Intraperitoneally (i.p)); and two experimental groups where mice were treated with either (3) Lin (25 mg/kg b.w, orally, daily for 15 days) or (4) pretreated with Lin (25 mg/kg b.w., orally, daily for 14 days) and intoxicated with CCl4 (1ml/kg of CCL4 in 1% olive oil. i.p) on day 14. The levels of the anti‐inflammatory cytokines interleukin 10 (IL‐10), pro‐inflammatory cytokines TNF‐ α, IL‐6 and TGF‐1β, and the histopathology of the liver were accessed. According to our findings, IL‐10 concentrations were significantly increased in Lin‐treated groups, while other cytokine levels were marked by a considerable decrease in the toxicity model group (CCl4‐treated group). Histopathological examinations for liver tissues showed that Lin treated groups had an almost normal structure. The current findings showed that Lin could inhibit the CCl4‐induced liver injury in mice, which warrants further investigation of Lin as a potential protective and therapeutic agent against hepatotoxicity. This article is protected by copyright. All rights reserved
Protection against liver injury and its consequences is considered an essential issue to minimize the number of annual deaths caused by liver diseases. The present study was designed to evaluate the potential role of pomegranate extract (PE) and/or curcumin in regression of thioacetamide (TAA)-induced liver fibrosis, focusing on their modulatory effects on Nrf2/HO-1, NF-κB, and TGF-β/Smad3 signaling pathways. Liver fibrosis was induced in male Wistar rats by intraperitoneal injection of TAA (100 mg/kg) three times a week, for 8 weeks. To assess the protective effects of PE and/or curcumin against TAA-induced liver fibrosis, rats were treated on a daily basis with oral doses of PE (200 mg/kg) and/or curcumin (200 mg/kg) for 8 weeks. The results indicated that PE and/or curcumin attenuated TAA-induced liver fibrogenesis, as evidenced by significant improvement in the liver function tests (AST, ALT, ALP, and albumin), oxidative stress biomarkers (MDA, SOD, and GSH), and inflammatory biomarkers (NF-ĸB, TNF-α, IL-1β, iNOS, TGF-β, and MPO), compared to TAA group. Moreover, treatment with PE and/or curcumin exerted a significant upregulation of Nrf2/HO-1 gene expressions along with significant downregulation of NF-ĸB, TGF-β, and phospho-Smad3 protein expressions, as well as α-SMA and collagen-1 gene expressions. The histopathological examination has corroborated these findings. In conclusion, hepatoprotective activities of PE and/or curcumin could be linked to their abilities to modulate Nrf2/HO-1, NF-κB, and TGF-β/Smad3 signaling pathways. It is worth noting that the combination of PE and curcumin exerted superior hepatoprotective effects against TAA-induced liver fibrosis, as compared to monotherapy.
Cirrhosis is a chronic liver disease. The present work aimed to evaluate the regulatory immune effect of curcumin in hepatic cirrhosis induced by carbon tetrachloride (CCl4) injections in experimental rats’ model. Chronic liver fibrosis was induced in experiment animals by recurrent injections of CCl4 for more than 5 weeks. They were divided into five groups: first group was injected with normal saline, second group with CCl4, third, fourth, and fifth groups were injected with CCl4 (intraperitoneal injection) at dose 3 ml/kg, two times weekly for 6 weeks supplemented with the administration of curcumin with concentrations 250, 200, and 150 mg/kg. Immune response was analyzed to different treatments. Interleukin 10 (IL‐10), pro‐inflammatory cytokines TNF‐α, TGF‐1β, and liver histopathological examinations were conducted. The results showed that estimations of IL‐10 concentrations were significantly increased in curcumin groups compared with CCl4 group, whereas TNF‐α and TGF‐1β levels were significantly decreased comparing with CCl4 group. The histopathological examinations for liver tissues showed that curcumin treated groups have almost retained the normal structure of liver tissues. In conclusion, curcumin inhibited hepatic fibrosis and liver fibrogenesis with regulation of the immune system mechanism against invader chemical toxicity.
Practical applications
Curcumin is well documented for its medicinal properties, commonly used as a spice. Our work has thus demonstrated its effectiveness as an immunomodulatory agent. Practically, clinical studies have suggested that curcumin displays a diverse and powerful array of pharmacological effects in nearly all of the human body's major organ systems. These are: antidiabetes, anti‐inflammatory, anticancer, antiaging, antioxidant, antibacterial infection, hepatoprotective, neurodegenerative, and cardiovascular effects.
Background: Bioactive food components are nonessential biomolecules, which help to give beneficial effects to human being against several diseases. Natural bioactive food components derived from plants and animals, such as phytosterols, carotenoids, polyphenols and fatty acids, have been proposed as valuable substitutions for anticipation and management of hepatotoxic effects and its chronic complications based on in vitro and in vivo studies.
