Biodistribution, cardiac and neurobehavioral assessments, and neurotransmitter quantification in juvenile rats following oral administration of aluminum oxide nanoparticles.

Little is known about the uptake, biodistribution, and biological responses of nanoparticles (NPs) and their toxicity in developing animals. Here, male and female juvenile Sprague-Dawley rats received four consecutive daily doses of 10 mg/kg Al2 O3 NP (diameter: 24 nm [transmission electron microscope], hydrodynamic diameter: 148 nm) or vehicle control (water) by gavage between postnatal days (PNDs) 17-20. Basic neurobehavioral and cardiac assessments were performed on PND 20. Animals were sacrificed on PND 21, and selected tissues were collected, weighed, and processed for histopathology or neurotransmitter analysis. The biodistribution of Al2 O3 NP in tissue sections of the intestine, liver, spleen, kidney, and lymph nodes were evaluated using enhanced dark-field microscopy (EDM) and hyperspectral imaging (HSI). Liver-to-body weight ratio was significantly increased for male pups administered Al2 O3 NP compared with control. HSI suggested that Al2 O3 NP was more abundant in the duodenum and ileum tissue of the female pups compared with the male pups, whereas the abundance of NP was similar for males and females in the other tissues. The abundance of NP was higher in the liver compared with spleen, lymph nodes, and kidney. Homovanillic acid and norepinephrine concentrations in brain were significantly decreased following Al2 O3 NP administration in female and male pups, whereas 5-hydroxyindoleacetic acid was significantly increased in male pups. EDM/HSI indicates intestinal uptake of Al2 O3 NP following oral administration. Al2 O3 NP altered neurotransmitter/metabolite concentrations in juvenile rats' brain tissues. Together, these data suggest that orally administered Al2 O3 NP interferes with the brain biochemistry in both female and male pups.

A Metabolomics Approach to Investigate Kukoamine B-A Potent Natural Product With Anti-diabetic Properties.

Due to the surge in type 2 diabetes mellitus (T2DM), treatments for chronic metabolic dysregulations with fewer side-effects are sought. Lycii Cortex (LyC), a traditional Chinese Medicine (TCM) herb has a long history of being widely prescribed to treat T2DM as alternative medicine; however, the bioactive molecules and working mechanism remained unknown. Previous studies revealed kukoamine B (KB) as a major and featured compound for LyC with bioactivities for anti-oxidation and acute inflammation, which may be related to anti-diabetes properties. This study aims to understand the efficacy and the mode of action of KB in the diabetic (db/db) mouse model using a metabolomics approach. Parallel comparison was conducted using the first-line anti-diabetic drugs, metformin and rosligtazone, as positive controls. The db/db mice were treated with KB (50 mg kg-1 day-1) for 9 weeks. Bodyweight and fasting blood glucose were monitored every 5 and 7 days, respectively. Metabolomics and high-throughput molecular approaches, including lipidomics, targeted metabolomics (Biocrates p180), and cytokine profiling were applied to measure the alteration of serum metabolites and inflammatory biomarkers between different treatments vs. control (db/db mice treated with vehicle). After 9 weeks of treatment, KB lowered blood glucose, without the adverse effects of bodyweight gain and hepatomegaly shown after rosiglitazone treatment. Lipidomics analysis revealed that KB reduced levels of circulating triglycerides, cholesterol, phosphatidylethanolamine, and increased levels of phosphatidylcholines. KB also increased acylcarnitines, and reduced systemic inflammation (cytokine array). Pathway analysis suggested that KB may regulate nuclear transcription factors (e.g., NF-κB and/or PPAR) to reduce inflammation and facilitate a shift toward metabolic and inflammatory homeostasis. Comparison of KB with first-line drugs suggests that rosiglitazone may over-regulate lipid metabolism and anti-inflammatory responses, which may be associated with adverse side effects, while metformin had less impact on lipid and anti-inflammation profiles. Our research from holistic and systemic views supports the conclusion that KB is the bioactive compound of LyC for managing T2DM, and suggests KB as a nutraceutical or a pharmaceutical candidate for T2D treatment. In addition, our research provides insights related to metformin and rosiglitazone action, beyond lowering blood glucose.

Metabolomics of urine for the assessment of microvesicular lipid accumulation in the liver following isoniazid exposure.

This study was conducted to develop a noninvasive marker of hepatic microvesicular lipid accumulation (MVLA), a histopathological effect currently diagnosed in humans following liver biopsy. MVLA is detected in animal studies of chemicals and drugs and occurs in some humans exposed to chemicals or pharmaceuticals. Because MVLA is a reversible histopathology, early detection of MVLA using a noninvasive method, could aid clinicians in the treatment of patients taking drugs that are known to induce this injury. Isoniazid (INH) was selected as a model compound for this investigation, because MVLA occurs in tuberculosis (TB) patients treated with a combination therapy, which includes INH. This study used male rats dosed daily with INH at 0, 10, or 300 mg/kg/day for up to 8 days. Urine, blood, and liver were obtained following 1 and 8 days. NMR metabolomics of urine revealed markers that correlated (100%) with the findings of MVLA in the right, left, and median liver lobes in 4/9 rats administered the high dose of INH for 8 days. Metabolomics of liver extracts also revealed markers that correlated with the MVLA injury. Serum enzymes that are clinically used to assess liver injury were not consistently correlated to the findings of MVLA. Metabolite changes consistent with the presence of MVLA correlated with interruptions in inositol, carbohydrate, glycerolipid, and glyoxylate metabolism. This study reveals markers that could find pre-clinical use, provides insights into mechanisms involved in MVLA, and demonstrates the need for the validation of noninvasive MVLA markers in human patients.