Synthesis of glucosamine-selenium compound and evaluation of its oral toxicity and in vitro anti-hepatitis B virus activity.

Selenium supplements are beneficial to human health, however, concerns regarding the toxicity of inorganic selenium have stimulated research on safer organic compounds. The main objective of this study was to develop a novel glucosamine-selenium compound (Se-GlcN), clarify its structure, and subsequently investigate its oral toxicity and in vitro anti-hepatitis B virus (HBV) activity. Electron microscopy, infrared, ultraviolet spectroscopy, nuclear magnetic resonance and thermogravimetric analyses revealed a unique binding mode of Se-GlcN, with the introduction of the Se-O bond at the C6 position, resulting in the formation of two carboxyl groups. In acute toxicity studies, the median lethal dose (LD50) of Se-GlcN in ICR mice was 92.31 mg/kg body weight (BW), with a 95 % confidence interval of 81.88-104.07 mg/kg BW. A 30-day subchronic toxicity study showed that 46.16 mg/kg BW Se-GlcN caused livers and kidneys damage in mice, whereas doses of 9.23 mg/kg BW and lower were safe for the livers and kidneys. In vitro studies, Se-GlcN at 1.25 µg/mL exhibited good anti-HBV activity, significantly reducing HBsAg, HBeAg, 3.5 kb HBV RNA and total HBV RNA by 45 %, 54 %, 84 %, 87 %, respectively. In conclusion, the Se-GlcN synthesized in this study provides potential possibilities and theoretical references for its use as an organic selenium supplement.

Xanthophyllomyces dendrorhous Is a Safe Dietary Supplement with Potent Antioxidant Defense Enhancing Activity.

Xanthophyllomyces dendrorhous (X. dendrorhous), previously known as Phaffia rhodozyma, is a red yeast that is widely recognized as a rich source of carotenoids, particularly astaxanthin, which exhibits potent antioxidant activity and other health-promoting functions. However, there is currently a lack of research on the safety of consuming X. dendrorhous. To address this, we conducted an acute toxicity study followed by a 90-day subchronic toxicity trial to evaluate the safety of X. dendrorhous and investigate its in vivo antioxidant activity. In the acute toxicity study, Sprague-Dawley rats were administered a maximum of 12 g/kg body weight of X. dendrorhous powder by gavage and survived without any adverse effects for 14 days. In the subsequent subchronic toxicity test, the rats were randomly divided into five groups, each with free access to their diet adulterated with 0% (control), 2.5% (low), 5% (middle), 10% (high), and 20% (extreme high) X. dendrorhous powder. The rats' behavior, body weight, and food intake were monitored during the 90-day experiment. At the end of the experiment, urine, blood, and organs were collected from the rats for biochemical testing. Additionally, the antioxidant activity in rat sera was evaluated. The results of the acute toxicity test demonstrated that the LD50 of X. dendrorhous was greater than 12 g/kg body weight, indicating that the substance was not toxic. Throughout the 90-day period of subchronic toxicity, the triglyceride levels of male rats fed with 10 and 20% X. dendrorhous increased to 1.54 ± 0.17 and 1.55 ± 0.25 mmol/L (P < 0.05), respectively. This may be attributed to the elevated fat content of the diet in the high-dose and extreme high-dose groups, which was 5.5 and 2.5% higher than that in the control, respectively. Additionally, the white pulp in the spleen exhibited an increase, and the number of white blood cells in the extreme high-dose group increased by 2.41 × 109/L (P < 0.05), which may contribute to enhanced immunity. Finally, the body weight, food intake, blood and urine indexes, and histopathological examination results of the organs of the rats did not demonstrate any regular toxic effects. With the adulteration of X. dendrorhous, the activity of GSH-Px in male rats increased by 16-36.32%. The activity of GSH-Px in female rats of the extreme high-dose group increased by 14.70% (P < 0.05). The free radical scavenging ability of ABTS in male rats in the two high-dose groups exhibited an increase of 6.5 and 11.41% (P < 0.05). In contrast, the MDA content of male rats in the extreme high-dose group demonstrated a reduction of 2.73 nmol/mL (P < 0.05). These findings indicate that X. dendrorhous has no toxic effects, can be taken in high doses, and has a beneficial antioxidant effect that may enhance the body's immunity.

