Marion Ehrich - Academia.edu (original) (raw)
Papers by Marion Ehrich
ACS Omega, 2019
In vitro experiments previously published demonstrated the ability of fullerenes to decrease the ... more In vitro experiments previously published demonstrated the ability of fullerenes to decrease the capability of organophosphorus (OP) compounds to inhibit acetylcholinesterase. Experiments described herein demonstrate molecular level affinity interactions between fullerenes and the OP test compound paraoxon with NMR spectroscopy. The calculated binding constant of 19 M −1 indicates that this binding was not covalent.
Inflammatory Bowel Diseases, 2019
BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) a... more BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) and ulcerative colitis (UC) that targets the lanthionine synthetase C-like 2 (LANCL2) pathway and immunometabolic mechanisms. Oral BT-11 was assessed for safety, tolerability, and pharmacokinetics (PK) in normal healthy volunteers (n = 70) in a randomized, double-blind, placebo-controlled trial. Subjects (n = 70) were randomly assigned to one of five single ascending dose cohorts (up to 100 mg/kg, p.o.) and three multiple ascending dose cohorts [up to 100 mg/kg daily (QD) for seven days, orally]. Safety and tolerability were assessed by adverse event (AE) reporting, vital signs, electrocardiogram, hematology, and clinical chemistry. BT-11 did not increase total or gastrointestinal AE rates, as compared with placebo, and no serious adverse events were observed. Oral BT-11 dosing does not result in any clinically significant findings by biochemistry, coagulation, electrocardiogram, hematolo...
MedChemComm, 2019
Iridium based antimicrobial agents have shown efficacy againstS. aureus, including MRSA, and appe... more Iridium based antimicrobial agents have shown efficacy againstS. aureus, including MRSA, and appear to be safe in mice.
Molecular Pharmaceutics, 2019
Adjuvants are a critical component for vaccines, especially for a poorly immunogenic antigen, suc... more Adjuvants are a critical component for vaccines, especially for a poorly immunogenic antigen, such as nicotine. However, the impact of adjuvant release rate from a vaccine formulation on its immunogenicity has not been well illustrated. In this study, we fabricated a series of hybridnanoparticle-based nicotine vaccines to study the impact of adjuvant release rate on their immunological efficacy. It was found that the nanovaccine with a medium or slow adjuvant release rate induced a significantly higher anti-nicotine antibody titer than that with a fast release rate. Furthermore, the medium and slow adjuvant release rates resulted in a significantly lower brain nicotine concentration than the fast release rate after nicotine challenge. All findings suggest that adjuvant release rate affects the immunological efficacy of nanoparticle-based nicotine vaccines, providing a potential strategy to rationally designing vaccine formulations against psychoactive drugs or even other antigens. The hybrid-nanoparticle-based nicotine vaccine with an optimized adjuvant release rate can be a promising next-generation immunotherapeutic candidate against nicotine.
Biomaterials, 2018
Polyethylene glycol (PEG) has long been used in nanoparticle-based drug or vaccine delivery platf... more Polyethylene glycol (PEG) has long been used in nanoparticle-based drug or vaccine delivery platforms. In this study, nano-nicotine vaccines (NanoNicVac) were PEGylated to different degrees to investigate the impact of PEG on the immunological efficacy of the vaccine. Hybrid nanoparticles with various degrees of PEGylation (2.5%-30%) were assembled. It was found that 30% PEGylation resulted in a hybrid nanoparticle of a compromised core-shell structure. A higher concentration of PEG also led to a slower cellular uptake of hybrid nanoparticles by dendritic cells. However, increasing the quantity of the PEG could effectively reduce nanoparticle aggregation during storage and improve the stability of the hybrid nanoparticles. Subsequently, nicotine vaccines were synthesized by conjugating nicotine haptens to the differently PEGylated hybrid nanoparticles. In both in vitro and in vivo studies, it was found that a nicotine vaccine with 20% PEGylation (NanoNicVac 20.0) was significantly m...
Biomaterials, 2018
Current clinically-tested nicotine vaccines have yet shown enhanced smoking cessation efficacy du... more Current clinically-tested nicotine vaccines have yet shown enhanced smoking cessation efficacy due to their low immunogenicity. Achieving a sufficiently high immunogenicity is a necessity for establishing a clinically-viable nicotine vaccine. This study aims to facilitate the immunogenicity of a hybrid nanoparticle-based nicotine vaccine by rationally incorporating toll-like receptor (TLR)-based adjuvants, including monophosphoryl lipid A (MPLA), Resiquimod (R848), CpG oligodeoxynucleotide 1826 (CpG ODN 1826), and their combinations. The nanoparticle-delivered model adjuvant was found to be taken up more efficiently by dendritic cells than the free counterpart. Nanovaccine particles were transported to endosomal compartments upon cellular internalization. The incorporation of single or dual TLR adjuvants not only considerably increased total anti-nicotine IgG titers but also significantly affected IgG subtype distribution in mice. Particularly, the nanovaccines carrying MPLA+R848 or...