Objectives of the study: To summarize drugs and chemical-induced hepatotoxicity and review how various bioactive food components attenuate the hepatotoxicity via cellular mechanisms.
Results: Remarkable studies demonstrated that the health promoting effects of bioactive components originated from plants have been frequently attributed to their antioxidant properties and facilitate to increase cellular antioxidant defense system and thereby scavenge free radicals, inhibit lipid peroxidation, augment anti-inflammatory potential, and further protect the liver from damage.
Conclusion: In this critical review, we summarize current progress in clarifying the molecular mechanism in hepatotoxicity and curative potential of the bioactive food components and its successive clinical outcomes in the field of drug discovery and overcome the problems of medication and chemical-induced hepatotoxic effects.
Liver is the versatile organ of our body and plays vital role in metabolism of Carbohydrate, Protein, Lipid / Fat, Vitamin and drugs. Liver cells produce bile; it also performs excretion and detoxification. It is the site of decomposition of erythrocytes and store glycogen. Rising number of cases in Liver injury or dysfunction due to consumption of prescribed drugs, medicines that are acquired over the counter and chemicals that are used in the process of agriculture, is endemicity in developing countries. Over doses of Paracetamol, antibiotics, chemotherapeutic agents, carbon tetrachloride (CCl4), excessive alcohol etc. contribute to hepatotoxicity. However, there is no effective drug available to stimulate and rejuvenate liver cells. Hence it is an urgent need to relook at natural sources that offer hepatoprotection. This review elucidates the list of commonly consumed seeds, root, fruit and Leafy vegetables, as food in south India and their proven hepatoprotective activity in recent times.
Liver is the versatile organ of our body and plays vital role in metabolism of Carbohydrate, Protein, Lipid / Fat, Vitamin and drugs. Liver cells produce bile; it also performs excretion and detoxification. It is the site of decomposition of erythrocytes and store glycogen. Rising number of cases in Liver injury or dysfunction due to consumption of prescribed drugs, medicines that are acquired over the counter and chemicals that are used in the process of agriculture, is endemicity in developing countries. Over doses of Paracetamol, antibiotics, chemotherapeutic agents, carbon tetrachloride (CCl 4), excessive alcohol etc. contribute to hepatotoxicity. However, there is no effective drug available to stimulate and rejuvenate liver cells. Hence it is an urgent need to relook at natural sources that offer hepatoprotection. This review elucidates the list of commonly consumed seeds, root, fruit and Leafy vegetables, as food in south India and their proven hepatoprotective activity in recent times.
The present study involved the recognition of the effect of aqueous extract of ginger to prevent carcinogen-induced genotoxicity in human peripheral blood lymphocytes ex-in vivo by single cell gel electrophoresis technique in the presence and absence of ginger extract. Blood was obtained from 30 human volunteers of which 10 were apparently normal male non-smokers, 10 male smokers and 10 females. Aqueous ginger extract at three concentrations namely 2.5, 5 and 10 μg were tested for protective effect against B(a)P (300 μM) induced DNA damage. The results indicated that DNA damage expressed as comet ratio was decreased in samples treated with only B(a)P. When ginger extracts were present in incubation mixtures the comet ratios have increased depending on the dose of ginger extract. At the highest concentration of ginger extract namely 10 μg, the comet ratios were similar to their respective controls demonstrating the protective effect of ginger on carcinogen induced DNA damage.
The present study aimed to evaluate the hepatoprotective effect of ginger aqueous infusion on the paracetamol induced hepatotoxicity in rats. Different groups (1, 2, 3) of rats were given ginger in three doses (100,200 and 400 mg /kg at 12 hours intervals for 48 hours prior to single paracetamol dose (640 mg /kg), group 4 rats were given silymarin (25mg/kg) as reference hepatoprotective drug, group 5 rats were given paracetamol alone(positive control group),group 6 rats were given distilled water(negative control group). Blood was collected from all teated groups for determination of liver enzymes:-alanine aminotransferase (ALT), alanine aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin after that rat were sacrificed and the livers were excised for the histopathological study in which the examination of liver tissue for rat treated with paracetamol and extract at dose of 200,400 mg/kg and also with silymarin revealed normal hepatic architecture than liver for rats treated with extract at a dose 100 mg. In vitro bioassay on primary culture of rat hepatocytes monolayer revealed that the LC 50 of ginger extract was at 750µg/ml while the hepatoprotective activity of the extract concentration at which extracts exhibit a hepatoprotective activity was of (15 µg/ml).
