morin and Body-Weight

Organ toxicity limits the therapeutic efficacy of methotrexate (MTX), an anti-metabolite therapeutic that is frequently used as an anti-cancer and immunosuppressive medicine. Hepatocellular toxicity is among the most severe side effects of long-term MTX use. The present study unveils new confirmations as regards the remedial effects of morin on MTX-induced hepatocellular injury through regulation of oxidative stress, apoptosis and MAPK signaling.. Rats were subjected to oral treatment of morin (50 and 100 mg/kg body weight) for 10 days. Hepatotoxicity was induced by single intraperitoneal injection of MTX (20 mg/kg body weight) on the 5th day. MTX related hepatic injury was associated with increased MDA while decreased GSH levels, the activities of endogen antioxidants (glutathione peroxidase, superoxide dismutase and catalase) and mRNA levels of HO-1 and Nrf2 in the hepatic tissue. MTX treatment also resulted in apoptosis in the liver tissue via increasing mRNA transcript levels of Bax, caspase-3, Apaf-1 and downregulation of Bcl-2. Conversely, treatment with morin at different doses (50 and 100 mg/kg) considerably mitigated MTX-induced oxidative stress and apoptosis in the liver tissue. Morin also mitigated MTX-induced increases of ALT, ALP and AST levels, downregulated mRNA expressions of matrix metalloproteinases (MMP-2 and MMP-9), MAPK14 and MAPK15, JNK, Akt2 and FOXO1 genes.. According to the findings of this study, morin may be a potential way to shield the liver tissue from the oxidative damage and apoptosis.

Topics: Animals; Antioxidants; bcl-2-Associated X Protein; Body Weight; Caspase 3; Chemical and Drug Induced Liver Injury; Flavonoids; Liver; Methotrexate; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Wistar; Signal Transduction

This study investigated the effect of morin, a flavonoid, on dexamethasone-induced muscle atrophy in C57BL/6J female mice. Dexamethasone (10 mg/kg body weight) for 10 days significantly reduced body weight, gastrocnemius and tibialis anterior muscle mass, and muscle protein in mice. Dexamethasone significantly upregulated muscle atrophy-associated ubiquitin ligases, including atrogin-1 and MuRF-1, and the upstream transcription factors FoxO3a and Klf15. Additionally, dexamethasone significantly induced the expression of oxidative stress-sensitive ubiquitin ligase Cbl-b and the accumulation of the oxidative stress markers malondialdehyde and advanced protein oxidation products in both the plasma and skeletal muscle samples. Intriguingly, morin treatment (20 mg/kg body weight) for 17 days effectively attenuated the loss of muscle mass and muscle protein and suppressed the expression of ubiquitin ligases while reducing the expression of upstream transcriptional factors. Therefore, morin might act as a potential therapeutic agent to attenuate muscle atrophy by modulating atrophy-inducing genes and preventing oxidative stress.

Topics: Animals; Body Weight; Dexamethasone; Female; Flavones; Malondialdehyde; Mice; Mice, Inbred C57BL; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Oxidative Stress; Tripartite Motif Proteins; Ubiquitin-Protein Ligases

Cachexia, observed in most cancer patients, is a syndrome that includes wasting of bodily energy reserves and is characterized by muscle atrophy and fat loss. We have previously demonstrated that isoflavones, such as genistein and daidzein, prevent muscle wasting in tumor-bearing mice. In this study, we examined the effect of morin, a flavonoid, on cachexia. The wet weight and myofiber size of muscles in Lewis lung carcinoma (LLC) cell-bearing mice fed a normal diet were decreased, compared with those in control mice fed a normal diet. In contrast, intake of morin prevented the reduction of muscle wet weight and myofiber size. Moreover, the tumor weight in mice fed the morin diet was lower than that in mice fed the normal diet. Both cell viability and protein synthetic ability of LLC cells were reduced by treatment with morin, but C2C12 myotubes were not affected. Binding assay using morin-conjugated magnetic beads identified ribosomal protein S10 (RPS10) as a target protein of morin. Consistent with the result of morin treatment, knockdown of RPS10 suppressed LLC cell viability. These results suggest that morin indirectly prevents muscle wasting induced by cancer cachexia by suppressing cancer growth via binding to RPS10.