DNA interaction of selected tetrahydropyrimidine and its effects against CCl4-induced hepatotoxicity in vivo: Part II.

Tetrahydropyrimidine (compound A = methyl 4-[4'-(heptyloxy)-3'-methoxyphenyl]-1,6-dimethyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate) was chosen for in vivo studies after exhibiting noteworthy in vitro activity against the K562 and MDA-MB-231 cell lines, with IC50 values of 9.20 ± 0.14 µM and 12.76 ± 1.93 µM, respectively. According to experimental (fluorescence titration, viscosity, and differential scanning calorimetry) results, A interacts with DNA via the minor groove. In vivo, acute oral toxicity studies in Wistar albino rats proved no noticeable symptoms of either toxicity or death during the follow-up period. Genotoxic and antigenotoxic studies at three different concentrations of A (5, 10, and 20 mg/kg of body weight) in Wistar albino rats showed that the dose of 5 mg/kg body weight did not cause DNA damage and had a remarkable DNA protective activity against CCl4-induced DNA damage, with a percentage reduction of 78.7%. It is also important to note that, under the investigated concentrations of A, liver damage is not observed. Considering all experimental outcomes realized under various in vivo investigations (acute oral toxicity, genotoxicity, antigenotoxicity, and biochemical tests), compound A could be a promising candidate for further clinical testing.

Safety of titanium dioxide (E171) as a food additive for humans.

Titanium dioxide (TiO2), also known as E171, is commonly used as a white colorant in food, pharmaceuticals, cosmetics, and toothpaste. However, in May 2021, the European Food Safety Authority (EFSA) expert panel, in evaluating the safety of titanium dioxide (E171) as a food additive, concluded that a concern for genotoxicity could not be ruled out. This occurred several years after EFSA had previously considered titanium dioxide to be safe as a food additive. EFSA based this new interpretation on the results of genotoxicity tests of TiO2 nanomaterials. EFSA noted that available data are insufficient to define threshold doses/concentrations of TiO2 particles below which genotoxicity will not occur in tissues containing these particles. Here, it is argued that EFSA made a manifest error regarding the safety of titanium dioxide (E171) particles as a food additive for humans. First, the notion of particle size distribution of TiO2 particles is explained. Second, the changing opinions from the various EFSA evaluations in 2016, 2018, 2019 vs. 2021 are discussed. Third, the low toxicity of TiO2 particles is described in rats exposed by oral gavage and feeding studies in rats and mice. Fourth, the importance of low absorption rates from the gastrointestinal tract vs. circulation in rats and humans but not in mice is identified. Fifth, other international health scientists have weighed in on the EFSA (EFSA J, 2021, 19 (5), 6585) decision and generally disagreed with EFSA's opinion on the safety of E171 TiO2. A common theme voiced by the United Kingdom, Canada, Australia, and New Zealand agencies is that it is inappropriate to compare nanoparticle toxicity studies of dispersed/sonicated nanoparticles with the content of E171 TiO2 in foods because the test materials used in key studies considered by EFSA (EFSA J, 2021, 19 (5), 6585) are not representative of E171 TiO2 particles. Finally, a group of experts recently considered the genotoxicity of TiO2 and could not find support for a direct DNA damaging mechanism of TiO2 (nano and other forms). For these reasons, it is suggested that EFSA made a manifest error on the safety of E171 as a food additive.

Preclinical evidence of the anti-inflammatory effect and toxicological safety of aryl-cyclohexanone in vivo.

