isoquercitrin and Body-Weight

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Antioxidants; Body Weight; Cell Differentiation; Hippocampus; Lipopolysaccharides; Male; Oligodendroglia; Rats; Rats, Sprague-Dawley

alpha-Glycosyl Isoquercitrin (AGIQ), is used in Japan as a food additive and was granted generally recognized as safe (GRAS) status in 2005 (FEMA) and 2007 (FDA). The safety and toxicity information for AGIQ is sparse and therefore, the carcinogenicity potential of AGIQ was examined in the CByB6F1-Tg(HRAS)2Jic (rasH2) model. One hundred female and male rasH2 mice, each, were allocated to one of four designated dose groups; 0 (control)%, 1.5%, 3.0% or 5.0% AGIQ. Animals were administered the diets for six months and an additional 10 females and 10 males, each, were administered a positive control, N-methyl-N-nitrosourea (MNU). Body weights and clinical observations were collected. A full screen necropsy, organ weights, clinical chemistry, urinalysis and histopathology were performed. The positive control animals elicited appropriate responses specific to this strain (rasH2) of mice. There were statistically significant sporadic non-dose-dependent changes in clinical chemistries without corresponding pathological correlation. No microscopic AGIQ-related findings were noted; the range of pathology observations were all considered background findings, either specific to rasH2 mice or common to inbred strains of mice. Therefore, under the study conditions, the no-observed-adverse-effect level (NOAEL) was determined to be more than 5.0% (7215.4 mg/kg BW/day in male mice and 14685.5 mg/kg/day in female mice).

Topics: Animals; Body Weight; Carcinogenicity Tests; Dose-Response Relationship, Drug; Feeding Behavior; Female; Food Additives; Male; Methylnitrosourea; Mice; Mice, Transgenic; No-Observed-Adverse-Effect Level; Organ Size; Quercetin

Flavonoids such as quercetin and its glycoside Isoquercitrin and are abundantly present in the diet and have various pharmacological effects. However, limited data about its potential toxicity is available. In this study, we aim to evaluate the subchronic toxicity of the isoquercitrin-γ-cyclodextrin (IQC-γCD) molecular inclusion complex (SunActive® QCD/EN) in Sprague-Dawley (SD) rats. The IQC-γCD was administrated orally to 40 male and 40 female SD rats at dietary doses up to 5.0 % for 13 consecutive weeks. During the experiment periods, the general clinical signs, mortality, hematological, urinalysis values, biochemical, and histopathological parameters were examined. All animals survived until the scheduled necropsy, and no statistically significant or clinical sign of toxicologically relevant differences including pathology parameters, and histopathological endpoints were observed in any of the IQC-γCD treatment groups, compared with the control group. However, certain observations were noted in the male rats treated with the highest concentration (5.0 %), but these were not seen in female rats. A slight inhibition of weight gain was observed, probably linked to a fall in red blood cells, and hematocrit index in female rats. Statistically significant changes were noted in some clinical measures, such as plasma bilirubin level, alkaline phosphatase total bile acid without evidence of systemic clinical toxicity. The results support no observed adverse effect level (NOAEL) of IQC-γCD of 5.0 % in the diet for males (3338.55 mg/kg/day), and 3.0 % in the diet for females (2177.33 mg/kg/day) SD rats. Therefore, in this 13 weeks repeated-dose SD rat study there were no treatment-related adverse clinical or pathological findings for IQC-γCD of 5.0 % in the diet for males, and 3.0 % in the diet for females SD rats. The results of the present study support the safe use of IQC-γCD as a functional food, food additive, and natural ingredient.

Topics: Alkaline Phosphatase; Animals; Body Weight; Female; gamma-Cyclodextrins; Male; No-Observed-Adverse-Effect Level; Organ Size; Quercetin; Rats, Sprague-Dawley; Sex Factors; Toxicity Tests, Subchronic