Doxorubicin (DOX) has a wide spectrum of antitumor activity with dose-related cardiotoxicity as a major side effect. This cardiotoxicity has been suggested to result from enhanced oxidative stress caused by oxygen centered free radicals. The present study was performed to investigate the influence of the antioxidant 6-gingerol on cardiotoxicity in-duced by doxorubicin (DOX). A single dose of DOX (20 mg/kg i.p.) induced myocardial toxicity after 48 hrs, manifested biochemically by a significant elevation in the following serum enzymes activities: creatine phosphokinase (E.C.2.7.3.2), lactate dehydrogenase (E.C.1.1.1.27), aspartate transaminase (E.C.2.6.1.1) and serum cardiac isoenzyme creatine phos-phokinase (MB). Administration of 6-gingerol (10 mg/kg/day p.o.) in drinking water starting 5 days before and continuing during the experimental period significantly ameliorated myocardial toxicity induced by DOX. The amelioration of car-diotoxicity was evidenced by significant reductions in serum enzymes activities and cardiac isoenzyme. The current data support 6-gingerol as a potentially selective cardioprotective agent, against cardiotoxicity induced by DOX and it may therefore improve the therapeutic index of DOX.
Grape is one of the most popular and widely cultivated fruits in the world. Although grape skin and seeds are waste product of the winery and grape juice industry, these wastes contain large amounts of phytochemicals such as flavonoids, phenolic acids, and anthocyanidins, which play an important role as chemopreventive and anticancer agents. We evaluated efficacies of grape skin and seeds on hepatic injury induced by dimethylnitrosamine (DMN) in rats. Treatment with DMN significantly increased levels of serum alanine transaminase, aspartate transaminase, alkaline phosphatase, and bilirubin. Diet supplementation with grape skin or seeds (10% daily for 4 weeks) prevented these elevations. The grape skin and seeds also restored serum albumin and total protein levels, and reduced the hepatic level of hydroxyproline and malondialdehyde. Furthermore, grape skin and seeds reduced DMN-induced collagen accumulation, as estimated by histological analysis of liver tissue stained with Sirius red. Grape skin and seeds also reduced hepatic stellate cell activation, as assessed by α-smooth muscle actin staining. In conclusion, grape skin and seeds exhibited in vivo hepatoprotective and antifibrogenic effects against DMN-induced liver injury, suggesting that grape skin and seeds may be useful in preventing the development of hepatic fibrosis.
To investigate the role of emodin in protecting the liver against fibrogenesis caused by carbon tetrachloride (CCl(4)) in rats and to further explore the underlying mechanisms.
Rat models of experimental hepatic fibrosis were established by injection with CCl(4); the treated rats received emodin via oral administration at a dosage of 20 mg/kg twice a week at the same time. Rats injected with olive oil served as a normal group. Histopathological changes were observed by hematoxylin and eosin staining. The activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and hepatic hydroxyproline content were assayed by biochemical analyses. The mRNA and protein relevant to hepatic stellate cell (HSC) activation in the liver were assessed using real-time reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, western blotting and enzyme-linked immunosorbent assay.
The degree of hepatic fibrosis increased markedly in the CCl(4) group compared to the normal group (P < 0.01), and decreased markedly in the emodin group compared to the CCl(4) group according to METAVIR scale (P < 0.01) compared with those in the normal control group (51.02 +/- 10.64 IU/L and 132.28 +/- 18.14 IU/L). The activities of serum ALT and AST were significantly higher in rats injected with CCl(4) (289.25 +/- 68.84 IU/L and 423.89 +/- 35.67 IU/L, both P < 0.05). The activities of serum ALT and AST were significantly reduced by administration of emodin (176.34 +/- 47.29 IU/L and 226.1 +/- 44.52 IU/L, both P < 0.05). Compared with the normal controls (54.53 +/- 13.46 mg/g), hepatic hydroxyproline content was significantly higher in rats injected with CCl(4) (120.27 +/- 28.47 mg/g, P < 0.05). Hepatic hydroxyproline content was significantly reduced in the rats treated with emodin at 20 mg/kg (71.25 +/- 17.02 mg/g, P < 0.05). Emodin significantly protected the liver from injury by reducing serum AST and ALT activities and reducing hepatic hydroxyproline content. The mRNA levels of transforming growth factor-beta1 (TGF-beta1), Smad4 and alpha-SMA in liver tissues were significantly down-regulated in SD rats that received emodin treatment. Furthermore, significant down-regulation of serum TGF-beta1 protein levels and protein expression of Smad4 and alpha-SMA in liver tissues was also observed in the rats. Emodin inhibited HSC activation by reducing the abundance of TGF-beta1 and Smad4.
Emodin protects the rat liver from CCl(4)-induced fibrogenesis by inhibiting HSC activation. Emodin might be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis.