BACKGROUND: Respiratory distress syndrome is a complex inflammatory condition defined by the presence of acute hypoxemia and cellular infiltration with diffuse alveolar injury following a tissue injury, such as acute lung injury. The inflammatory process involved in this pathology is a defense mechanism of the body against infectious agents and/or tissue injuries. However, when the condition is not reversed, it becomes a significant cause of tissue damage, sometimes leading to loss of function of the affected organ. Therefore, it is essential to understand the mechanisms underlying inflammation, as well as the development of new therapeutic agents that reduce inflammatory damage in these cases. Aryl-cyclohexanone derivatives have previously shown significant anti-inflammatory activity linked to an immunomodulatory capacity in vitro and may be good candidates for therapies in which inflammation plays a central role. METHODS: Was evaluated the anti-inflammatory capacity of a synthesized molecule aryl-cyclohexanone in the murine model of lipopolysaccharide (LPS)-induced acute lung injury. The assessment of acute oral toxicity follows the Organization for Economic Co-operation and Development (OECD) guideline 423. RESULTS: The results demonstrated that the studied molecule protects against LPS-induced inflammation. We observed a decrease in the migration of total and differential leukocytes to the bronchoalveolar lavage fluid (BALF), in addition to a reduction in exudation, myeloperoxidase (MPO) activity, nitric oxide metabolites, and the secretion of pro-inflammatory cytokines (alpha tumor necrosis factors [TNF-α], interleukin-6 [IL-6], interferon-gamma [IFN-γ], and monocyte chemoattractant protein-1 [MCP-1]). Finally, aryl cyclohexanone did not show signs of acute oral toxicity (OECD 423). CONCLUSIONS: The results prove our hypothesis that aryl-cyclohexanone is a promising molecule for developing a new, safe anti-inflammatory drug.

Subchronic oral toxic effects of 2,4-dinitroaniline in wistar rats: A comprehensive toxicity evaluation.

2,4-dinitroaniline (2,4-D), a widely used dye intermediate, is one of the typical pollutants, and its potential health risks and toxicity are still largely unknown. To explore its subchronic oral toxicity, Wistar rats (equal numbers of males and females) were used as test animals, and a 90-day oral dosing experiment was conducted, divided into control group, low-dose group (0.055 mg/kg), medium-dose group (0.22 mg/kg), medium-high dose group (0.89 mg/kg), and high-dose group (3.56 mg/kg). The body weight data, clinical appearance, and drug reactions of each test rat within 90 days of dosing were recorded; morning urine samples were collected four times to test for eight urinary indicators; blood samples were collected to test for nineteen hematological indicators and sixteen biochemical indicators; tissue samples were collected for pathological analysis; moreover, the no-observed-adverse-effect level (NOAEL) was determined, and the benchmark dose method was used to support this determination and provide a statistical estimate of the dose corresponding. The results indicated that the chronic toxicity of 2,4-dinitroaniline showed certain gender differences, with the eyes, liver, and kidneys being the main potential target organs of toxicity. Moreover, the subchronic oral NOAEL for 2,4-dinitroaniline was determined to be 0.22 mg/kg body weight (0.22 mg/kg for males and 0.89 mg/kg for females), and a preliminary calculation of the safe exposure limit for human was 0.136 mg/kg. The research results greatly enriched the safety evaluation data of 2,4-dinitroaniline, contributing to a robust scientific foundation for the development of informed safety regulations and public health precautions.

Hemocompatible and biocompatible hybrid nanocarriers for enhanced oral bioavailability of paclitaxel: in vivo evaluation.

Oral administration of BCS class IV anticancer agents has always remained challenging and frequently results in poor oral bioavailability. The goal of the current study was to develop hybrid nanoparticles (HNPs) employing cholesterol and poloxamer-407 to boost paclitaxel's (PTX) oral bioavailability. A series of HNPs with different cholesterol and poloxamer-407 ratios were developed utilizing a single-step nanoprecipitation technique. The PTX loaded HNPs were characterized systematically via particle size, zeta potential, polydispersity index, surface morphology, in vitro drug release, FTIR, DSC, XRD, acute oral toxicity analysis, hemolysis evaluation, accelerated stability studies, and in vivo pharmacokinetic analysis. The HNPs were found within the range of 106.6±55.60 - 244.5±88.24 nm diameter with the polydispersity index ranging from 0.20±0.03 - 0.51±0.11. SEM confirmed circular, nonporous, and smooth surfaces of HNPs. PTX loaded HNPs exhibited controlled release profile. The compatibility between the components of formulation, thermal stability, and amorphous nature of HNPs were confirmed by FTIR, DSC, and XRD, respectively. Acute oral toxicity analysis revealed that developed system have no deleterious effects on the animals' cellular structures. HNPs demonstrated notable cytotoxic effects and were hemocompatible at relatively higher concentrations. In vivo pharmacokinetic profile (AUC0-∞, AUMC0-∞, t1/2, and MRT0-∞) of the PTX loaded HNPs was improved as compared to pure PTX. It is concluded from our findings that the developed HNPs are hemocompatible, biocompatible and have significantly enhanced the oral bioavailability of PTX.