Topics: Animals; Body Weight; Cachexia; Carcinoma, Lewis Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Diet; Flavonoids; Male; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Muscle, Skeletal; Organ Size; Protein Binding; Protein Biosynthesis; Ribosomal Proteins

Targeting tumor metabolism by natural products is a novel approach and provides rationale for anti-cancer drug discovery. The present study aims to explore the impact of morin and/or esculetin on c-myc induced energy metabolism in 1,2-dimethylhydrazine (DMH) induced colon cancer in rats. In order to achieve this aim we analyzed the expression of glucose and glutamine transporters and the key enzymes of glycolytic pathway besides the markers of neoplastic changes viz., mucin depleted foci (MDF), beta catenin accumulated crypts (BCAC), and markers of cell proliferation viz., proliferating cell nuclear antigen (PCNA), argyrophilic nucleolar antigen (AgNOR), c-myc, c-jun and c-fos. All the parameters tested in the present study are highly influenced by the phytochemicals morin and/or esculetin in a way to prevent colon carcinogenesis. Morin and/or esculetin supplementation effectively targets tumor metabolism via β-cateinin/c-myc signaling and affects glycolysis and glutaminolysis to abrogate colon cancer in rats. The anti-cancer effect of morin is more pronounced than esculetin. The effect obtained through the combined treatment of morin and esculetin is comparable to that of individual supplementation of morin and there is no synergistic effect. Overall individual supplementation of morin scores well as a potential anticancer agent targeting glycolysis and glutaminolysis in colon cancer.

Topics: 1,2-Dimethylhydrazine; Animals; Anticarcinogenic Agents; beta Catenin; Body Weight; Carcinogenesis; Cell Proliferation; Colon; Colonic Neoplasms; Energy Metabolism; Flavonoids; Glycolysis; Male; Proto-Oncogene Proteins c-myc; Rats; Rats, Wistar; Signal Transduction; Survival Rate; Tumor Burden; Umbelliferones

Endothelial dysfunction is a critical factor during the initiation of diabetic cardiovascular complications. Polyphenols may represent beneficial dietary components eliciting cardiovascular protection. Although we previously reported that the polyphenol morin (MO) ameliorated diabetes-induced endothelial dysfunction, the underlying mechanism remains unclear. Here, we investigated protective effects and mechanisms of MO in streptozotocin STZ induced diabetic aorta endothelial dysfunction.. Diabetes was induced by tail vein injection of STZ (200 mg/kg). At 12 wk after injection, the thoracic aorta was isolated and endothelial function was assessed by acetylcholine (ACh) induced, endothelial-dependent vasorelaxation in aortas. Nitric oxide (NO) levels and endothelial NO synthase (eNOS), phosphorylated-eNOS (p-eNOS), Akt, and phosphorylated-Akt (p-Akt) levels were also evaluated in aortas. Diabetic aortas showed attenuated endothelial function, which was improved by MO treatment. MO treatment alone increased NO levels and endothelial-dependent relaxation responses via Akt signaling, although ACh did not activate this pathway. Moreover, MO upregulated p-Akt (at Ser473 and Thr308) and p-eNOS (at Ser1177) expression in diabetic aortas, but ACh stimulation had no effect on p-Akt and p-eNOS levels.. These results indicate a novel role for MO in protection against endothelial dysfunction in diabetes. The protective effects of MO are dependent on Akt-dependent activation of eNOS signaling.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Body Weight; Diabetes Mellitus, Experimental; Dietary Supplements; Endothelium, Vascular; Flavonoids; Male; Mice; Nitric Oxide; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-akt; Streptozocin; Vasodilation

