scholarly journals A Toxicological Evaluation of Methylliberine (Dynamine®)

2019 ◽  
Vol 2019 ◽  
pp. 1-25
Author(s):  
Timothy S. Murbach ◽  
Róbert Glávits ◽  
John R. Endres ◽  
Amy E. Clewell ◽  
Gábor Hirka ◽  
...  
Keyword(s):  
Body Weight ◽  
Micronucleus Test ◽  
Recovery Period ◽  
High Dose ◽  
Clinical Effects ◽  
Oral Toxicity ◽  
Food Ingredient ◽  
Toxicological Evaluation ◽  
Potential Health

Methylliberine (CAS 51168-26-4), a methoxiuric acid, is a caffeine metabolite present at low levels in various Coffea plants; however, very little has been published regarding this compound and we could find no toxicological data in the public domain. Therefore, we undertook the toxicological investigation of a pure, synthetic form of methylliberine in order to evaluate its potential health hazards as a food ingredient. A (1) bacterial reverse mutation test, (2) in vitro mammalian chromosomal aberration test, (3) in vivo mammalian micronucleus test, and (4) 90-day repeated-dose oral toxicity study in rats with a 28-day recovery period were conducted. No in vitro mutagenic or clastogenic activity was observed in the presence or absence of metabolic activation up to the maximum OECD recommended test concentrations. No genotoxicity was observed in the mammalian micronucleus study up to the highest dose tested of 700 mg/kg bw. In the 90-day study, methylliberine was administered to Han:WIST rats at doses of 0, 75, 112, 150, 187, and 225 mg/kg bw/day. No mortality or morbidity was observed and no toxicologically relevant clinical effects or effects on clinical pathology parameters were observed. In male animals, test item-related effects on body weight and sexual organs, which were not reversible after a 28-day recovery period without treatment, were observed in the high-dose group. Body weight development was also slightly and reversibly depressed in the 187 mg/kg bw/day male group. No toxicological effects were observed in females. The NOAEL for females was determined to be 225 mg/kg bw/day, the highest dose tested, while the NOAEL for males was determined to be 150 mg/kg bw/day. Future studies are encouraged to corroborate the safety, and assess efficacy, of methylliberine in humans.

scholarly journals A Toxicological Evaluation of Chlamydomonas reinhardtii, a Green Algae

2018 ◽  
Vol 37 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Timothy S. Murbach ◽  
Róbert Glávits ◽  
John R. Endres ◽  
Gábor Hirka ◽  
Adél Vértesi ◽  
...  
Keyword(s):  
Chlamydomonas Reinhardtii ◽  
Green Algae ◽  
Micronucleus Test ◽  
Repeated Dose ◽  
Continuous Exposure ◽  
Oral Toxicity ◽  
Food Ingredient ◽  
Toxicological Evaluation ◽  
Dose Oral

There is a current worldwide interest in developing novel sustainable nonanimal nutritional sources, and one such source is the green algae Chlamydomonas reinhardtii, the only green algae that has been studied as a model organism for many biological processes ranging from photosynthesis to flagellar movement. However, its potential as a safe nutritional source for use in various foods has not been thoroughly investigated. To assess the safety of C reinhardtii for use as a nutritional human food ingredient, in accordance with internationally accepted standards, the genotoxic potential and repeated-dose oral toxicity of the dried C reinhardtii (THN 6) algal biomass was investigated. The following studies were conducted: (1) a bacterial reverse mutation test, (2) an in vitro mammalian chromosomal aberration test, (3) an in vivo mammalian micronucleus test, and (4) a 28-day repeated-dose oral toxicity study in rats. No evidence of mutagenicity or genotoxic activity was observed in the first 3 tests under the applied test systems. In the 28-day study, male and female Hsd.Han Wistar rats were exposed to daily doses of 0, 1,000, 2,000, and 4,000 mg/kg bw by gavage. Following 28 days of continuous exposure, no mortality or treatment-related adverse effects were observed and no target organs were identified. Therefore, a no observed adverse effect level was concluded as 4,000 mg/kg bw/day, the highest dose tested.

scholarly journals A Toxicological Evaluation of a Standardized Hydrogenated Extract of Curcumin (CuroWhite™)

