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UMBELLIFERONE WITH VITAMIN C MODULATES LIPID PROFILE INDICES IN DIETHYLNITROSAMINE INDUCED HEPATOCELLULAR CARCINOMA
Abstract
Umbelliferone (UMB) and v itamin C are naturally available antioxidants with the capacity to inhibit the formation of tumors in several cancer models. In the pres ent study, the authors have investigated if the combination of UMB and v itamin C had any role in lipid metabolism in d iethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) in rats. Rats were randomly distributed into 6 groups of 6 rats each. Rats in g roup 1 received standard pellet diet and served as controls. HCC was induced in Group 2 rats by providing 0.01 % DEN through drink ing water for 15 weeks. Group 3 rats received UMB via intra gastric intubation at a daily dose of (30 mg/kg body weight) + v itamin C (200 mg/kg body weight) through drinking water for 16 weeks. Group 4 rats were pretreated with UMB + v itamin C, 1 week prior to the administration of DEN and it was also continued until the end of the experiment. Group 5 rats were post - treated with UMB + v itamin C for 5 weeks after the administration of DEN for 10 weeks and further continued until the end of experiment. Group 6 rats were treated with UMB + v itamin C along with DEN for the entire 15 weeks of experimental period. DEN - induced rats showed increased levels of total cholesterol and triglycerides and decreased levels of phospholipids and free fatty acids. These changes were reversed to near normal levels in groups treated with UMB + v itamin C. The histopathological and ultra - structural studies were performed to further confirm the occurrence of apoptotic morphological changes at the cellular level.
... Bushuty and Shanshan (2006) reported that TC and TG were significantly decreased after feeding rats with ginger. Ramalingam and Vaiyapuri (2014) found that TG and TC were increased significantly after injecting rats with DEN. ...
Context:
Chronic liver damage has serious medical consequences.
Objective:
To investigate the hepatoprotective effect of dry Zingiber officinale (ginger) and its essential (volatile) oil against diethylnitrosamine (DEN) toxicity in rats.
Materials and methods:
Phenols and flavonoids components were characterized in dry ginger using HPLC-UV instrument while ginger essential oil (E.O.) was investigated via GC-MS technique. Antioxidant activity was determined in vitro. In rat model, ginger was administrated for 2 months. Lipid profile, antioxidant biomarkers, liver functions and histopathology were assessed.
Results:
Chlorogenic acid (63.85 ppm) and hesperidin (156.91 ppm) are among the major phenolic and flavonoid constituents in dry ginger. Curcumene (15.21%) and linalool (13.47%) represent the main E.O. constituents. In rats treated with ginger E.O., a significant elevation in serum HDL (31.14%) was accompanied by a decrease in LDL (55.14%). A significant decrease in serum ALT and ALP was reported (56.85% and 53.84%, respectively). Serum GSH-Px activity has significantly increased 75.06%. Meanwhile, E.O. showed anticancer potential against HepG2 cell line (IC50 = 40 µg/mL). Liver histopathological examinations confirmed the protective effect against abnormalities.
Conclusion:
Ginger was able to reduce the severity of DEN-cytotoxicity in rats, which suggests a novel antioxidant role originating from this medicinal plant.
... These results are agreement with [10]. [47] who reported that TC and TG were significantly increased after treated rats with Diethylnitrosamine (DEN). Effect of fish oil and virgin olive oil on the liver functions levels in experimental injected with den rats: The obtained results showed that feeding on ration mixed with fish oil, virgin olive oil and mixed with fish oil and virgin olive oil at concentration 5g/100g diet for 60 successive days did not induce changes in serum AST, ALT and ALP when compared with control N1 group. ...