Reactive oxygen or nitrogen species (ROS/RNS) generated endogenously or in response to environmental stress have long been implicated in tissue injury in the context of a variety of disease states. ROS/RNS can cause cell death by nonphysiological (necrotic) or regulated pathways (apoptotic). The mechanisms by which ROS/RNS cause or regulate apoptosis typically include receptor activation, caspase activation, Bcl-2 family proteins, and mitochondrial dysfunction. Various protein kinase activities, including mitogen-activated protein kinases, protein kinases-B/C, inhibitor-of-I-kappaB kinases, and their corresponding phosphatases modulate the apoptotic program depending on cellular context. Recently, lipid-derived mediators have emerged as potential intermediates in the apoptosis pathway triggered by oxidants. Cell death mechanisms have been studied across a broad spectrum of models of oxidative stress, including H2O2, nitric oxide and derivatives, endotoxin-induced inflammation, photodynamic therapy, ultraviolet-A and ionizing radiations, and cigarette smoke. Additionally ROS generated in the lung and other organs as the result of high oxygen therapy or ischemia/reperfusion can stimulate cell death pathways associated with tissue damage. Cells have evolved numerous survival pathways to counter proapoptotic stimuli, which include activation of stress-related protein responses. Among these, the heme oxygenase-1/carbon monoxide system has emerged as a major intracellular antiapoptotic mechanism.
There is increasing interest in the discovery of natural compounds that could favorably affect the skeletal system. Curcumin is a constituent of turmeric, a plant which has been used for centuries as a dietary spice and a traditional Indian medicine. Curcumin has been reported to affect differentiation, activity and the lifespan of osteoblasts and osteoclasts in vitro. The aim of the present study was to investigate the effects of curcumin on the skeletal system of rats in vivo. Curcumin (10 mg/kg, po daily) was administered for four weeks to normal (non-ovariectomized) and bilaterally ovariectomized (estrogen-deficient) three-month-old female Wistar Cmd:(WI)WU rats. Ovariectomy was performed seven days before the start of curcumin administration. Bone mass, mineral and calcium content, macrometric and histomorphometric parameters, as well as the mechanical properties of the bone, were examined. Serum total cholesterol and estradiol levels were also determined. In rats with normal estrogen levels, curcumin decreased serum estradiol level and slightly increased cancellous bone formation, along with decreased mineralization. Estrogen deficiency induced osteoporotic changes in the skeletal system of the ovariectomized control rats. In ovariectomized rats, curcumin decreased body mass gain and serum total cholesterol level, slightly improved some bone histomorphometric parameters impaired by estrogen deficiency, but did not improve bone mineralization or mechanical properties. In conclusion, the results of the present in vivo study in rats did not support the hypothesis that curcumin, at doses that are readily achievable through dietary intake, could be useful for the prevention or treatment of osteoporosis.
Oxidative stress induced by carbon tetrachloride (2 ml/kg body weight i.p.) in rat substantially decreases the increase in body weight and relative testis weight. It also markedly increases the level of TBARS and nitrites along with corresponding decrease in reduced glutathione and various antioxidant enzymes in testis, i.e., catalase, peroxidase, superoxide dismutase and glutathione peroxidase. Serum level of testosterone, luteinizing hormone and follicle stimulating hormone was significantly decreased while estradiol and prolactin were increased with carbon tetrachloride treatment. Histopathology of CCl(4)-treated rats indicated the partial degeneration of germ and Leydig cells along with deformities in spermatogenesis. Supplementation of Digera muricata (100, 150, 200mg/kg body weight orally) once a week for 16 weeks results in decrease of TBARS and nitrite, while increase in antioxidant enzymes; catalase, peroxidase, superoxide dismutase, GSH-Px and GSH contents. Serum level of testosterone, luteinizing hormone, follicle stimulating hormone, estradiol, prolactin, histology, body weight and relative testis weight was also concomitantly restored to near normal level by D. muricata supplementation to carbon tetrachloride intoxicated rat. The results clearly demonstrate that D. muricata treatment augments the antioxidants defense mechanism against carbon tetrachloride induced toxicity and provides evidence that it may have a therapeutic role in free radical mediated diseases.
Ginger (Zingiber officinale) supplements are being promoted for arthritis treatment in western societies on the basis of ginger's traditional use as an anti-inflammatory in Chinese and Ayurvedic medicine. However, scientific evidence of ginger's antiarthritic effects is sparse, and its bioactive joint-protective components have not been identified. Therefore, the ability of a well-characterized crude ginger extract to inhibit joint swelling in an animal model of rheumatoid arthritis, streptococcal cell wall-induced arthritis, was compared to that of a fraction containing only gingerols and their derivatives. Both extracts were efficacious in preventing joint inflammation. However, the crude dichloromethane extract, which also contained essential oils and more polar compounds, was more efficacious (when normalized to gingerol content) in preventing both joint inflammation and destruction. In conclusion, these data document a very significant joint-protective effect of these ginger samples and suggest that nongingerol components are bioactive and can enhance the antiarthritic effects of the more widely studied gingerols.