Toxicological Evaluation Verifies the Safety of Oral Administration of Steamed Mature Silkworm Powder in Rats.

Globally, the edible insect industry is emerging due to its potential contributions to food security and environmental sustainability. Edible insects are rapidly being integrated into the development of alternative foods and new pharmaceuticals. Silkworms, known for their high protein content, are not only a potential new source of human food and animal feed but have also been traditionally used for medicinal purposes. However, conventional silkworms are difficult to ingest. To address this, we have developed a steamed and freeze-dried mature silkworm larva powder (SMSP), and it is essential to investigate its potential toxicity and food safety for further studies and applications. Therefore, this study aimed to evaluate the toxicity of SMSP. A toxicity assessment of SMSP was conducted according to OECD guidelines. An oral repeat-administration study was performed on male and female SD rats at doses of 625, 1250, and 2500 mg/kg/day for 4 and 13 weeks. No toxicological changes were observed in clinical signs, body weight, water and food intake, urine tests, hematology, clinical biochemistry, gross findings, or histopathological examination. In conclusion, the no observed adverse effect level (NOAEL) of SMSP was 2500 mg/kg/day, with no target organs identified in either sex of the rats. These results suggest that SMSP is safe, is without side effects and has potential for use as an edible ingredient and in health functional food applications.

Toxicological evaluation of porcine bile powder in Kunming mice and Sprague-Dawley rats.

Background: Porcine bile powder (PBP) is a traditional Chinese medicine that has been used for centuries in various therapeutic applications. However, PBP has not previously undergone comprehensive component analysis and not been evaluated for safety through standard in vivo toxicological studies. Methods: In our study, we characterized the component of PBP by liquid chromatography-mass spectrometry. The acute and subchronic oral toxicity, genotoxicity, and teratogenicity studies of PBP were designed and conducted in Kunming mice and Sprague-Dawley (SD) rats. Results: The chemical analysis of PBP showed that the main components of PBP were bile acids (BAs), especially glycochenodeoxycholic acid. There were no signs of toxicity observed in the acute oral test and the subchronic test. In the genotoxicity tests, no positive results were observed in the bacterial reverse mutation test. Additionally, in the mammalian micronucleus test and mouse spermatocyte chromosomal aberration test, no abnormal chromosomes were observed. In the teratogenicity test, no abnormal fetal development was observed. Conclusion: Our findings demonstrate that PBP, composed mainly of BAs, is non-toxic and safe based on the conditions tested in this study.

Toxicological evaluation of Alpinia oxyphylla-derived molecule (PD-00105): In vitro genotoxicity studies and 90-day oral toxicity study in rats.

PD-00105 corresponds to a compound initially identified in the fruit of Alpinia oxyphylla Miq., obtained by chemical synthesis and proposed to be use in dietary supplements for its potential neuroprotective properties. The aim of this study was to perform a toxicological evaluation of PD-00105 in accordance with the testing strategy recommended by food regulatory authorities. All studies were conducted in accordance with Good Laboratory Practice (GLP), and followed the Organization for Economic Co-operation and Development (OECD) test guidelines for chemicals. Studies included a bacterial reverse mutation test, one in vitro micronucleus test in mammalian cells, and a repeated dose 90-day oral toxicity study. No sign of toxicity was observed in the two genotoxicity tests. The test item induced a significant liver and kidney toxicity at high doses (50 and 100 mg/kg BW/day), highlighted by significant increases in liver and kidney absolute and relative weights, associated with histopathological findings and concomitant changes in hematology and clinical chemistry. Increases in alanine aminotransferase, alkaline phosphatase, total protein, albumin, globulin, cholesterol, LDL, and HDL have been measured in these two groups. However, findings observed in the low-dose group (10 mg/kg BW/day) were considered as minimal and non-adverse, and were limited to an increase in liver weight in males and in kidneys weight in females, without concomitant changes in blood chemistry. The No Observed Adverse Effect Level (NOAEL) of PD-00105 was established as 10 mg/kg BW/day under the conditions of this study. This study substantiates the use of PD-00105 in dietary supplements at doses of 10 mg/day, taking into account a safety margin factor for dose conversion to humans.