Liver injury induced by viruses, toxic chemicals, certain drugs and environmental pollutants, has been on the increase for the past few decades and recognized as a toxicological problem. Nitrosamine compounds are known hepatic carcinogens. The present study was carried out to investigate the hepatoprotective effect of fish oil and virgin olive oil against diethylnitrosamine (DEN) intoxication in rats compared with drug (25mg/kg diet). Wister rats weighing 200 ± 5 g were induced hepatotoxicity by injection of DEN (via single intraperitoneally injection at 150 mg/kg/body weight). Rats were divided into 9 groups (n = 6) of non- hepatotoxicity, non- hepatotoxicity and treated, hepatotoxicity non-treated and hepatotoxicity treated with drug, fish oil, virgin olive oil. After 8 weeks the rats feeding with fish oil, virgin olive oil supplied to hepatotoxicity rats instead of diet significant improvement in lipid profile and liver function. However, a significantly increment in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSPx) and glutathione reduced (GSH) were observed in blood of hepatotoxicity rats treated with fish oil, virgin olive oil and mixtures. The treated groups showed a significant decrement in thiobarbituric acid reactive substances (MDA) in serum. Since the study of induction of the redox enzymes is considered to be a reliable marker for evaluating the antiperoxidative efficacy of the fish oil and virgin olive oil. Treatment with fish oil and virgin olive oil reduces the histopathological liver abnormalities associated with hepatotoxicity. Moreover to the anti hepatotoxicity effect and possess antioxidant potential that may be used for therapeutic purposes suggested. The present study showed that fish oil, virgin olive oil were able to prevent or reduce the severity of diethylnitrosamine -induced liver injury.
Context: The kidney plays a central role in detoxification and excretion of toxic metabolites, and therefore, is susceptible to toxicity by xenobiotics.
Objective: To investigate the protective effect of Rosmarinus officinalis (rosemary) powder and its essential (volatile) oil against diethylnitrosamine (DEN)-induced renal injury in rats.
Materials and methods: Phenolic and flavonoid components were characterised in rosemary powder using HPLC-UV instrument while rosemary essential oil (E.O) was investigated via GC-MS technique. In rat model, rosemary was administrated orally (in diet) for two months. Lipid profile, antioxidant biomarkers, kidney functions and histopathological examinations were assessed.
Results: Hesperidin (4878.88 ppm) and ellagic acid (403.57 ppm) are among the major phenolic and flavonoid constituents in rosemary powder. Camphor (18.36%) and α-pinene (12.74%) represent the main E.O active ingredients. Rats treated with rosemary E.O showed a significant elevation in serum HDL (28.28%) accompanied by a decrease in LDL (115.47%). A significant decrease in serum creatinine and urea was also reported (69.72 and 109.89%, respectively). Moreover, serum glutathione peroxidise (GSH-Px) activity has been significantly increased. Kidney histopathological examinations confirmed the protective effect against DEN-induced abnormalities.
Conclusion: Rosemary (powder/E.O) was able to reduce or even prevent the severity of diethylnitrosamine-induced renal dysfunction.
Nanotechnology is a multidisciplinary field that covers a vast and diverse array of devices and machines derived from engineering, physics, materials science, chemistry and biology. These devices have found applications in biomedical sciences, such as targeted drug delivery, bio-imaging, sensing and diagnosis of pathologies at early stages. In these applications, nano-devices typically interface with the plasma membrane of cells. On the other hand, naturally occurring nanostructures in biology have been a source of inspiration for new nanotechnological designs and hybrid nanostructures made of biological and non-biological, organic and inorganic building blocks. Lipids, with their amphiphilicity, diversity of head and tail chemistry, and antifouling properties that block nonspecific binding to lipid-coated surfaces, provide a powerful toolbox for nanotechnology. This review discusses the progress in the emerging field of lipid nanotechnology.