The root of Aralia continentalis Kitagawa has been used in traditional Korean medicine to relieve pain and to treat inflammation. The purpose of this study was to investigate the protective effects of the extract of A. continentalis roots (AC) against hepatotoxicity induced by carbon tetrachloride (CCl4) and the mechanism of its hepatoprotective effect. In mice, pretreatment with AC prior to the administration of CCl4 significantly prevented the increased serum enzymatic activity of ALT and AST as well as the formation of hepatic malondialdehyde. Histopathological evaluation of the livers also revealed that AC reduced the incidence of liver lesions induced by CCl4. In addition, pretreatment with AC significantly prevented both the depletion of reduced glutathione (GSH) content and the decrease in glutathione-S-transferase (GST) activity in the liver of CCl4-intoxicated mice. Hepatic GSH levels and GST activity were increased by treatment with AC alone. Heme oxygenase-1 (HO-1) is known to be induced by oxidative stress and to confer protection against oxidative tissue injuries. Interestingly, AC markedly upregulated hepatic HO-1 expression in CCl4-treated mice, which might provide anti-oxidative activity in the liver. These results indicate that AC plays a critical protective role in CCl4-induced acute liver injury by promoting anti-oxidative protein expression.
Curcumin, a yellow pigment present in the Indian spice turmeric (associated with curry powder), has been linked with suppression of inflammation; angiogenesis; tumorigenesis; diabetes; diseases of the cardiovascular, pulmonary, and neurological systems, of skin, and of liver; loss of bone and muscle; depression; chronic fatigue; and neuropathic pain. The utility of curcumin is limited by its color, lack of water solubility, and relatively low in vivo bioavailability. Because of the multiple therapeutic activities attributed to curcumin, however, there is an intense search for a "super curcumin" without these problems. Multiple approaches are being sought to overcome these limitations. These include discovery of natural curcumin analogues from turmeric; discovery of natural curcumin analogues made by Mother Nature; synthesis of "man-made" curcumin analogues; reformulation of curcumin with various oils and with inhibitors of metabolism (e.g., piperine); development of liposomal and nanoparticle formulations of curcumin; conjugation of curcumin prodrugs; and linking curcumin with polyethylene glycol. Curcumin is a homodimer of feruloylmethane containing a methoxy group and a hydroxyl group, a heptadiene with two Michael acceptors, and an alpha,beta-diketone. Structural homologues involving modification of all these groups are being considered. This review focuses on the status of all these approaches in generating a "super curcumin.".
A simple and inexpensive assay method of superoxide dismutase (SOD) activity of various biological materials has been developed. SOD activity can easily be measured by reading the medium's intense absorbance directly, and many samples can be treated in a short time using a reaction stopper which acts for a long time. Reproducibility of the assay method was excellent for the sample from an individual estimated at two different times (a week to a month) and the coefficient of variance was 5.1%. The mean and standard deviation of SOD activities of 45 blood samples from normal Japanese males 32.9 +/- 10.5 microgram per ml of blood; estimated using bovine SOD standard. The SOD activity of the fluid from lavaged lungs was 15.7 +/- 1.8 microgram/ml, and that of lung tissue homogenates from rats was 2.85 +/- 0.66 microgram/mg of protein.
Free radical (FR) mechanisms have both beneficial and deleterious actions in vivo. Intensive scientific interest in FRs over the last 20 years has led to a clearer understanding of their roles and helped to clarify the contribution of our intrinsic defence systems (antioxidants) in limiting FR-induced tissue damage. As more and more conditions are shown to have a FR aetiology it becomes imperative to develop newer therapies to prevent and treat FR-induced disease.
The thiobarbituric acid reacting material produced during enzymatic microsomal lipid peroxidation has been identified as malonaldehyde. The malonaldehyde was condensed with urea to form 2-hydroxy-pyrimidine, which was identified by its ultraviolet spectrum, chromato-graphic properties, and mass spectrum. Incubations with phosphatidyl choline labelled with tritiated arachidonate yielded 2-hydroxy-pyrimidine with a specific activity nearly equal to that of the phospholipid arachidonate. Incubations with tritiated arachidonic acid yielded 2-hydroxy-pyrimidine with a specific activity nearly 2 orders of magnitude less than that of free arachidonic acid. Therefore, phospholipid arachidonate has been established as the major source of the malonaldehyde produced during microsomal lipid peroxidation.
A simple colorimetric assay for catalase activity has been described using K2Cr2O7/acetic acid reagent. Kat. f values of different enzyme sources were determined by the colorimetric method and compared with the values obtained by titrimetric methods.
A rapid and reliable method for measuring serum albumin employing bromcresol green is described. The addition of albumin to a solution of bromcresol green in a 0.075 M succinate buffer pH 4.20 results in an increase in absorbance at 628 nm. The absorbance-concentration relationship is linear for samples containing up to 6 g/dl albumin. Bilirubin, moderate lipemia, and salicylate do not interfere with the analysis. The use of nonionic surfactant (Brij-35) reduces the absorbance of the blank, prevents turbidity and provides linearity. The results by this method agree very well with those obtained by electrophoresis and salt fractionation. The method is simple, it has excellent precision and the reagents are stable. A protein standard is introduced which can be employed for both the total serum proteins and albumin determinations.
