Dose-Response Study of Microcystin Congeners MCLA, MCLR, MCLY, MCRR, and MCYR Administered Orally to Mice.
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ABSTRACT:
SUBMITTER: Chernoff N
PROVIDER: S-EPMC7911753 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Oral supplemented nutraceuticals derived from food sources are surmised to improve the human health through interaction with the gastrointestinal bacteria. However, the lack of fundamental quality control and authoritative consensus (e.g., formulation, route of administration, dose, and dosage regimen) of these non-medical yet bioactive compounds are one of the main practical issues resulting in inconsistent individual responsiveness and confounded clinical outcomes of consuming nutraceuticals. Herein, we studied the dose effects of widely used food supplement, microalgae spirulina (Arthrospira platensis), on the colonic microbiota and physiological responses in healthy male Balb/c mice. Based on the analysis of 16s rDNA sequencing, compared to the saline-treated group, oral administration of spirulina once daily for 24 consecutive days altered the diversity, structure, and composition of colonic microbial community at the genus level. More importantly, the abundance of microbial taxa was markedly differentiated at the low (1.5 g/kg) and high (3.0 g/kg) dose of spirulina, among which the relative abundance of Clostridium XIVa, Desulfovibrio, Eubacterium, Barnesiella, Bacteroides, and Flavonifractor were modulated at various degrees. Evaluation of serum biomarkers in mice at the end of spirulina intervention showed reduced the oxidative stress and the blood lipid levels and increased the level of appetite controlling hormone leptin in a dose-response manner, which exhibited the significant correlation with differentially abundant microbiota taxa in the cecum. These findings provide direct evidences of dose-related modulation of gut microbiota and physiological states by spirulina, engendering its future mechanistic investigation of spirulina as potential sources of prebiotics for beneficial health effects via the interaction with gut microbiota.
| S-EPMC6624478 | biostudies-literature
Project description:Microcystins (MC), representing >100 congeners being produced by cyanobacteria, are a hazard for aquatic species. As MC congeners vary in their toxicity, the congener composition of a bloom primarily dictates the severity of adverse effects and appears primarily to be governed by toxicokinetics, i.e., whether transport of MCs occurs via organic anion-transporting polypeptides (Oatps). Differences in observed MC toxicity in various fish species suggest differential expression of Oatp subtypes leading to varying tissue distribution of the very same MC congener within different species. The objectives of this study were the functional characterization and analysis of the tissue distribution of Oatp subtypes in zebrafish (Danio rerio) as a surrogate model for cyprinid fish. Zebrafish Oatps (zfOatps) were cloned, and the organ distribution was determined at the mRNA level. zfOatps were transiently expressed in HEK293 cells for functional characterization using the Oatp substrates estrone-3-sulfate, taurocholate and methotrexate and specific MC congeners (MC-LR, MC-RR, MC-LF and MC-LW). Novel zfOatp isoforms were isolated. Among these isoforms, the organ-specific expression of zfOatp1d1 and of members of the zfOatp1f subfamily was identified. At the functional level, zfOatp1d1, zfOatp1f2, zfOatp1f3 and zfOatp1f4 transported at least one of the Oatp substrates, and zfOatp1d1, zfOatp1f2 and zfOatp1f4 were shown to transport MC congeners. MC-LF and MC-LW were generally transported faster than MC-LR and MC-RR. The subtype-specific expression of zfOatp1d1 and of members of the zfOatp1f subfamily as well as differences in the transport of MC congeners could explain the MC congener-dependent differences in toxicity in cyprinids.
| S-EPMC4674391 | biostudies-literature
Project description:About 2-3 % of the population participates in blood donation programmes. Each whole blood donation or ten apheresis donations cause a loss of 200-250 mg of iron. As a result, one of the most common risks of regular blood donors is iron deficiency. Although this has been known for decades, in most countries, iron status is currently not assessed or treated in this population. Premenopausal women are particularly affected, as they have lower iron reserves and higher daily requirements. Besides anaemia, iron deficiency may lead to fatigue and impaired cognitive and physical performance. Current iron preparations for intravenous administration are well tolerated and allow for application of large doses up to 1 g in one visit. Our hypothesis is that in blood donors with iron deficiency, intravenously administered iron is more efficient and as safe as oral iron supplementation. Since anaemia is one of the most frequent reasons for permanent or intermittent donor deferral, maintaining an iron-replete donor pool may help to prevent shortages in blood supply and to avoid iron deficiency-related comorbidities.In this randomised clinical trial we include male and female blood donors aged ?18 and ?65 years with a ferritin value of ?30 ng/ml. Stratified by gender, participants are randomized with a web-based randomisation tool in a 1:1 ratio to either 1 g of intravenously administered ferric carboxymaltose or 10 g of iron fumarate supplements at one to two daily doses of 100 mg each. Eight to 12 weeks after the first visit, iron status, blood count and symptoms are assessed in both groups. The primary endpoint is the difference in transferrin saturation (%) following the intervention between both groups. Secondary endpoints include other parameters of iron metabolism and red blood cell count, the number of patients with drug-related adverse events, and subjective symptoms including those of the restless legs syndrome, quality of life, and fatigue.Iron supplementation administered intravenously in non-anaemic but iron-deficient blood donors could represent an effective strategy to protect blood donors from comorbidities related with iron deficiency and therefore improve blood donor wellbeing. Furthermore, iron supplementation will help to maintain an iron-replete blood donor pool.EudraCT: 2013-000327-14, Clinical Trials Identifier: NCT01787526 . Registered on 6 February 2013.