Antioxidants are one of the key players in tumorigenesis, several natural and synthetic antioxidants were shown to have anticancer effects. In the present investigation the efficacy of silymarin on the antioxidant status of N-nitrosodiethylamine (NDEA) induced hepatocarcinogenesis in Wistar albino male rats were assessed. The animals were divided into five groups. The animals in the groups 1 and 3 were normal control and silymarin control, respectively. Groups 2, 4 and 5 were administered with 0.01% NDEA in drinking water for 15 weeks to induce hepatocellular carcinoma (HCC). Starting 1 week prior to NDEA administration group 4 animals were treated with silymarin in diet for 16 weeks, 10 weeks after NDEA administration group 5 animals were treated with silymarin and continued till the end of the experiment period (16 weeks). After the experimental period the body weight, relative liver weight, number of nodules, size of nodules, the levels of lipid peroxidation, glutathione (GSH), and the activities of antioxidant enzymes were assessed in both haemolysate and liver tissue. In group 2 hepatocellular carcinoma induced animals there was an increase in the number of nodules, relative liver weight. The levels of lipid peroxides were elevated with subsequent decrease in the body weight, (glutathione) GSH, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD). In contrast, silymarin + NDEA treated groups 4 and 5 animals showed a significant decrease in the number of nodules with concomitant decrease in the lipid peroxidation status. The levels of GSH and the activities of antioxidant enzymes in both haemolysate and liver were improved when compared with hepatocellular carcinoma induced group 2 animals. The electron microscopy studies were also carried out which supports the chemopreventive action of the silymarin against NDEA administration during liver cancer progression. These findings suggest that silymarin suppresses NDEA induced hepatocarcinogenesis by modulating the antioxidant defense status of the animals.
Silymarin is a naturally available bioflavonoid and is a strong antioxidant with a capacity to inhibit the formation of tumors in several cancer models. In the present study, we investigated whether dietary supplementation of silymarin has any role in lipid components, lipid-metabolizing enzymes, free fatty acid profile, and expression of cyclooxygenase-2 (COX-2) in N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma in rats. NDEA-induced rats showed severe hyperlipidemia along with upregulated expression of COX-2 as revealed by western blotting and immunohistochemistry. Dietary silymarin supplementation attenuated this hyperlipidemia and downregulated the expression of COX-2. Thus we conclude that compounds like silymarin with potent hypolipidemic effect are strong candidates as chemopreventive agents for the treatment of liver cancer.
Aim
Hepatocellular carcinoma (HCC) represents a major source of global mortality, still rising in worldwide. The present study aims at elucidating the antioxidant efficiency of umbelliferone (UMB) in N-Nitrosodiethylamine (DEN) induced rat liver carcinogenesis.
Methods
Rats were randomly divided into six groups of six rats each as follows. Rats are in group I received standard pellet diet and served as control, group II rats were induced with hepatocellular carcinoma by providing 0.01 % DEN through drinking water 15 weeks. Group III rats received umbelliferone via intragastric intubation at a daily dose of 30 mg/kg body weight for 16 weeks every day. Groups IV–VI rats received 0.01% of DEN as in group II along with umbelliferone via intragastric intubation at a daily dose of 10, 20 and 30 mg/kg body weight for throughout the experimental period of 16 weeks.
Results
DEN induction in experimental animals resulted in increased activities of liver marker enzymes and lipid peroxidation levels and decreased levels of antioxidant enzymes. Umbelliferone treatment restored the elevated activities of liver marker enzymes and antioxidant status to near-normal with decreased lipid peroxidation levels. Histological observations of liver tissue too correlated with the above biochemical findings.
Conclusion
These results clearly suggest that umbelliferone treatment prevents liver damage, lipid peroxidation and protects the antioxidant defense system in DEN-induced liver carcinogenesis in rats.