Diabetes-induced damages in brain are known as diabetic encephalopathy, which is well characterized by cellular, molecular and functional changes in the brain of diabetic subjects and rodents. However, little is known about the mechanism of damages and the therapeutic strategies in ameliorating those damages in the diabetic brain. In this study, we utilized a flavonoid, morin which is emerging as a potent drug against a wide range of free radical-mediated as well as neurodegenerative diseases. Morin (15 and 30 mg/kg body weight/day) was orally administered to two different groups of rats after 1 week of diabetes induction, and continued for five consecutive weeks. Two other untreated groups of diabetic and non-diabetic rats were used to compare with drug-treated groups. After drug treatments, cerebral cortex of the brain harvested and analyzed for different factors. Morin supplementation especially at high dose increased the levels of insulin, reduced glutathione, superoxide dismutase and catalase activities, and decreased fasting glucose and thiobarbituric acid reactive substances in the diabetic brain compared to untreated diabetic rats (P < 0.05). Morin also significantly decreased the level of inflammatory markers (TNFα, IL1β, IL-6) in the diabetic brain compared to untreated diabetic rats. Furthermore, the drug influenced an increase in the level of neurotrophic factors (BDNF, NGF and IGF-1) in the diabetic brain compared to untreated diabetic rats (P < 0.05). Thus, our results indicate a beneficial effect of morin by decreasing oxidative stress, inflammation and increasing the neurotrophic support in the diabetic brain, which may ameliorate diabetic encephalopathy.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Brain; Catalase; Cytokines; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Flavonoids; Glutathione; Inflammation; Male; Nerve Growth Factors; Oxidative Stress; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Phytonutrients reportedly extend the life span of Caenorhabditis elegans, Drosophila, and mice. We tested extracts of blueberry, pomegranate, green and black tea, cinnamon, sesame, and French maritime pine bark (Pycnogenol and taxifolin), as well as curcumin, morin, and quercetin for their effects on the life span of mice. While many of these phytonutrients reportedly extend the life span of model organisms, we found no significant effect on the life span of male F1 hybrid mice, even though the dosages used reportedly produce defined therapeutic end points in mice. The compounds were fed beginning at 12 months of age. The control and treatment groups were iso-caloric with respect to one another. A 40% calorically restricted and other groups not reported here did experience life span extension. Body weights were un-changed relative to controls for all but two supplemented groups, indicating most supplements did not change energy absorption or utilization. Tea extracts with morin decreased weight, whereas quercetin, taxifolin, and Pycnogenol together increased weight. These changes may be due to altered locomotion or fatty acid biosynthesis. Published reports of murine life span extension using curcumin or tea components may have resulted from induced caloric restriction. Together, our results do not support the idea that isolated phytonutrient anti-oxidants and anti-inflammatories are potential longevity therapeutics, even though consumption of whole fruits and vegetables is associated with enhanced health span and life span.

Topics: Animals; Blueberry Plants; Body Weight; Cinnamomum zeylanicum; Crosses, Genetic; Curcumin; Feeding Behavior; Female; Flavonoids; Flavonols; Hybridization, Genetic; Longevity; Lythraceae; Male; Mice; Mice, Inbred C57BL; Plant Extracts; Quercetin; Sesamum; Tea

This study was undertaken to investigate the antihypertensive and antihyperlipedimic potential of morin against deoxycorticosterone acetate (DOCA)-salt hypertensive rats.. Hypertension was induced in uninephrectomized rats (UNX) by weekly twice subcutaneous injection of DOCA (25 mg/kg) and 1% NaCl in the drinking water for six consecutive weeks. Morin (50 mg/kg) was administered to DOCA-salt rats orally using an intragastric tube daily for a period of 6 weeks.. The DOCA-salt hypertensive rats showed significant elevation in mean arterial pressure (MAP), heart rate (HR) and reduction in body weight. A significant increase in the concentrations of plasma and tissue (liver, kidney, heart, and aorta) lipids such as total cholesterol, triglycerides, free fatty acids, phospholipids, plasma low-density and very low-density lipoproteins cholesterol, and a decrease in the concentration of high-density lipoprotein cholesterol were noticed in DOCA-salt hypertensive rats. Also, the levels of urinary protein and the activity of 3-hydroxy 3-methylglutaryl coenzyme A reductase in the plasma and tissues were increased, and lecithin cholesterol acyl transferase activity in the plasma was decreased in DOCA-salt rats. Morin supplementation (50 mg/kg) throughout the experimental period restored all the above parameters significantly.. Morin has a potential role in attenuating severe hypertension and hyperlipedimia.

Topics: Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Body Weight; Cholesterol; Desoxycorticosterone; Drug Evaluation, Preclinical; Flavonoids; Heart Rate; Hydroxymethylglutaryl CoA Reductases; Hyperlipidemias; Hypertension; Hypolipidemic Agents; Kidney; Lipid Metabolism; Liver; Male; Phosphatidylcholine-Sterol O-Acyltransferase; Phytotherapy; Rats; Rats, Wistar; Sodium Chloride

Morin, a plant-derived flavonoid, has been reported to exhibit a wide range of pharmacological properties. In this study, we investigated the protective effect of morin on hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats. Oral administration of morin remarkably prevented weight loss in the body and liver from DMN and inhibited the elevation of serum alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin levels. For the evaluation of hepatic fibrosis-related factors, we investigated expressions of collagen type I, transforming growth factor beta(1) (TGF-beta(1)), and alpha-smooth muscle actin (alpha-SMA) in mRNA and protein levels. We observed that morin significantly reduced the expression of collagen type I, TGF-beta(1), and alpha-SMA on hepatic fibrosis induced by DMN. Taken together, this study demonstrated that morin showed hepatoprotective and antifibrogenic effects against DMN-induced hepatic injury. This suggests that morin may be useful in preventing the development of hepatic fibrosis and cirrhosis.