A regulatory compliant short-term oral toxicity study of soluble [60]fullerenes in rats.

Thirty-eight years after its discovery, the safety of [60]fullerene (C60), the most abundant fullerene with many potential applications, particularly in oxidative stress-related medicine, remains controversial. This is mainly due to the alleged dangers of C60 nanomaterial, which are regularly supported by some publications. While several academic studies have confirmed the safety of C60 in various experimental models, it is well known that C60 aggregates can carry toxic elements. Meanwhile, countless websites offer C60-oily solutions to consumers, without any regulatory consideration. Therefore, an officially certified toxicity study is urgently needed to avoid any public health problems. In this context, we report on the first certified short-term oral toxicity study of soluble C60, designed according to the guidelines of the Organization for Economic Cooperation and Development, with a deviation in the duration (2 weeks instead of 4 weeks) accepted by the U.S. Food and Drug Administration. The results of this study, conducted in an independent accredited European Laboratory, clearly show that C60 in soluble form (0.8 mg/ml of extra virgin olive oil), administered at the highest possible dose of 3.8 mg/kg body weight/day, did not cause any adverse effects in rats after 14 days of daily oral administration. This report should settle the debate on the acute oral toxicity of C60 and pave the way for further preclinical studies. The study is accompanied by a comprehensive report that includes documentation of the raw data.

Oral and cutaneous immune-related adverse events in cancer patients: Prevalence and overall survival.

OBJECTIVES: To assess the prevalence of cutaneous and oral immune-related adverse events (irAEs) in cancer patients, risk factors for its development, and overall survival (OS). MATERIALS AND METHODS: This retrospective observational study which included 748 medical records of cancer patients who received immune checkpoint inhibitors (ICIs). Demographic and clinicopathological characteristics were collected and analyzed. RESULTS: Most patients were male (59.4%), with stage IV cancer (65%) and received pembrolizumab (46.7%). Four hundred fourteen (55.34%) patients developed cutaneous lesions, 84 (11.2%) developed oral mucosal lesions, and 70 (9.3%) developed xerostomia. The median time for irAEs development was 11 weeks for cutaneous and oral mucosal lesions, and 21.5 weeks for xerostomia. Patients who received PD-1 + CTLA-4 had a higher risk for developing cutaneous irAEs (p = 0.001), while those who underwent ICI and concurrent chemotherapy had a higher risk (p = 0.008) for developing oral mucosal lesions. Patients who presented oral and cutaneous irAEs had better OS than those who did not present (p = 0.0001). CONCLUSION: Cutaneous effects affected more than half of the patients, while oral effects and xerostomia were found in around 11% and 9% of patients, respectively. Concurrent chemotherapy and PD-1 + CTLA-4 were more associated with oral and cutaneous irAEs, respectively. Patients who developed such irAEs had better overall survival.

Morin inhibits the activity of pancreatic lipase and adipogenesis.