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Alastimmanahalli Narasimhiah Ravikumar ◽  
Joby Jacob ◽  
Sreeraj Gopi ◽  
Tumkur Subbarao Jagannath
Keyword(s):  
Test Item ◽  
Micronucleus Test ◽  
Repeated Dose ◽  
High Dose ◽  
Sprague Dawley ◽  
Oral Toxicity ◽  
Toxicological Evaluation ◽  
Chromosomal Aberration Test

A series of toxicological investigations were conducted in order to evaluate the genotoxic potential and repeated-dose oral toxicity of CuroWhite, a proprietary extract of curcumin that has been hydrogenated and standardized to not less than 25% hydrogenated curcuminoid content. All tests were conducted in general accordance with internationally accepted standards. The test item was not mutagenic in the bacterial reverse mutation test or in vitro mammalian chromosomal aberration test, and no in vivo genotoxic activity was observed in rat bone marrow in the micronucleus test. A 90-day repeated-dose study was conducted in male and female Sprague-Dawley rats. Two mortalities occurred in the main and satellite high-dose groups and were determined due to gavage error. No organ specific or other toxic effects of the test item were observed up to the maximum dose of 800 mg/kg bw/day, administered by gavage. NOAEL was, therefore, estimated as 800 mg/kg bw/day.

scholarly journals A Toxicological Evaluation of Germanium Sesquioxide (Organic Germanium)

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Robin A. Reddeman ◽  
Róbert Glávits ◽  
John R. Endres ◽  
Timothy S. Murbach ◽  
Gábor Hirka ◽  
...  
Keyword(s):  
Micronucleus Test ◽  
Germanium Dioxide ◽  
Oral Toxicity ◽  
Toxicological Evaluation ◽  
Toxicological Studies ◽  
Adverse Effect Level ◽  
Dose Oral ◽  
Chromosomal Aberration Test

A battery of OECD- and GLP-compliant toxicological studies was performed to assess the safety of a highly purified germanium sesquioxide, an organic form of the naturally occurring, nonessential trace element germanium. Germanium dioxide and germanium lactate citrate (inorganic germaniums) have been shown to induce renal toxicity, whereas germanium sesquioxide (an organic germanium) has been shown to have a more favorable safety profile. However, past toxicity studies on germanium sesquioxide compounds have not clearly stated the purity of the tested compounds. In the studies reported herein, there was no evidence of mutagenicity in a bacterial reverse mutation test or an in vitro mammalian chromosomal aberration test. There was no genotoxic activity observed in an in vivo mammalian micronucleus test at concentrations up to the limit dose of 2000 mg/kg bw/day. In a 90-day repeated-dose oral toxicity study in Han:WIST rats conducted at doses of 0, 500, 1000, and 2000 mg/kg bw/day by gavage, there were no mortalities, treatment-related adverse effects, or target organs identified. The no-observed-adverse-effect-level (NOAEL) was determined to be 2000 mg/kg bw/day.

scholarly journals A Toxicological Evaluation of Mango Leaf Extract (Mangifera indica) Containing 60% Mangiferin

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Robin A. Reddeman ◽  
Róbert Glávits ◽  
John R. Endres ◽  
Amy E. Clewell ◽  
Gábor Hirka ◽  
...  
Keyword(s):  
Leaf Extract ◽  
Micronucleus Test ◽  
Mangifera Indica ◽  
Female Rats ◽  
Oral Toxicity ◽  
Toxicological Evaluation ◽  
Male And Female Rats ◽  
Toxicological Studies

A battery of OECD- and GLP-compliant toxicological studies was performed on mango leaf extract (Mangifera indica) containing 60% mangiferin (MLE). No evidence of genotoxicity was found in a bacterial reverse mutation test (Ames). While evidence of clastogenic activity was noted in an in vitro chromosomal aberration test, an in vivo mammalian micronucleus test showed no findings up to the limit dose (2000 mg/kg bw). A 90-day repeated dose oral toxicity study was conducted in rats using doses of 0 (vehicle control), 500, 1000, and 2000 mg/kg bw/day. Based on the lack of mortality or toxic effects in the 90-day study, the NOAEL for MLE in Han:Wist male and female rats was determined to be 2000 mg/kg bw/day, the highest dose tested.