Topics: Actins; Animals; Antioxidants; Body Weight; Collagen Type I; Dimethylnitrosamine; Flavonoids; Liver; Liver Cirrhosis; Liver Function Tests; Male; Organ Size; Phytotherapy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta1

The purpose of this study was to investigate possible beneficial effects of morin on CCl(4)-induced acute hepatotoxicity in rats. Rats received a single dose of CCl(4) (150 microL/100 g 1:1 in corn oil). Morin treatment (20 mg/kg) was given at 48, 24, and 2 h before CCl(4) administration. CCl(4) challenge elevated serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) levels, but these effects were prevented by the pretreatment of rats with morin. To identify the mechanism of protective activity of morin in CCl(4)-induced hepatotoxicity in rats, we investigated expressions of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and inducible nitric oxide (iNOS). The expressions of TNF-alpha, IL-1beta, IL-6, and iNOS were increased by CCl(4) treatment and increased expressions of those were decreased by morin. These findings suggest that morin prevents acute liver damage by inhibiting the production of TNF-alpha, IL-1beta, IL-6, and iNOS.

Topics: Acute Disease; Animals; Antioxidants; Body Weight; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Enzyme Inhibitors; Flavonoids; Inflammation; Interleukin-1beta; Interleukin-6; Liver; Male; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA; Tumor Necrosis Factor-alpha

Morin (3,5,7,2',4'-pentahydroxyflavone), a plant-derived flavonoid belonging to the subclass of flavonol is believed to play a role in chemoprevention and cancer chemotherapy. In this study, we found that the cotreatment of morin (500 ppm in diet) for 16 weeks to N-nitosodiethylamine-induced (200 mg/kg bodyweight in drinking water) rats provides protection against the oxidative stress caused by the carcinogen and thereby prevents hepatocellular carcinogenesis. On administration of the carcinogen, the level of lipid peroxidation increased markedly, but was found to be significantly lowered by morin treatment. On the contrary, the antioxidant levels in both liver and serum were decreased in carcinogen-administered animals, which was improved to normalcy upon morin administration. Cotreatment with morin prevented the elevation of marker enzymes induced by N-nitrosodiethylamine. The body weight of the animals decreased and their relative liver weight increased significantly on N-nitrosodiethylamine administration when compared to control group. However, cotreatment with morin significantly prevented the decrease of the body weight and increase in relative liver weight caused by DEN. Histological observations of liver tissue too correlated with the biochemical observations. In conclusion, these findings indicate that morin prevents lipid peroxidation, hepatic cell damage and protects the antioxidant system in N-nitrosodiethylamine-induced hepatocellular carcinogenesis.

Topics: alpha-Fetoproteins; Animals; Antioxidants; Body Weight; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Diethylnitrosamine; Enzymes; Flavonoids; Hydroxyl Radical; Lipid Peroxides; Liver; Liver Neoplasms, Experimental; Male; Organ Size; Rats; Rats, Wistar; Superoxide Dismutase

A subchronic toxicity study of a flavonoid morin was performed in both sexes of F344 rats with dietary administration at concentrations of 0%, 0.625%, 1.25%, 2.5% and 5% (w/w) for 13 weeks. No mortality or abnormal clinical signs were observed throughout the experimental period in any group. Although a slight tendency for increase in food intake was noted in both sexes of the 2.5% and 5.0% groups, slight non-significant body weight decrease was observed in 5.0% males. Significant increases in alanine transaminase (ALT; over 2.5%), alkali phosphatase (ALP; 1.25% and 5.0%) and relative liver weights (1.25% and 2.5%) in males and in gamma-glutamyl transpeptidase (gamma-GT), aspartate transaminase (AST), ALT, relative liver weights in the 2.5% and 5.0% females and ALP in 5.0% females were noted. Increased urea nitrogen and relative kidney weights at dose of 1.25% and above and creatinine at 5.0% were observed also in females. On histopathological observation, hepatocyte hypertrophy was detected in 3 of 10 5.0% females. Based on the above findings, the no-observed-adverse-effect level (NOAEL) for both sexes was estimated to be 0.625% (299 and 356 mg/kg b.w./day for males and females, respectively).