5-Fluorouracil (5-FU) is one of the widely used chemotherapeutic drugs targeting various cancers including colon cancer, but its chemoresistance remains as a major obstacle in clinical settings. Towards this goal, we evaluated the in vivo efficacy of umbelliferone (UMB) with 5-flurouracil (5-fu) against 1, 2-dimethylhydrazine (DMH) induced colon carcinogenesis in rats. Rats were divided into seven groups of six rats each. Rats in group 1 received high fat diet and served as control, group 2 rats received high fat diet with DMH (20 mg/kg body weight) once a week subcutaneously for the first 15 weeks which represent the colon cancer bearing rats. Group 3 rats received umbelliferone via intragastric injection at a daily dose of 30 mg/kg body weight for 30 weeks every day. Groups 4–7 rats received high fat diet with DMH (20 mg/kg body weight) as in group 2. In addition group 4 rats (initiation) received UMB starting 1 week before 1st DMH injection and continued till the end of last DMH injection, group 5 rats (post-initiation) received UMB after 1 week of last DMH injection and continued till the end of the experimental period, group 6 rats (Entire period) received UMB throughout the experimental period. Group 7 cancer bearing rats received 5-flurouracil (100 mg/kg body weight) once a week intravenously for first 4 weeks and UMB was given as in group 6 throughout the experimental period of 30 weeks Levels of glutathione-s-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), glutathione reductase (GR) and reduced glutathione (GSH) decreased following DMH treatment, and also the levels of lipid peroxidation end products like thiobarbituric acid substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dines (CD) were significantly decreased in DMH-treated rats. Administration of UMB alone and combined effect of UMB with 5-Fu significantly reversed these activities to near normal, which concludes the anti-carcinogenic efficacy of UMB. This effect was further confirmed by histopathological studies and finally proved that UMB as an effective and potential chemotherapeutic agent against DMH-induced colon carcinogenesis.
Alterations in lipid content and composition in the N-nitrosodiethylamine-induced hepatocarcinoma were investigated. Rats were administered with N-nitrosodiethylamine in the drinking water for 12 weeks followed by normal tap water for another 6 weeks. The cholesterol content in the liver was increased shortly after the administration of N-nitrosodiethylamine and remained elevated after the removal of the nitrosoamine from the water. The phosphatidylethanolamine level was elevated during N-nitrosodiethylamine administration with a concomitant reduction in phosphatidylcholine level. Lysophosphatidylcholine and sphingomyelin levels were increased during the last four weeks of the study. The level of phosphatidylinositol was substantially reduced after eight weeks of N-nitrosodiethylamine treatment, and remained low during the post-treatment period. We postulate that changes in lysophosphatidylcholine and sphingomyelin may be a compensatory mechanism for maintaining the asymmetrical distribution of choline-containing lipids in the outer leaflet of the membrane. The elevated level of cholesterol may be a useful indicator for the early detection of N-nitrosodiethylamine-induced hepatocarcinoma.
In this direct colorimetric procedure, serum triglycerides are hydrolyzed by lipase, and the released glycerol is assayed in a reaction catalyzed by glycerol kinase and L-alpha-glycerol-phosphate oxidase in a system that generates hydrogen peroxide. The hydrogen peroxide is monitored in the presence of horseradish peroxidase with 3,5-dichloro-2-hydroxybenzenesulfonic acid/4-aminophenazone as the chromogenic system. The high absorbance of this chromogen system at 510 nm affords useful results with a sample/reagent volume ratio as low as 1:150, and a blank sample measurement is not needed. A single, stable working reagent is used; the reaction is complete in 15 min at room temperature. The standard curve is linear for triglyceride concentrations as great as 13.6 mmol/L. Average analytical recovery of triglycerides in human sera is 100.1%, and within-run and between-run precision studies showed CVs of less than or equal to 1.6 and less than or equal to 3.0%, respectively. The method is suitable for automation.