scholarly journals In Vitro Bioaccessibility of Bioactive Compounds from Citrus Pomaces and Orange Pomace Biscuits

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3480
Author(s):  
Adriana Maite Fernández-Fernández ◽  
Eduardo Dellacassa ◽  
Tiziana Nardin ◽  
Roberto Larcher ◽  
Adriana Gámbaro ◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
Total Phenol Content ◽  
No Production ◽  
Food Ingredient ◽  
Potential Health ◽  
Raw264.7 Macrophages ◽  
In Vitro Bioaccessibility ◽  
Health Promoting ◽  
Orange Pomace

The present investigation aimed to provide novel information on the chemical composition and in vitro bioaccessibility of bioactive compounds from raw citrus pomaces (mandarin varieties Clemenule and Ortanique and orange varieties Navel and Valencia). The effects of the baking process on their bioaccessibility was also assessed. Samples of pomaces and biscuits containing them as an ingredient were digested, mimicking the human enzymatic oral gastrointestinal digestion process, and the composition of the digests were analyzed. UHPLC-MS/MS results of the citrus pomaces flavonoid composition showed nobiletin, hesperidin/neohesperidin, tangeretin, heptamethoxyflavone, tetramethylscutellarein, and naringin/narirutin. The analysis of the digests indicated the bioaccessibility of compounds possessing antioxidant [6.6–11.0 mg GAE/g digest, 65.5–97.1 µmol Trolox Equivalents (TE)/g digest, and 135.5–214.8 µmol TE/g digest for total phenol content (TPC), ABTS, and ORAC-FL methods, respectively; significant reduction (p < 0.05) in Reactive Oxygen Species (ROS) formation under tert-butyl hydroperoxide (1 mM)-induced conditions in IEC-6 and CCD-18Co cells when pre-treated with concentrations 5–25 µg/mL of the digests], anti-inflammatory [significant reduction (p < 0.05) in nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages], and antidiabetic (IC50 3.97–11.42 mg/mL and 58.04–105.68 mg/mL for α-glucosidase and α-amylase inhibition capacities) properties in the citrus pomaces under study. In addition, orange pomace biscuits with the nutrition claims “no-added sugars” and “source of fiber”, as well as those with good sensory quality (6.9–6.7, scale 1–9) and potential health promoting properties, were obtained. In conclusion, the results supported the feasibility of citrus pomace as a natural sustainable source of health-promoting compounds such as flavonoids. Unfractionated orange pomace may be employed as a functional food ingredient for reducing the risk of pathophysiological processes linked to oxidative stress, inflammation, and carbohydrate metabolism, such as diabetes, among others.

scholarly journals Toxicological Evaluation of a Mixture of Astragalus membranaceus and Panax notoginseng Root Extracts (InnoSlim®)

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Timothy S. Murbach ◽  
Róbert Glávits ◽  
John R. Endres ◽  
Gábor Hirka ◽  
Adél Vértesi ◽  
...  
Keyword(s):  
Micronucleus Test ◽  
Panax Notoginseng ◽  
Astragalus Membranaceus ◽  
Human Consumption ◽  
Oral Toxicity ◽  
Toxicological Evaluation ◽  
Root Extracts ◽  
Dose Oral ◽  
History Of

Astragalus spp. and Panax spp. have a long history of traditional human use. A blend, InnoSlim®, of highly purified and fractionated root extracts from Astragalus membranaceus and Panax notoginseng has now been developed for human consumption; however, the unique constituent content of this blend has not been specifically evaluated with respect to safety. Therefore, the toxicological potential of the blend was formally investigated in a series of studies—genetic toxicity was evaluated in a bacterial reverse mutation test followed by an in vivo mammalian micronucleus test, and general toxicity was evaluated in a 28-day repeated-dose oral toxicity study in rats. No evidence of mutagenicity was observed in the bacterial tester strains used, and no evidence of in vivo chromosomal damage resulting in increased frequency of micronucleated cells was observed in male Crl:NMRI BR mice. No mortality or toxic effects were observed, and no target organs were identified, in male and female Han:WIST rats exposed to 0, 400, 800, or 1200 mg/kg bw/day of the blend by gavage for 28 consecutive days. The highest dose—1200 mg/kg bw/day—was determined to be the NOAEL. Based on these results, extrapolation towards a safe human consumption level can be explored.