Administration of the diuretic, spironolactone (SR), can inhibit chronic liver diseases. We determined the effects of SR alone or in combination with the antioxidant α-glycosyl isoquercitrin (AGIQ) on hyperlipidemia- and steatosis-related precancerous lesions in high-fat diet (HFD)-fed rats subjected to a two-stage hepatocarcinogenesis model. Rats were fed with control basal diet or HFD, which was administered with SR alone or in combination with an antioxidant AGIQ in drinking water. An HFD increased body weight, intra-abdominal fat (adipose) tissue weight, and plasma lipids, which were reduced by coadministration of SR and AGIQ. SR and AGIQ coadministration also reduced hepatic steatosis and preneoplastic glutathione S-transferase placental form-positive foci, in association with decrease in NADPH oxidase (NOX) subunit p22phox-positive cells and an increase in active-caspase-3-positive cells in the foci. Hepatic gene expression analysis revealed that the coadministration of SR and AGIQ altered mRNA levels of lipogenic enzymes ( Scd1 and Fasn), antioxidant-related enzymes ( Catalase), NOX component ( P67phox), and anti-inflammatory transcriptional factor ( Pparg). Our results indicated that SR in combination with AGIQ had the potential of suppressing hyperlipidemia- and steatosis-related early hepatocarcinogenesis through the reduced expression of NOX subunits.

Topics: Animals; Body Weight; Diet, High-Fat; Drug Therapy, Combination; Fatty Liver; Liver Neoplasms, Experimental; Male; NADPH Oxidases; Organ Size; Oxidative Stress; Precancerous Conditions; Quercetin; Rats, Inbred F344; Spironolactone

Glycosylation of natural flavonoids with various sugar moieties can affect their physicochemical and pharmacological properties. In this study, the plant flavonoids quercetin aglycon (Quer) and quercetin 3-O-glucoside (Q3G) were evaluated and compared for their potential anti-obesity effects. The Q3G dose-dependently reduced the TG contents and lipid accumulation in 3T3-L1 adipocyte cells, by 52% and 60% at 20μM, respectively, compared to differentiated control (100%), which were 1.6-fold and 2.4-fold higher reduction than Quer. The Q3G (20μM) also more significantly reduced the expression of adipogenic markers such as C/EBP-β, C/EBP-α, PPAR-γ, and aP2 than Quer, indicating that the Q3G suppresses both adipocyte differentiation and lipogenesis more effectively than Quer in vitro. Comparing to those in the high-fat diet (HFD) fed mice control group for 10 weeks, both the body and liver weights and the size of adipocytes in epididymal adipose tissues were significantly reduced in HFD mice fed with Q3G for another 6 weeks (30mg/kg body weight by oral administration), accompanied by the reductions of TG, total cholesterol, and HDL-cholesterol in serum. The Q3G also reduced the levels of the lipid metabolism-associated proteins, PPAR-γ, SREBP-1c, and FAS in the liver tissues. These results clearly demonstrated that Q3G exhibits a stronger anti-obesity effect than Quer and its anti-obesity effect is mediated via inhibition of adipocyte differentiation and lipogenesis, decreasing serum lipid levels by altering hepatic lipid metabolism, and reducing body weight gain. The results of this study suggest that the Q3G, but not Quer, can be a potent functional ingredient of beneficial health foods or a therapeutic agent to prevent or treat obesity.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Biomarkers; Body Weight; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-beta; Cell Differentiation; Cell Survival; Diet, High-Fat; Dyslipidemias; Glycosylation; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Obesity; PPAR gamma; Quercetin

alpha-Glycosyl isoquercitrin (AGIQ) is highly absorbable and has been shown to possess antioxidative properties. Based on a favorable safety profile, it has been confirmed as generally recognized as safe (GRAS) compound by the FDA. Nevertheless, safety and toxicity information for AGIQ is still sparse. Therefore, the aim of this study was to test the safety and toxicokinetics of AGIQ in a 90-day study in 60 male and 60 female Sprague-Dawley rats at dietary doses up to 5%. All animals survived until scheduled euthanasia with no clinical signs of toxicity in any animal. AGIQ was rapidly absorbed with metabolism to quercetin and quercetin glucuronide at all dose levels. Statistically significant changes were noted in some tissue weights and clinical chemistry analytes, without evidence of systemic toxicity. The most prominent finding was systemic dose dependent yellow discoloration of bones of treated animals. However, no changes were observed microscopically, and this observation was concluded as toxicologically insignificant. The overall lack of adverse clinical signs, changes in body weight, feed consumption, clinical pathology parameters, and histopathological endpoints in animals administered AGIQ supports no observable adverse effect levels (NOAEL) of 5.0% in diet for both male and female rats (3461 mg/kg/day and 3867 mg/kg/day, respectively).