Tumor necrosis factor (TNF)-alpha is associated with increased mortality in alcoholics, but its role in early alcohol-induced liver injury is not fully understood. Recently, it was shown that injury induced by the enteral alcohol delivery model of Tsukamoto and French was reduced by antibodies to TNF-alpha. To obtain clear evidence for or against the hypothesis that TNF-alpha is involved, we studied TNF receptor 1 (TNF-R1, p55) or 2 (TNF-R2, p75) knockout mice.
Long-term enteral alcohol delivery was modified for male gene-targeted mice lacking TNF-R1 and TNF-R2. Animals were given a high-fat liquid diet continuously with either ethanol or isocaloric maltose-dextrin as a control for 4 weeks.
Ethanol elevated serum levels of alanine aminotransferase nearly 3-fold in wild-type and TNF-R2 knockout mice but not in TNF-R1 knockout mice. Likewise, ethanol caused severe liver injury in wild-type mice (pathology score, 5.5 +/- 0.6) and TNF-R2 knockout mice (pathology score, 5.0 +/- 0.4), but not in TNF-R1 knockout mice (pathology score, 0.8 +/- 0.4; P < 0.001).
Long-term ethanol feeding caused liver injury in wild-type and TNF-R2 knockout mice but not in TNF-R1 knockout mice, providing solid evidence in support of the hypothesis that TNF-alpha plays an important role in the development of early alcohol-induced liver injury via the TNF-R1 pathway. Moreover, the long-term enteral ethanol feeding technique we described for the first time for knockout mice provides a useful new tool for alcohol research.
Based on recent studies, pungent constituents of ginger (Zingiber officinale) and related substances represent a potential new class of anti-platelet agents. The ability of 20 pungent constituents of ginger and related substances to inhibit arachidonic acid (AA) induced platelet activation in human whole blood was studied.
Anti-platelet activity of the compounds was measured in vitro by the Chrono Log whole blood platelet aggregometer. Molecular hydrophobicity (log P) was measured by reversed-phase high-performance liquid chromatography. COX-1 (ovine) inhibitory effect of [8]-paradol and analogues 1 and 5 was carried out using a COX-1 inhibitor assay kit.
[8]-Gingerol, [8]-shogaol, [8]-paradol and gingerol analogues (1 and 5) exhibited anti-platelet activities with IC(50) values ranging from 3 to 7 microM, whilst under similar conditions the IC(50) value for aspirin was 20+/-11 microM. The COX-1 inhibitory activity of [8]-paradol (IC(50)=4+/-1 microM) was more potent than the gingerol analogues (1 and 5) (IC(50) approximately 20 microM).
The above findings show that gingerol compounds and their derivatives are more potent anti-platelet agents than aspirin under the conditions described in this study. [8]-Paradol, a natural constituent of ginger, was found to be the most potent COX-1 inhibitor and anti platelet aggregation agent. The mechanism underlying AA-induced platelet aggregation inhibition may be related to attenuation of COX-1/Tx synthase enzymatic activity. Lastly, important features of phenolic compounds for inhibition of AA-induced platelet aggregation and COX-1 activity were revealed in this study.
The aim of this study was to investigate the immunomodulatory effects of the volatile oil of ginger (Zingiber officinale Roscoe) in vitro and in vivo in mice. In vitro, the volatile oil of ginger (0.001-10 ng/mL) significantly inhibited T lymphocyte proliferation (P < 0.01), decreased the number of the total T lymphocytes and T helper cells (P < 0.01) in a concentration-dependent manner, but increased the percentage of T suppressor cells to the total T lymphocytes in the mice. In addition, the volatile oil of ginger (0.001-10 ng/mL) inhibited IL-1alpha secretion by the mice peritoneal macrophages in a concentration-dependent manner. In vivo, oral administration of the volatile oil of ginger in the doses of 0.125, 0.25 and 0.5 g/kg body weight dose-dependently weakened the delayed type of hypersensitivity response to 2,4-dinitro-1-fluorobenzene in the sensitized mice (P < 0.05). These results suggest that the volatile oil of ginger influences both cell-mediated immune response and nonspecific proliferation of T lymphocyte, and may exert beneficial effects in a number of clinical conditions, such as chronic inflammation and autoimmune diseases.