scholarly journals Delving into the Antiurolithiatic Potential of Tribulus terrestris Extract Through –In Vivo Efficacy and Preclinical Safety Investigations in Wistar Rats

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jyoti Kaushik ◽  
Simran Tandon ◽  
Rishi Bhardwaj ◽  
Tanzeer Kaur ◽  
Surinder Kumar Singla ◽  
...  
Keyword(s):  
Body Weight ◽  
Aqueous Extract ◽  
Kidney Stones ◽  
Wistar Rats ◽  
Lethal Dose ◽  
Tribulus Terrestris ◽  
Oral Toxicity ◽  
Preclinical Safety

Abstract Modern treatment interventions for kidney stones are wrought with side-effects, hence the need for alternative therapies such as plant-based medicines. We have previously documented through in vitro studies that statistically optimized aqueous extract of Tribulus terrestris (Zygophyllaceae family) possesses antiurolithic and antioxidant potential. This provides strong scientific foundation to conduct in vivo efficacy and preclinical safety studies to corroborate and lend further proof to its ability to prevent and cure kidney stones. The preventive and curative urolithiatic efficacy in experimentally induced nephrolithiatic Wistar rats, along with preclinical toxicity was evaluated following oral administration of statistically optimized aqueous extract of T. terrestris. Treatment showed augmented renal function, restoration of normal renal architecture and increase in body weight. Microscopic analysis of urine revealed excretion of small sized urinary crystals, demonstrating that treatment potentially modulated the morphology of renal stones. Tissue enzymatic estimation affirmed the antioxidant efficacy of treatment with reduced free radical generation. Significant upregulation of p38MAPK at both the gene and protein level was noted in hyperoxaluric group and interestingly treatment reversed it. Acute oral toxicity study established the Median Lethal Dose (LD50) to be greater than 2000 mg/kg body weight (b.wt.) No observed adverse effect level (NOAEL) by repeated oral toxicity for 28 days at 750 mg/kg b.wt. was noted. This study lends scientific evidence to the safe, preventive and curative potential of statistically optimized aqueous extract of T. terrestris at a dose of 750 mg/kg b.wt. and suggests that the extract shows promise as a therapeutic antiurolithic agent.

scholarly journals Subchronic Oral Toxicity Study of Decitabine in Combination With Tetrahydrouridine in CD-1 Mice

2014 ◽  
Vol 33 (2) ◽  
pp. 75-85 ◽  
Author(s):  
Pramod Terse ◽  
Kory Engelke ◽  
Kenneth Chan ◽  
Yonghua Ling ◽  
Douglas Sharpnack ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Combination Therapy ◽  
Food Consumption ◽  
Blood Cells ◽  
Recovery Period ◽  
White Blood Cells ◽  
Clinical Pathology ◽  
High Dose ◽  
Severe Toxicity ◽  
Oral Toxicity

Decitabine (5-aza-2′-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and β-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on 2 consecutive days/week for up to 9 weeks followed by a 28-day recovery to support its clinical trials up to 9-week duration. Tetrahydrouridine, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. End points evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry, or urinalysis parameters. Dose- and gender-dependent changes in plasma DAC levels were observed with a Cmax within 1 hour. At the 1 mg/kg dose tested, THU increased DAC plasma concentration (∼10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high-dose 1 mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes and decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils, and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis, and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoiesis, and genotoxicity. Following the recovery period, a complete or trend toward resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity correlating with DAC plasma levels, and females are more sensitive compared to their male counterparts.

scholarly journals Validation of Cocoa Shell as a Novel Antioxidant Dietary Fiber Food Ingredient: Nutritional Value, Functional Properties, and Safety

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 773-773
Author(s):  
Miguel Rebollo-Hernanz ◽  
Silvia Cañas ◽  
Yolanda Aguilera ◽  
Vanesa Benitez ◽  
Andrea Gila-Díaz ◽  
...  
Keyword(s):  
Dietary Fiber ◽  
Functional Properties ◽  
Nutritional Value ◽  
Antioxidant Properties ◽  
Potential Candidate ◽  
Oral Toxicity ◽  
Food Ingredient ◽  
Sustainable Food ◽  
Cocoa Shell