Topics: Administration, Oral; Animals; Body Weight; Dose-Response Relationship, Drug; Female; Glycosides; Hematologic Tests; Male; Motor Activity; Organ Size; Quercetin; Rats; Rats, Sprague-Dawley; Toxicokinetics

The aim was to investigate both individual and synergistic effects of quercetin-3-O-β-glucoside (Q3G) and fructooligosaccharide (FOS) on indices of metabolic syndrome and plasma total cholesterol level with potential mechanisms of action.. Five groups of rats were fed a dextrin-based diet as the normal reference group, or sucrose-based (S) diets with 0.3% Q3G, 5% FOS, or 0.3% Q3G + 5% FOS (Q3G + FOS) for 48 days. Oral glucose tolerance tests (OGTTs) were conducted on days 0, 14, 28, and 45, and adipose tissue and aortic blood were collected on day 48. Effects of Q3G and FOS on portal GLP-1 secretion were separately examined using rats after ileal administration.. Abdominal fat weight reduced in FOS-fed groups. Blood glucose levels of the Q3G + FOS group at 60 min in OGTT and HOMA-IR (0.25 ± 0.03 vs 0.83 ± 0.12 on day 45) were clearly lower in the Q3G + FOS group than in S group throughout the experimental period. Muscle Akt phosphorylation was enhanced only in the Q3G group. The plasma quercetin was largely increased by FOS feeding on day 48 (18.37 ± 1.20 with FOS, 2.02 ± 0.30 without FOS). Plasma total cholesterol levels in the Q3G + FOS group (3.10 ± 0.12, P < 0.05 on day 45) were clearly suppressed compared to the S group (4.03 ± 0.18). GLP-1 secretion was enhanced in Q3G + FOS group than in Q3G or FOS group.. Q3G + FOS diet improved glucose tolerance, insulin sensitivity, and total cholesterol level with increasing GLP-1 secretion and a higher level of blood quercetin. Q3G + FOS may reduce the risk of T2DM.

Topics: Absorption; Animals; Blood Glucose; Body Weight; Cecum; Cholesterol; Diabetes Mellitus, Type 2; Diet; Flavonoids; Fructose; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hydrogen-Ion Concentration; Insulin Resistance; Male; Oligosaccharides; Phosphorylation; Proto-Oncogene Proteins c-akt; Quercetin; Rats; Rats, Wistar; Sucrose

Laetia suaveolens, known as "casinga-cheirosa", crude extract EB719 has previously shown cytotoxic activity against prostate cancer and squamous cell carcinoma. For the first time, seven molecules were isolated from its apolar-α-tocopherol (1) and sitosterol (2)-and polar-3-O-caffeoylquinic acid (3), 4-O-caffeoylquinic acid (4), 5-O-feruloylquinic acid (5), hyperoside (6), and isoquercitrin (7)-fractions. Acute toxicity was determined in a two-stage experiment: (1) a reduced number of Balb-c male mice received 5000 mg/kg of EB719 to allow evaluation of general activity and other 27 parameters, plus death, up to the establishment of non-lethal dose (NLD), as well as lethal dose 50% (LD50); (2) NLD was administered and diazepam introduced as reference drug. EB719 showed LD50=178.0 mg/kg, and NLD 156.3 mg/kg. In stage one EB719 did not influence general activity, but provoked impairment in grasp reflexes, tail squeeze and breathing; piloerection and cyanosis were increased. In stage two, alterations occurred in auricular reflex, piloerection and breathing after diazepam administration, but not in response to EB719. Intestinal hemorrhage caused by local bleeding was observed after necropsy, and may be the main cause of animals' death other than a systemic effect of the extract. Although the isolated compounds are biologically and pharmacologically active in both men and animal systems, it is premature to relate their occurrence in EB719 to the observed intestine hemorrhage in mice.