Major complications of cirrhosis include ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, portal hypertension, variceal bleeding, and hepatorenal syndrome. Diagnostic studies on ascitic fluid should include a differential leukocyte count, total protein level, a serum-ascites albumin gradient, and fluid cultures. Therapy consists of sodium restriction, diuretics, and complete abstention from alcohol. Patients with ascitic fluid polymorphonuclear leukocyte counts of 250 cells per mm3 or greater should receive empiric prophylaxis against spontaneous bacterial peritonitis with cefotaxime and albumin. Patients who survive an episode of spontaneous bacterial peritonitis should receive long-term prophylaxis with norfloxacin or trimethoprim/sulfamethoxazole. Patients with gastrointestinal hemorrhage and cirrhosis should receive norfloxacin or trimethoprim/sulfamethoxazole twice daily for seven days. Treatment of hepatic encephalopathy is directed toward improving mental status levels with lactulose; protein restriction is no longer recommended. Patients with cirrhosis and evidence of gastrointestinal bleeding should undergo upper endoscopy to evaluate for varices. Endoscopic banding is the standard treatment, but sclerotherapy with vasoconstrictors (e.g., octreotide) also may be used. Prophylaxis with propranolol is recommended in patients with cirrhosis once varices have been identified. Transjugular intrahepatic portosystemic shunt has been effective in reducing portal hypertension and improving symptoms of hepatorenal syndrome, and can reduce gastrointestinal bleeding in patients with refractory variceal hemorrhage. When medical therapy for treatment of cirrhosis has failed, liver transplantation should be considered. Survival rates in transplant recipients have improved as a result of advances in immunosuppression and proper risk stratification using the Model for End-Stage Liver Disease and Child-Turcotte-Pugh scoring systems.
Curcumin, the major polyphenolic compound in turmeric, has been shown to attenuate hepatic damage in several animal models of liver injury. The aim of the present study was to examine the efficacy of curcumin in preventing thioacetamide-induced cirrhosis and to unravel the mechanism of curcumin's effect on hepatic fibrosis in rats.
Liver cirrhosis was induced by thioacetamide (TAA; 200 mg/kg, i.p.) twice weekly for 12 weeks. One group of rats concomitantly received curcumin (300 mg/kg/day, by gavage for 12 weeks); the control group received the solvent at identical amounts and duration.
TAA administration induced liver cirrhosis, which was inhibited by curcumin. Liver histopathology, hydroxyproline levels and spleen weights were significantly lower in the rats treated with TAA+curcumin compared with TAA only (P<0.001). Immunohistochemical studies and in situ hybridization demonstrated inhibition of hepatic stellate cell (alpha smooth muscle actin-positive) activation and collagen alpha1 (I) gene expression in the livers of the TAA+curcumin-treated rats. Curcumin reduced oxidative stress as shown by the decreased hepatic nitrotyrosine staining in the curcumin+TAA-treated rats. Curcumin treatment had no effect on pre existing liver cirrhosis. As determined by in vitro studies using the rat HSC-T6 cell line, curcumin had no direct inhibitory effect on collagen alpha1 (I) messenger RNA expression. Further studies in these cells using reverse transcriptase-polymerase chain reaction demonstrated that curcumin had no effect on the expression of PDGF-induced TIMP-1 and TIMP-2, TGFbeta1, TGFbeta2 and MCP-1 but significantly inhibited tumor necrosis factor alpha expression. Curcumin had no effect on hepatic stellate cells proliferation. Zymography showed that curcumin had no effect on matrix metalloproteinase-2 activity.
Curcumin inhibited the development of TAA-induced liver cirrhosis mainly due to its anti-inflammatory activities and not by a direct anti-fibrotic effect. As curcumin ingestion is safe in humans, it may be reasonable to assess in clinical studies the beneficial effect of curcumin in slowing the development of liver cirrhosis.
Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 Bc) numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than monotargeted therapy for most diseases, curcumin can be considered an ideal "Spice for Life".
Stronger Neo-Minophagen C (SNMC), a glycyrrhizin-containing preparation, has been used as a treatment for chronic hepatitis for more than 30 years in Japan, and shown to be effective in preventing the development of hepatocellular carcinoma in chronic hepatitis C patients, but its underlying mechanisms remain elusive. The aim of this study was to investigate if SNMC had an anti-oxidative effect, as oxidative stress has been proposed to be one of the mechanisms of liver injury in hepatitis C virus (HCV)-associated chronic liver diseases.
The protective effect of SNMC against carbon tetrachloride (CCl4)-induced liver injury was examined using transgenic mice expressing the HCV polyprotein.
A small dose of CCl4 (10 microl/kg of body weight) significantly increased the serum alanine aminotransferase (ALT) level and hepatic malondialdehyde content, decreased hepatic reduced glutathione (GSH) content and induced ultrastructural alterations of hepatic mitochondria in transgenic mice, but not in nontransgenic mice. A single SNMC treatment equivalent to a clinical dose significantly restored the serum ALT level and hepatic malondialdehyde and GSH contents, attenuated the ultrastructural alterations of hepatic mitochondria, and increased mRNA expression of gamma-glutamylcysteine synthetase (gamma-GCS).