Obesity is a major health issue that contributes significantly to increased mortality and morbidity worldwide. Obesity is caused by uncontrolled adipogenesis and lipogenesis, leading to several metabolism-associated problems. Pancreatic lipase, an enzyme that breaks down dietary lipids, is a prominent target for obesity. Orlistat, a known inhibitor of pancreatic lipase, is commonly employed for the management of obesity. However, its side effects, such as diarrhoea, nausea and bladder pain, urge to look out for safer alternatives. Morin is a pentahydroxyflavone, exerts a broad spectrum of pharmacological effects including antioxidant, anti-inflammatory, lipid lowering, anti-diabetic, anti-fibrotic, anti-cancer, etc. This study investigated the effect of morin on pancreatic lipase activity, in vitro and in vivo adipogenesis. Molecular docking and simulation studies showed morin to have a higher binding affinity towards pancreatic lipase compared with orlistat, which also inhibited its activity in vitro. Morin also reduced lipid droplet accretion and downregulated the expression of adipogenic and lipogenic genes. The acute oral toxicity of morin was determined in C57BL/6 mice, where morin did not show toxicity up to 2000 mg/kg body weight dose. Oral administration of morin to high fat diet fed mice reduced body weight, glucose and insulin levels. Also, the histopathological examination revealed reduction in adipocyte size and decreased mRNA expression of adipogenesis markers in white adipose tissue of morin administered group compared to high fat diet group. Overall, the results suggested morin inhibited pancreatic lipase activity, adipogenesis and further studies are warranted to explore its therapeutic potential for obesity.

Assessment of oral toxicity and safety profile of cyanidin: acute and subacute studies on anthocyanin.

Aim: Purified anthocyanins lack a detailed safety profile, prompting the need for comprehensive oral toxicity research. Materials & methods: Sprague-Dawley rats aged 8 weeks received 300 mg/kg cyanidin orally for 14 days in acute toxicity (OECD 423). In the subacute study (OECD 407), adult SD rats were administered 7.5, 15 and 30 mg/kg/day cyanidin orally for 28 days. Results: Acute toxicity indicated an LD50 exceeding 300 mg/kg/day without adverse effects. Subacute toxicity at 7.5-30 mg/kg/day showed well-tolerated responses in both genders. No significant alterations in organ weights, hematological parameters, liver/kidney functions or adverse histopathological findings were observed. Conclusion: Oral cyanidin administration demonstrated high safety and tolerance in rats, establishing a NOAEL at 30 mg/kg/day, affirming cyanidin's safety for oral use.

Anthocyanins, natural pigments found in fruits and vegetables, lack a detailed safety profile. This study investigated the oral toxicity of cyanidin, a common anthocyanin. Acute toxicity testing in rats showed no adverse effects at doses up to 300 mg/kg. In the subacute study, doses of 7.5­30 mg/kg/day over 28 days were well tolerated, with no significant negative effects on organ function or histopathology. The findings suggest that cyanidin is safe for oral use in rats, with a No Observed Adverse Effect Level (NOAEL) established at 30 mg/kg/day.

Rat studies reveal cyanidin, a common anthocyanin, shows high oral safety at doses up to 300 mg/kg/day, paving the way for safer dietary supplement use. #Toxicology #SafetyResearch.

13-Week Repeated Oral Toxicity and Toxicokinetic Studies of Rabeprazole Sodium and Sodium Bicarbonate Combination in Dogs.

The subchronic toxicity and toxicokinetics of a combination of rabeprazole sodium and sodium bicarbonate were investigated in dogs by daily oral administration for 13 consecutive weeks with a 4-week recovery period. The dose groups consisted of control (vehicles), (5 + 200), (10 + 400), and (20 + 800) mg/kg of rabeprazole sodium + sodium bicarbonate, 20 mg/kg of rabeprazole sodium only, and 800 mg/kg of sodium bicarbonate only. Esophageal ulceration accompanied by inflammation was observed in only one animal in the male (20 + 800) mg/kg rabeprazole sodium + sodium bicarbonate group. However, the severity of the ulceration was moderate, and the site of occurrence was focally extensive; thus, it was assumed to be a treatment-related effect of rabeprazole sodium + sodium bicarbonate. In the toxicokinetics component of this study, systemic exposure to rabeprazole sodium (AUClast and Cmax at Day 91) was greater in males than females, suggesting sex differences. AUClast and Cmax at Day 91 were increased compared to those on Day 1 in a dose-dependent manner. A delayed Tmax and no drug accumulation were observed after repeated dosage. In conclusion, we suggest under the conditions of this study that the no-observed-adverse-effect level (NOAEL) of the combination of rabeprazole sodium + sodium bicarbonate in male and female dogs is (10 + 400) and (20 + 800) mg/kg, respectively.