The combined effect of cyclophosphamide and ascorbic acid on plasma lipids and lipoprotein profiles are important since, ascorbic acid encumbered the lipid abnormalities initiated by cyclophosphamide during cancer chemotherapy. Hence, the study was launched to appraise the salutary role of ascorbic acid in cyclophosphamide administered fibrosarcoma bearing rats. Fibrosarcoma cell line induced rats were treated with cyclophosphamide (10 mg/kg body weight) and ascorbic acid (200 mg/kg body weight) individually and in combination for 28 days. The concentration of plasma lipids and lipoprotein profiles were determined in control and experimental animals. The untreated, as well as cyclophosphamide administered fibrosarcoma bearing rats, divulged significantly increased levels of plasma total cholesterol, triglycerides, phospholipids, VLDL- and LDL-cholesterol, as compared with their respective control animals. In contrast, ester and HDL-cholesterol levels exhibited a marked decrease in these animals. Similar observations were also noticed in liver lipid values, as well. However, these lipid abnormalities were corrected by the co-administration of ascorbic acid. These results suggested, that some clinical entanglement of cyclophosphamide was refrained by co-administration of ascorbic acid in tumor stress condition.
A direct method for the quantitative determination of total serum cholesterol is described. The procedure consists of adding a reagent containing sulfuric acid, acetic acid, and ferric chloride to a 0.1 ml. sample of serum. The sensitivity achieved is several times that of current procedures and the time required for a single determination is in the order of minutes. Precision and reproducibility are demonstrated as well as the absorption characteristics of the purple color produced through the spectral range of 400 to 700 mμ. Finally, the method is compared with samples in which total cholesterol is determined by the Kingsley-Schaffert and Schoenheimer-Sperry procedures.
With the aim of establishing bio-indices for the development of multistep hepatotumorigenesis, rats were fed water containing 0.01% diethylnitrosamine (DEN) ad libitum for 13 weeks. This treatment with DEN only made it possible to induce hepatic tumors in 100%. After the DEN administration, several clinical symptoms were observed including minor behavioral changes, brittleness of hair and a decrease in water and food intake. The concentration of total serum protein and albumin in all treated groups was significantly lower than in non-treated controls (P<0.05). Increase of specific enzyme (AST, ALT and GGT) activity (P<0.05), variable tumor size and hepatomegaly of the liver was observed in all rats treated with DEN for 10 weeks. Both hepatocellular carcinoma and cholangiocarcinoma were found in the same livers at the same time, and were prominently developed after 12 weeks. In case of carcinoma, some of the livers showed more or less advanced states over the 12-15 weeks period. In the present study, hepatocellular carcinoma was developed by treating DEN in only the drinking water, without any other carcinogens or without partial hepatectomy. These results indicate that DEN is a new carcinogen that acts directly on it the liver, moreover, it might be very useful for investigating hepatotumorigenesis.
Although increased dietary fat or cholesterol has been reported to be a risk factor for the development of certain cancers, the effect of the serum lipid level on tumor metastasis has not been well documented. Fasting serum levels of total cholesterol (TC) and triglycerides (TG) were examined in 54 patients with superficial esophageal cancer (SEC) invading lamia musucularis or submucosal layer who underwent esophagectomy with classical lymphadenectomy. The association between lymph node metastasis and the preoperative serum lipid levels as well as the pathological findings was retrospectively analyzed. The levels of TC and TG were significantly higher in 18 node-positive than in 36 node-negative patients (TC: 205.4+/-38.9 vs. 174.5+/-26.8 mg/dl, P<0.01; TG: 152.0+/-68.5 vs. 88.7+/-28.6 mg/dl, P<0.001). Patients with hypercholesterolemia (TC >/= 220 mg/dl) and hypertriglyceridemia (TG >/= 150 mg/dl) showed extremely high rates of nodal metastasis (80 and 91%, respectively), that were significantly higher than those of patients with normal lipid levels (P<0.01 and P<0.001). When hyperlipidemia was defined as the presence of either hypertriglyceridemia or hypercholesterolemia, hyperlipidemia was an independent risk factor for nodal metastasis in SEC. Elevated serum lipid levels might bring favorable circumstances for the development of lymph node metastasis in the early stage of EC. Hyperlipidemia might prompt us to perform more studies to investigate possible metastasis.