Abstract Objectives To study the nutritional value of cocoa shell, analyzing the chemical composition and functional properties as antioxidant, hypoglycemic and hypocholesterolemic effects, as well as validate the safety of cocoa shell as a sustainable food ingredient. Methods Proximate composition was determined following the AOAC methods. Soluble and insoluble fractions of dietary fiber (DF) were determined using enzymatic-gravimetric and chemical methods. The phenolic profile was analyzed by UPLC-MS/MS and antioxidant properties were tested using ABTS. Furthermore, physicochemical, hypoglycemic, and hypocholesterolemic properties were assessed in vitro. Acute and subchronic oral toxicity experiments were performed following OECD Guidelines 452 and 408 (5 male and 5 female C57BL/6 mice per group, vehicle/cocoa shell) to assess the food safety of cocoa shell flours. Results Cocoa shell was composed of carbohydrates (62%), proteins (16%), and fat (2%). DF represents 59%, being the insoluble dietary fiber (IDF) the main fraction (82%). IDF fraction was constituted by lignin (58%) and polysaccharides (42%); cellulose was inferred as the main polysaccharide of IDF, followed by hemicelluloses (arabinans and galactans). High content of phenolic compounds (33.7 mg/g) was shown, being a significant phenolic fraction (51%) bound to DF, which confers cocoa shell its antioxidant potential (73.1 mg Trolox eq/g). The main phenolics were protocatechuic acid, (−)-epicatechin, and (+)-catechin. Cocoa shell exhibited adequate water and oil holding properties to be included in food matrices. During in vitro digestion, starch hydrolysis and dialyzed glucose diminished (34 and 13%, respectively) due to α-amylase inhibition (18%) and glucose adsorption (31%). Cocoa shell also inhibited cholesterol and bile salts absorption (72 and 70%, respectively). The intake of acute (2000 mg/kg) and subcronical (1000 mg/kg) doses of the ingredient did not cause significant lesions in selected isolated vital organs (liver, spleen, and kidney) nor changes in histological parameters, ensuring the safety of this sustainable food ingredient. Conclusions Results validate the use of cocoa shell as an antioxidant dietary fiber ingredient, being a safe potential candidate to be incorporated in the development of foods for specific health uses. Funding Sources Ministry of Science and Innovation.

In vivo hepatotoxicity of chemically modified nanocellulose in rats

2019 ◽  
Vol 39 (2) ◽  
pp. 212-223 ◽  
Author(s):  
CA Otuechere ◽  
A Adewuyi ◽  
OL Adebayo ◽  
IA Ebigwei
Keyword(s):  
Body Weight ◽  
Relative Weight ◽  
High Dose ◽  
Hydroxyl Groups ◽  
Oral Toxicity ◽  
Tissue Samples ◽  
Liver Histopathology ◽  
Biological Functionality ◽  
Oxide Synthase

Chemical modification of cellulose is currently attracting attention as researchers attempt to take advantage of the abundance of hydroxyl groups on its surface to introduce extra biological functionality. However, the possible deleterious effect of exposure to functionalized nanocellulose (CSN) remains a concern. Therefore, this study aims to explore the potential mechanisms of hepatotoxicity of CSN modified with oxalate ester (NCD) in rats. A 7-day repeated oral toxicity study of NCD at the doses of 50 and 100 mg kg−1 body weight was conducted, and plasma and liver tissue samples were assayed using biochemical analysis, liver histopathology, and protein expression. NCD, at both doses, did not significantly ( p > 0.05) alter the relative weight of liver, alkaline phosphatase activity, and lipid peroxidation levels of the animals. However, NCD at the dose of 100 mg kg−1 body weight significantly elevated aspartate aminotransferase, alanine aminotransferase, and myeloperoxidase activities. NCD also enhanced the immunohistochemical expression of inducible nitric oxide synthase and Bcl-2-associated X protein in the liver of rats. Histological observations revealed necrosis and severe cellular infiltration at the high-dose treatment. Our study provides an experimental basis for the safe application of NCDs.

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