Bioproduction of yeast single cell oil with acute oral toxicity study intended for edible oil application.

Human nutrition and health rely on edible oils. Global demand for edible oils is expanding, necessitating the discovery of new natural oil sources subjected to adequate quality and safety evaluation. However, in contrast to other agricultural products, India's edible oil supply is surprisingly dependent on imports. The microbial oil is generated by fermentation of oleaginous yeast Rhodotorula mucilaginosa IIPL32 MTCC 25056 using biodiesel plant byproduct crude glycerol as a fermentable carbon source. Enriched with monounsaturated fatty acid, nutritional indices mapping based on the fatty acid composition of the yeast SCO, suggested its plausible use as an edible oil blend. In the present study, acute toxicity evaluation of the yeast SCO in C57BL/6 mice has been performed by randomly dividing the animals into 5 groups with 50, 300, 2000, and 5000 mg/Kg yeast SCO dosage, respectively, and predicted the median lethal dose (LD50). Detailed blood biochemistry and kidney and liver histopathology analyses were also reported. The functions of the liver enzymes were also evaluated to check and confirm the anticipated toxicity. To determine cell viability and in vitro biocompatibility, the 3T3-L1 cell line and haemolysis tests were performed. The results suggested the plausible use of yeast SCO as an edible oil blend due to its non-toxic nature in mice models.

Testing of acute and sub-acute toxicity profile of novel naproxen sodium nanoformulation in male and female mice.

Nanodrugs offer promising alternatives to conventionally used over the counter drugs. Compared to its free form, therapeutic benefits, and gastric tissue safety of naproxen sodium nanoformulation (NpNF) were recently demonstrated. Essential regulatory safety data for this formulation are, however, not available. To address this, male and female BALB/c mice were subjected to acute and 14-day repeated-oral dose assessments. Our data indicate that NpNF was well tolerated up to 2000 mg/kg b.w. A 14-day subacute toxicity testing revealed that the oral administration of low dose (30 mg/kg) NpNF did not produce any adverse effects on blood profile and serum biochemical parameters. Levels of oxidative stress markers and antioxidant enzymes neared normal. Histology of selected tissues also showed no evidence of toxicity. In contrast, a ten-fold increase in NpNF dosage (300 mg/kg), demonstrated, irrespective of gender, mild to moderate toxicity (p < 0.05) in the brain, stomach, and heart tissues, while ROS, LPO, CAT, SOD, POD, and GSH levels remained unaffected in the liver, kidney, spleen, testis, and seminal vesicles. No effect on serum biochemical parameters, overall indicated a no-observed-adverse-effect level (NOAEL) is 300 mg/kg. Further increase in dosage (1000 mg/kg) significantly altered all parameters demonstrating that high dose is toxic.

Toxicology study profile of Nicotinamide mononucleotide after acute and 90-day sub chronic dosing in Wistar rats and mutagenicity tests.

Nicotinamide mononucleotide (NMN) is an intermediate in biosynthesis pathway of Nicotinamide adenine dinucleotide (NAD+), an essential cofactor in all living cells involved in fundamental biological processes. Evidence stemming from recent studies have unveiled numerous roles of NAD+ metabolism on aging, longevity, delaying the progression of age-related diseases. A three-study genetic toxicity (genetox) battery (bacterial mutagenesis, in vitro cytogenetics, and in vivo mammalian test) is usually required to confirm safety of a new dietary ingredient and this study showed the data from in vivo mutagenicity test for the first time. The acute oral LD50 of NMN was greater than 2000 mg/kg body weight with 5000 mg/kg body weight as LD50 cut-off value and was classified under "Category 5 or Unclassified" as per Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Based on 90 days repeated dose toxicity test the NOAEL was considered to be NLT 800 mg NMN/kg body weight in Wistar rats. The bacterial reverse mutation test, the in vitro and in vivo chromosomal aberration test, found NMN to be non-mutagenic. In the mammalian bone marrow chromosomal aberration test, it was concluded that NMN is non clastogenic at and up to 2,000 mg/kg body weight in all the animals tested to confirm safety of a new dietary ingredient and this study showed the data from in vivo mutagenicity test for the first time.