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antioxidants; Aspartate Aminotransferases; Body Weight; Diet; Eating; Female; Flavonoids; gamma-Glutamyltransferase; Kidney; Liver; Male; Organ Size; Rats; Rats, Inbred F344; Sex Characteristics

Male Wistar rats were fed a high fat diet (HFD) containing 2.5% cholesterol and 16% lard supplemented with polyphenolic natural products namely quercetin, morin or tannic acid (100 mg/rat/day) for 4, 7 and 10 wk. Rats fed HFD without the supplements served as control. The effects of these compounds on blood lipid profiles, enzymes, liver fat and aorta of the rat were studied. In rats fed HFD containing tannic acid, plasma total cholesterol (TC), low density lipoprotein cholesterol (LDLC) and triglyceride (TG) were reduced by 33.3%, 29.6% and 65.1%, respectively, at week 10. High density lipoprotein cholesterol (HDLC) concentration was not altered. Fat deposition was also decreased in the liver of these rats. Morin significantly reduced plasma TG (65.1%) and liver fat only at week 7 while at week 10 it reduced plasma TC and LDLC by 30.9% and 29.3% respectively. The plasma HDLC concentration was increased by 47.3% at week 4 but no effect was seen at weeks 7 and 10. In the rats fed HFD containing quercetin, plasma HDLC was increased by 28.6% at week 7 but at week 10, plasma LDLC was increased by 21.2%. Quercetin did not cause any significant changes on the plasma TC, TG and liver fat at weeks 4, 7 and 10. Plasma alanine aminotransferase, alkaline phosphatase and bilirubin in control and treated groups were not significantly different. However, hepatic lipase activity in rats fed tannic acid was significantly lower. Aortae of all groups of rats showed no abnormalities. The present report indicates that tannic acid and morin are effective in reducing plasma and liver lipids when supplemented with a high fat diet in rats.

Topics: Animals; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Fats; Flavonoids; Hydrolyzable Tannins; Lipid Metabolism; Liver; Male; Organ Size; Quercetin; Rats; Rats, Inbred Strains; Reference Values; Time Factors; Triglycerides

The effects of inhibitors of arachidonic acid metabolism and antioxidants on the rat liver tumor promotion activity of phenobarbital (PB) were assessed using the enzyme-altered focus as the end-point lesion. Fischer 344 male rats were initiated with N-nitrosodiethylamine (200 mg/kg) and then divided into five groups placed on basal diet, diet containing 0.05% PB, diet containing 0.05% PB plus 0.75%, 1% or 1.5% levels of various inhibitors of arachidonic acid metabolism or antioxidants, or diet containing 1% or 1.5% inhibitors or antioxidants alone for 10 weeks, and then killed. p-Bromophenacyl bromide, an inhibitor of phospholipase A2, significantly inhibited the promotion activity of PB at dose levels of 0.75% and 1.5%, reaching plateau at 0.75%. Both quercetin, an inhibitor of lipoxygenase, and morin, a dual inhibitor of lipoxygenase-cyclooxygenase, significantly reduced the promotion activity of PB at the 1.5% but not 0.75% dose levels. Moreover, acetylsalicylic acid, an inhibitor of cyclooxygenase dose-dependently inhibited the promotion activity of PB. Among the antioxidants investigated, vitamin E did not affect, but n-propyl gallate and ethoxyquin exerted a dose-dependent inhibition of PB promotion. These results are strongly suggestive of an involvement of phospholipase A2, lipoxygenase and cyclooxygenase arachidonic acid metabolic pathways in the mechanisms underlying PB enhancement of hepatocarcinogenesis.

Topics: Acetophenones; Animals; Arachidonic Acid; Arachidonic Acids; Biomarkers, Tumor; Body Weight; Diethylnitrosamine; Ethoxyquin; Flavonoids; gamma-Glutamyltransferase; Liver; Liver Neoplasms, Experimental; Male; Organ Size; Phenobarbital; Quercetin; Rats; Rats, Inbred F344; Tetradecanoylphorbol Acetate