Topics: alpha-Tocopherol; Animals; Body Weight; Diazepam; Gastrointestinal Hemorrhage; Humans; Lethal Dose 50; Male; Mice; Mice, Inbred BALB C; Organ Size; Piloerection; Plant Extracts; Quercetin; Quinic Acid; Respiration; Salicaceae; Sitosterols

The present study investigated the effects of a flavonoid extract from Cynomorium songaricum on the swimming endurance of rats by measuring changes of free radical scavenging enzymes, such as CuZn-SOD (copper, zinc-superoxide dismutase) and GSH-px (glutathione peroxidase), and body weights. Significant and dose-dependent antioxidant and anti-fatigue effects of flavonoids (rutin, catechin and isoquercitrin) on swimming rats were observed during 10 days of swimming exercise. After treatment with the flavonoid extract at doses of 0.5, 1.0, and 2.0 g/kg body weight, the CuZn-SOD and GSH-px activities in swimming rats were increased by 1.4%, 3.3%, 4.1% and 112.2%, 208.7%, 261.7%, respectively, while the levels of MDA (malondialdehyde) were decreased by 64.7%, 79.4%, and 86.4% respectively. Furthermore, the average body weight and the total swimming time were increased by 3.1%, 8.8%, 10.6%, and 7.7%, 34.5%, 61.5%, respectively. Our experimental results suggest that flavonoid supplementation could not only reduce free radical formation and scavenge free radicals, but also enhance endurance exercise performance by reducing muscle fatigue.

Topics: Animals; Antioxidants; Body Weight; Catechin; Cynomorium; Dose-Response Relationship, Drug; Flavonoids; Glutathione Peroxidase; Male; Muscle Fatigue; Physical Conditioning, Animal; Physical Endurance; Plant Extracts; Plant Stems; Quercetin; Rats; Rats, Wistar; Rutin; Superoxide Dismutase; Swimming

Enzymatically modified isoquercitrin (EMIQ) is a water-soluble glycoside of quercetin produced from rutin by enzymatic treatment. We investigated the anti-hypertensive effect of orally administered EMIQ in spontaneously hypertensive rats (SHR). The systolic blood pressure (SBP) in SHR administered EMIQ at a dose of 3 and 26 mg/kg/d was significantly lower than that in the control group on d 22, 36 and 50 of administration. The effect of EMIQ (26 mg/kg/d) was higher than equimolar administration of quercetin. Diltiazem administered as a positive control also suppressed the increase in SBP. and the effect was stronger than that of EMIQ. In the control group, the mean values of mean blood pressure (MBP) and diastolic blood pressure (DBP) were increased after the start of administration. Although diltiazem suppressed the increase in MBP, no significant changes were observed in the EMIQ groups. Compared with the control group, EMIQ groups showed the incidental changes of MBP and heart rate on day 22 of administration only. These results indicate that EMIQ suppressed the increase in SBP in SHR dose-dependently, and was more effective than the aglycone quercetin. It was also speculated that EMIQ showed higher anti-hypertensive effect than quercetin due to the high bioavailability, and the mechanism of SBP suppression is possibly through the improvement of endothelial NO production. In conclusion, our results suggest that EMIQ shows possibility as a naturally-derived safe food material which has an antihypertensive effect.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Diltiazem; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Male; Quercetin; Rats; Rats, Inbred SHR; Time Factors

The subchronic toxicity of enzymatically decomposed rutin, which consists mainly of isoquercitrin, was investigated in male and female Wistar rats with dietary administration at concentrations of 0, 0.2, 1 and 5% for 13 weeks. No mortality or abnormal clinical signs were observed throughout the experimental period in any groups. Body weight gain was reduced from week 10 to the end of the experiment in the 5% dosed males as compared to the 0% controls. Decreased erythrocytic parameters, i.e. red blood cell count, hemoglobin concentration and hematocrit, and significantly lowered serum triglyceride levels were also detected in the 5% males. Organ weight measurement, macro and microscopic observation revealed no test substance-related toxicological changes. Based on the above findings, no-observed-adverse-effect levels (NOAELs) for male and female rats were estimated to be 1 and 5%, respectively, translating into 539 and 3227 mg/kg b.w./day.

Topics: Animals; Body Weight; Diet; Erythrocyte Indices; Female; Food Additives; Male; No-Observed-Adverse-Effect Level; Quercetin; Rats; Rats, Wistar; Rutin; Specific Pathogen-Free Organisms; Triglycerides