1. 1. A method is presented in which plasma phospholipids can be determined in 0.2 ml. of plasma. 2. 2. The method is simpler and more rapid than methods involving the use of fat solvents. 3. 3. In addition to phospholipid phosphorus, the method lends itself to the determination of inorganic plasma phosphate.
The objective of the study was to investigate the role of Umbelliferone (UMB) on lipid peroxidation, nonenzymic and enzymic antioxidants in the plasma and liver of streptozotocin (STZ)-induced diabetic rats. Adult male albino rats of Wistar strain, weighing 180-200 g, were induced diabetes by administration of STZ (40 mg/kg b.wt.) intraperitoneally. The normal and diabetic rats were treated with UMB (30 mg/kg b.wt.) dissolved in 10% dimethyl sulfoxide (DMSO) for 45 days. Diabetic rats had an elevation in the levels of lipid peroxidation markers (thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (HP) and conjugated dienes (CD)), and a reduction in nonenzymic antioxidants (vitamin C and reduced glutathione (GSH) except vitamin E in the plasma and liver, and enzymic antioxidants (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in the liver. Decreased level of beta-carotene and increased level of ceruloplasmin (Cp) were observed in the plasma of diabetic rats. Treatment with UMB and glibenclamide brought back lipid peroxidation markers, nonenzymic and enzymic antioxidants to near normalcy. Since UMB treatment decreases lipid peroxidation markers and enhances antioxidants' status it can be considered as a potent antioxidant.
The aim of the study was to evaluate blood glucose and lipid lowering effects of Umbelliferone (UMB) in streptozotocin (STZ) diabetic rats. Male albino Wistar rats (180 to 200 g) were induced diabetes by administration of STZ (40 mg/kg) intraperitonially. Normal and diabetic rats were treated with UMB in 10 percent dimethyl sulfoxide (DMSO) for 45 days. Diabetic rats had increased plasma glucose and decreased insulin, total proteins (TP), and albumin in addition to decreased food intake and body weight. Elevation in total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), triglycerides (TG), free fatty acids (FFA), and phospholipids (PL), and reduction in high density lipoprotein cholesterol (HDL-C) in the plasma were observed. Liver and kidney tissues of diabetic rats had elevation in the levels of TC, TG, FFA, and PL. Treatment with UMB decreased plasma glucose and increased insulin, TP, and albumin apart from food intake and body weight. In UMB-treated diabetic rats, plasma and tissue TC, TG, PL and FFA, and plasma LDL-C, VLDL-C, and HDL-C reversed to near normal. Thus, reduction of blood glucose and lipid profiles indicates that UMB has antidiabetic and antihyperlipidemic effects in diabetic rats.
The present study was designed to investigate the antihyperglycemic effect of Umbelliferone (UMB) in normal and streptozotocin (STZ)-diabetic rats. Diabetes was induced in adult male albino rats of the Wistar strain, weighing 180-200 g, by administration of STZ (40 mg/kg of body weight) intraperitoneally. Diabetic rats showed an increase in levels of blood glucose and glycosylated hemoglobin (HbA(1c)) and activities of gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase, and a decrease in levels of plasma insulin, hemoglobin (Hb), and liver glycogen and activities of glucokinase and glucose-6-phosphate dehydrogenase. Intraperitoneal administration of UMB (10, 20, and 30 mg/kg of body weight) and glibenclamide (600 micro g/kg of body weight) in 10% dimethyl sulfoxide dissolved in water, for 45 days, produced significantly decreased levels of blood glucose and HbA(1c) and activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase, while elevating levels of plasma insulin, Hb, and liver glycogen and activities of glucokinase and glucose-6-phosphate dehydrogenase to near normal levels in STZ-diabetic rats when compared with normal control rats. Normal rats treated with UMB (30 mg/kg of body weight) also showed a significant effect on glycemic control. Thus, our results show that UMB at 30 mg/kg of body weight possesses a promising antihyperglycemic effect that is comparable with glibenclamide.
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