Transgenic mice expressing the HCV polyprotein are abnormally vulnerable to oxidative stress. SNMC protects hepatocytes against CCl4-induced oxidative stress and mitochondrial injury in the presence of HCV proteins by restoring depleted cellular GSH.
Assessing liver damage in basic toxicology research and in preclinical toxicity testing is usually evaluated by serum biochemical parameters prior to confirmation by histopathology. With the advent of newer methods such as genomics and proteomics, there is increased enthusiasm to generate "novel" predictive markers to detect liver pathology even before the alterations in clinical and histopathology parameters occur. However, serum biochemical parameters (clinical pathology) when employed accurately, can provide important and useful information in assessing not only the extent and severity of liver damage, but also the type of liver damage (membrane injury versus cholestasis and hepatic function). In order to accurately detect hepatobiliary pathologies, it is important to have a basic understanding of liver associated clinical pathology parameters with reference to their exact location, serum half-lives, tissue concentration gradient and species differences. Such understanding as discussed in this article will enable a toxicologist to identify commonly encountered toxic hepatic lesions such as necrosis, cholestasis and compromised liver function by hepatic-associated clinical pathology parameters. In addition, toxicologists will have a better grasp to effectively communicate their clinical pathology findings and interpretations to the target audiences.
We previously demonstrated that curcumin, a polyphenolic antioxidant purified from turmeric, up-regulated peroxisome proliferator-activated receptor (PPAR)-gamma gene expression and stimulated its signaling, leading to the inhibition of activation of hepatic stellate cells (HSC) in vitro. The current study evaluates the in vivo role of curcumin in protecting the liver against injury and fibrogenesis caused by carbon tetrachloride (CCl(4)) in rats and further explores the underlying mechanisms. We hypothesize that curcumin might protect the liver from CCl(4)-caused injury and fibrogenesis by attenuating oxidative stress, suppressing inflammation, and inhibiting activation of HSC. This report demonstrates that curcumin significantly protects the liver from injury by reducing the activities of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, and by improving the histological architecture of the liver. In addition, curcumin attenuates oxidative stress by increasing the content of hepatic glutathione, leading to the reduction in the level of lipid hydroperoxide. Curcumin dramatically suppresses inflammation by reducing levels of inflammatory cytokines, including interferon-gamma, tumor necrosis factor-alpha, and interleukin-6. Furthermore, curcumin inhibits HSC activation by elevating the level of PPARgamma and reducing the abundance of platelet-derived growth factor, transforming growth factor-beta, their receptors, and type I collagen. This study demonstrates that curcumin protects the rat liver from CCl(4)-caused injury and fibrogenesis by suppressing hepatic inflammation, attenuating hepatic oxidative stress and inhibiting HSC activation. These results confirm and extend our prior in vitro observations and provide novel insights into the mechanisms of curcumin in the protection of the liver. Our results suggest that curcumin might be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis.
Because most cancers are caused by dysregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. Curcumin, a yellow coloring agent in turmeric, has been shown to interact with a wide variety of proteins and modify their expression and activity. These include inflammatory cytokines and enzymes, transcription factors, and gene products linked with cell survival, proliferation, invasion, and angiogenesis. Curcumin has been found to inhibit the proliferation of various tumor cells in culture, prevents carcinogen-induced cancers in rodents, and inhibits the growth of human tumors in xenotransplant or orthotransplant animal models either alone or in combination with chemotherapeutic agents or radiation. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy. These aspects of curcumin are discussed further in detail in this review.
Fractionation with supercritical CO(2) is employed to divide ethanolic extract (E) of B. kaoi into four fractions (R, F1, F2 and F3). To assess the selectivity of the fractionation, extracts of the four fractions were characterized in terms of the hepatoprotective capacity and activity of antioxidant enzymes to against CCl(4)-induced damage. The in vitro study revealed that pretreatment with B. kaoi extract or its fractions, except F3, significantly protected primary hepatocytes against damage by CCl(4) (P<0.05). The R and F1 fractions had the highest saikosaponins content (175 and 200 mg/g dry weight, respectively) and most effectively protected the liver from damage by CCl(4). This study demonstrated that the oral pretreatment of B. kaoi (100 and 500 mg/kg), except F3, three days before a single dose of CCl(4) (CCl(4)/olive oil=1:1, 3 ml/kg, sc) was administered significantly lowered the serum levels of hepatic enzyme markers (AST and ALT) (P<0.05). A pathological examination showed that lesions, including ballooning degeneration, necrosis, hepatitis and portal triaditis were partially healed by treatment with B. kaoi extract and fractions. Oxidative stress induced by CCl(4) led to lipid peroxidation (MDA) and changes in the levels of the antioxidant enzymes in the liver. However, all the fractions, except F3, markedly suppressed lipid peroxidation and reversed the activities of the antioxidant enzymes to the normal levels.