| S-EPMC5084417 | biostudies-literature
Project description:Cyanobacterial blooms increasingly impair inland waters, with the potential for a concurrent increase in cyanotoxins that have been linked to animal and human mortalities. Microcystins (MCs) are among the most commonly detected cyanotoxins, but little is known about the distribution of different MC congeners despite large differences in their biomagnification, persistence, and toxicity. Using raw-water intake data from sites around the Great Lakes basin, we applied multivariate canonical analyses and regression tree analyses to identify how different congeners (MC-LA, -LR, -RR, and -YR) varied with changes in meteorological and nutrient conditions over time (10 years) and space (longitude range: 77°2'60 to 94°29'23 W). We found that MC-LR was associated with strong winds, warm temperatures, and nutrient-rich conditions, whereas the equally toxic yet less commonly studied MC-LA tended to dominate under intermediate winds, wetter, and nutrient-poor conditions. A global synthesis of lake data in the peer-reviewed literature showed that the composition of MC congeners differs among regions, with MC-LA more commonly reported in North America than Europe. Global patterns of MC congeners tended to vary with lake nutrient conditions and lake morphometry. Ultimately, knowledge of the environmental factors leading to the formation of different MC congeners in freshwaters is necessary to assess the duration and degree of toxin exposure under future global change.
| S-EPMC6891300 | biostudies-literature
Project description:(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3'-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of ?-tubulin insufficiently occupied by (+)-discodermolide, thereby conferring improved ligand-target interaction. It was recently demonstrated, however, that the C-3'-phenyl side chain occupied a different space, instead extending toward the M-loop of ?-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-discodermolide. Since (+)-discodermolide is a potent inducer of accelerated senescence, a fate that contributes to drug resistance, congeners were also screened for senescence induction. Flow cytometric and transcriptional analysis revealed that the hybrids largely retained the senescence-inducing properties of (+)-discodermolide. In taxol-sensitive cell models, the congeners had improved dose-response parameters relative to (+)-discodermolide and, in some cases, were superior to taxol. However, in cells susceptible to senescence, EMax increased without concomitant improvements in EC50 such that overall dose-response profiles resembled that of (+)-discodermolide.
| S-EPMC6026530 | biostudies-literature
Project description:BackgroundPeriodontitis is a chronic multifactorial inflammatory disease. Porphyromonas gingivalis is a primary periopathogen in the initiation and development of periodontal disease. Evidence has shown that P. gingivalis is associated with systemic diseases, including IBD and fatty liver disease. Inflammatory response is a key feature of diseases related to this species.MethodsC57BL/6 mice were administered either PBS, or P. gingivalis. After 9 weeks, the inflammatory response in gut, spleen, and liver was analyzed.ResultsThe findings revealed significant disturbance of the intestinal microbiota and increased inflammatory factors in the gut of P. gingivalis-administered mice. Administrated P. gingivalis remarkably promoted the secretion of IRF-1 and activated the inflammatory pathway IFN-γ/STAT1 in the spleen. Histologically, mice treated with P. gingivalis exhibited hepatocyte damage and lipid deposition. The inflammatory factors IL-17a, IL-6, and ROR-γt were also upregulated in the liver of mice fed with P. gingivalis. Lee's index, spleen index, and liver index were also increased.ConclusionThese results suggest that administrated P. gingivalis evokes inflammation in gut, spleen, and liver, which might promote the progression of various systemic diseases.
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Project description:Oxytocin (OXT) regulates adult social behavior and has been implicated in its development. Because mammalian milk contains OXT and we have recently identified OXT receptors (OXTR) in the face and oronasal cavity of pre-weaning mice, we hypothesize that orally applied OXT may impact brain activity and acute behavior in developing mice. Oral OXT may have effects in the absence of sensory stimulation or perhaps by modulating sensory input, such as whisker stimulation. The present study investigates the acute c-Fos response in the paraventricular nucleus of the hypothalamus (PVN) and along whisker sensory processing brain regions (trigeminothalamocortical circuit) to orally applied OXT, compared to saline, with and without whisker stimulation in postnatal day (P) 14 and P21 male and female mice. Acute behavioral responses were also quantified after oral OXT with whisker stimulation in a non-social context. Oral OXT with and without whisker stimulation increased c-Fos activity in the PVN of males and decreased c-Fos in the ventroposterior medial thalamus in both males and females compared to saline. Additionally, oral OXT with whisker stimulation decreased c-Fos activity across whisker sensory processing brain regions in males and females and decreased c-Fos activity in the trigeminal motor nucleus of females. Lastly, oral OXT with whisker stimulation increased males' locomotor behavior and decreased females' oromotor behavior compared to saline-treated controls. These data indicate that orally applied OXT has acute brain and behavioral effects on developing mice. OXT-modulated sensory signals may bias brain and behavior development toward the social world.