Integration of transcriptomics and metabolomics reveals toxicological mechanisms of ZhuRiHeng drop pill in the 180-day repeated oral toxicity study.

Background: ZhuRiHeng Drop Pill (ZRH) is a traditional Mongolian medicinal preparation. Despite its long history of use for the treatment of coronary heart disease, there have been few toxicological studies of the safety profile of ZRH. Purpose: In order to comprehensively elucidate the underlying mechanisms behind the observed toxicity of ZRH on rat livers in the 180-day repeated oral toxicity study, we conducted a comprehensive analysis by integrating transcriptomic and metabolomic data. Methods: High-resolution mass spectrometry was conducted to evaluate the constituents of ZRH. For the acute oral toxicity study, mice were administered a dose of 32 g/(kg·d) of ZRH, while rats were instead orally administered 0.934, 1.868, or 3.736 g/(kg·d) of ZRH over a 180-day period in a 180-day repeated oral toxicity study. Conventional index and organ weights/histology were then monitored to detect any potential ZRH treatment-related toxicity. To identify key genes and metabolites involved in ZRH toxicological processes, we performed transcriptomic and metabolomic analyses of liver tissue upon ZRH treatment using RNA-seq techniques, qPCR and liquid chromatography-mass spectrometry analyses. Results: A total of 60 compounds in ZRH were identified and speculated in positive and negative ion modes. Mice in the acute toxicity study exhibited no signs of ZRH-related toxicity. In a protracted oral toxicity investigation spanning 180 days, discernible elevations in liver ratios were noted in both male and female rats across all three dose cohorts, relative to the control group (p < 0.05 or p < 0.01). Upon subjecting to ZRH treatment, our transcriptomic and qPCR analyses unveiled notable upregulation of crucial genes, exemplified by Abcb1b and Cyp2b2, known for theirs involvement in liver drug transport and metabolism function. Furthermore, our untargeted metabolomic analysis provided supplementary insights, revealing significant regulation in pyrimidine metabolism, as well as alanine, aspartate, and glutamate metabolism pathways. Conclusion: Our study unveils a panoramic understanding of the temporal, dosage-specific, and gene dimensions surrounding the metabolic and transcriptional shifts induced by ZRH exposure. As we peer into the future, recommendations emerge for further exploration, encompassing aspects such as time dynamics, dosage considerations, and gene-centric avenues to enhance therapeutic efficacy.

Physicochemical Evaluation and Pharmacological Screening of Fernando Adenophylla Steenis Fruits.

The current study aimed to evaluate the physicochemical properties of Fernandoa adenophylla. Powder studies were carried out to estimate the quantitative physicochemical characteristics of the crude drug, including moisture content, ash content, and extractive values. Using a Soxhlet apparatus and different analytical grade solvents, 3 sample extracts of a crude drug were made. To evaluate the potentially toxic nature, an acute oral toxicity study was performed as per OECD guideline no. 423. Sample extracts were tested and analyzed by ANOVA for pharmacological potential (analgesic, antipyretic, and antidiabetic) using Wister-Albino rats. Where physicochemical analysis indicated purity, quality, and presence of organic/inorganic materials in crude drug extracts, no sign of mortality was found up to 2000 mg/kg of body weight of Fernandoa adenophyllas extracts. Analgesic activity was observed in all sample extracts, whereas only chloroform and ethanolic extracts expressed antipyretic and antidiabetic potential. Ethanolic extract was found to be most potent in pharmacological potential as 200 mg/kg extract dose exhibited %age pain inhibition of 55.12 % and reduced body temperature from 39.78±0.03 °C to 37.22±0.02 °C in hyperthermic rats. A decrease in blood glucose levels up to 57.88 % was observed on the 21st day of the treatment with 500 mg/kg ethanolic extract.