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Project description:Excessively generated reactive oxygen species are associated with age-related neurodegenerative diseases. We investigated whether scavenging of reactive oxygen species in the brain by orally administered redox nanoparticles, prepared by self-assembly of redox polymers possessing antioxidant nitroxide radicals, facilitates the recovery of cognition in 17-week-old senescence-accelerated prone (SAMP8) mice. The redox polymer was delivered to the brain after oral administration of redox nanoparticles via a disintegration of the nanoparticles in the stomach and absorption of the redox polymer at small intestine to the blood. After treatment for one month, levels of oxidative stress in the brain of SAMP8 mice were remarkably reduced by treatment with redox nanoparticles, compared to that observed with low-molecular-weight nitroxide radicals, resulting in the amelioration of cognitive impairment with increased numbers of surviving neurons. Additionally, treatment by redox nanoparticles did not show any detectable toxicity. These findings indicate the potential of redox polymer nanotherapeutics for treatment of the neurodegenerative diseases.
| S-EPMC4425673 | biostudies-literature
Project description:Synthetic cathinones in bath salts products are psychostimulant drugs of abuse, and 3,4-methylenedioxypyrovalerone (MDPV) is a common constituent of these products. Oral MDPV has been show to stimulate locomotor activity but reinforcing, locomotor and appetitive stimulus effects of oral MDPV are unknown. Choice procedures evaluated preference for 0.03, 0.10, 0.30, and 1.00mg/mL MDPV solutions versus 0.10mg/mL quinine solution or water. To verify that oral MDPV produced pharmacological effects, locomotor activity was monitored during and after consumption of water, quinine, or MDPV solutions. Conditioned place preference (CPP) tested the apparent appetitive effects of a preferred concentration of oral MDPV with locomotor stimulant effects (0.30mg/mL), using water as a control, and compared with results from intraperitoneally-administered MDPV. Consumption of MDPV solutions (0.03-1.00mg/mL) was low when the alternative fluid was water, but a history of MDPV consumption increased MDPV choice. When paired with a quinine control solution, MDPV solutions (0.03-0.30mg/mL) were almost exclusively preferred, and treatment with the catecholamine synthesis inhibitor αMPT decreased MDPV choice. Consumption of MDPV concentrations (0.1-1.0mg/mL) stimulated locomotor activity. Chronic (10day) access to 0.30mg/mL MDPV resulted in escalated consumption, but locomotor effects did not systematically change across the access period. Finally, consumption of 0.30mg/mL MDPV elicited CPP with a magnitude similar to the preference observed following intraperitoneal administration of MDPV. Consistent with human abuse patterns, oral MDPV has reinforcing effects in the mouse which are most likely related to its psychostimulant-like pharmacological profile.
| S-EPMC5708564 | biostudies-literature
Project description:Branaplam is a therapeutic agent currently in clinical development for the treatment of infants with type 1 spinal muscular atrophy (SMA). Since preclinical studies showed that branaplam had cell-cycle arrest effects, we sought to determine whether branaplam may affect postnatal cerebellar development and brain neurogenesis. Here, we describe a novel approach for developmental neurotoxicity testing (DNT) of a central nervous system (CNS) active drug. The effects of orally administered branaplam were evaluated in the SMA neonatal mouse model (SMNΔ7), and in juvenile Wistar Hannover rats and Beagle dogs. Histopathological examination and complementary immunohistochemical studies focused on areas of neurogenesis in the cerebellum (mice, rats, and dogs), and the subventricular zone of the striatum and dentate gyrus (rats and dogs) using antibodies directed against Ki67, phosphorylated histone H3, cleaved caspase-3, and glial fibrillary acidic protein. Additionally, image-analysis based quantification of calbindin-D28k and Ki67 was performed in rats and dogs. The patterns of cell proliferation and apoptosis, and neural migration and innervation in the cerebellum and other brain regions of active adult neurogenesis did not differ between branaplam- and control-treated animals. Quantitative image analysis did not reveal any changes in calbindin-D28k and Ki67 expression in rats and dogs. The data show that orally administered branaplam has no impact on neurogenesis in juvenile animals. Application of selected immunohistochemical stainings in combination with quantitative image analysis on a few critical areas of postnatal CNS development offer a reliable approach to assess DNT of CNS-active drug candidates in juvenile animal toxicity studies.
| S-EPMC8565466 | biostudies-literature