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology, Jul 1, 2017
Cerium oxide nanoparticles have widespread use in the materials industry, and have recently come ... more Cerium oxide nanoparticles have widespread use in the materials industry, and have recently come into consideration for biomedical use due to their potent regenerative antioxidant properties. Given that the brain is one of the most highly oxidative organs in the body, it is subject to some of the greatest levels of oxidative stress, particularly in neurodegenerative disease. Therefore, cerium oxide nanoparticles are currently being investigated for efficacy in several neurodegenerative disorders and have shown promising levels of neuroprotection. This review discusses the basis for cerium oxide nanoparticle use in neurodegenerative disease and its hypothesized mechanism of action. The review focuses on an up-to-date summary of in vivo work with cerium oxide nanoparticles in animal models of neurodegenerative disease. Additionally, we examine the current state of information regarding biodistribution, toxicity, and safety for cerium oxide nanoparticles at the in vivo level. Finally, ...
Biomaterials, 2017
A lipid-polymeric hybrid nanoparticle-based next-generation nicotine nanovaccine was rationalized... more A lipid-polymeric hybrid nanoparticle-based next-generation nicotine nanovaccine was rationalized in this study to combat nicotine addiction. A series of nanovaccines, which had nicotine-haptens localized on carrier protein (LPKN), nanoparticle surface (LPNK), or both (LPNKN), were designed to study the impact of hapten localization on their immunological efficacy. All three nanovaccines were efficiently taken up and processed by dendritic cells. LPNKN induced a significantly higher immunogenicity against nicotine and a significantly lower anti-carrier protein antibody level compared to LPKN and LPNK. Meanwhile, it was found that the anti-nicotine antibodies elicited by LPKN and LPNKN bind nicotine stronger than those elicited by LPKN, and LPNK and LPNKN resulted in a more balanced Th1-Th2 immunity than LPKN. Moreover, LPNKN exhibited the best ability to block nicotine from entering the brain of mice. Collectively, the results demonstrated that the immunological efficacy of the hybr...
Biomaterials, Nov 18, 2016
Owing to the urgent need for more effective treatment against nicotine addiction, a hybrid nanopa... more Owing to the urgent need for more effective treatment against nicotine addiction, a hybrid nanoparticle-based nicotine vaccine (NanoNiccine) was developed in this study. NanoNiccine was composed of a poly(lactide-co-glycolide) acid (PLGA) core, keyhole limpet hemocyanin (KLH) as an adjuvant protein enclosed within the PLGA core, a lipid layer, and nicotine haptens conjugated to the outer surface of the lipid layer. In contrast to the traditional nicotine vaccine, NanoNiccine is not a nicotine-protein conjugate vaccine. Instead, the nicotine hapten and protein are separately located in the nanostructure to minimize antibody production towards KLH. The cellular uptake study demonstrated that NanoNiccine was ideal for internalization and processing by dendritic cells (DCs). Mice immunized with NanoNiccine produced much lower IgG level against KLH as compared to that immunized with the traditional nicotine-KLH (Nic-KLH) vaccine. In addition, NanoNiccine achieved up to a 400% higher tite...
International Journal of Toxicology, 2016
Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn’s... more Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn’s disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/d. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/d for 14 days (n = 10 rats dosed/group). Treated and control rats were observed for behavioral detriments, and blood and tissues were collected for clinical pathology and histopathological examination. A functional observational battery demonstrated no differences between treated and control groups over multiple times of observation for quantal, categorical, and continuous end points, including posture, in cage activity, approach, response to touch, weight, grip strength, body temperature, and time on a rotarod. Histopathological examination of the brain, kidney, liver, adrenal g...
Acta biomaterialia, 2015
Lipid-polymer hybrid nanoparticles (NPs), consisting of a polymeric core and a lipid shell, have ... more Lipid-polymer hybrid nanoparticles (NPs), consisting of a polymeric core and a lipid shell, have been intensively examined as delivery systems for cancer drugs, imaging agents, and vaccines. For applications in vaccine particularly, the hybrid NPs need to be able to protect the enclosed antigens during circulation, easily be up-taken by dendritic cells, and possess good stability for prolonged storage. However, the influence of lipid composition on the performance of hybrid NPs has not been well studied. In this study, we demonstrate that higher concentrations of cholesterol in the lipid layer enable slower and more controlled antigen release from lipid-poly(lactide-co-glycolide) acid (lipid-PLGA) NPs in human serum and phosphate buffered saline (PBS). Higher concentrations of cholesterol also promoted in vitro cellular uptake of hybrid NPs, improved the stability of the lipid layer, and protected the integrity of the hybrid structure during long-term storage. However, stabilized hy...
Toxicologic pathology, 2007
Military use of depleted uranium (DU) has renewed interest in the toxicology of this metal. In th... more Military use of depleted uranium (DU) has renewed interest in the toxicology of this metal. In this study, the nephrotoxicity of single exposure DU was assessed with and without pre-exposure stress. Adult male Sprague-Dawley rats (n=288) were administered a single IM dose of 0, 0.1, 0.3 or 1.0 mg/kg DU. Corticosterone concentrations (ng/ml, mean+/-SD) were 763.65+/-130.94 and 189.80+/-90.81 for swim stressed and unstressed rats. Serum and kidney uranium concentration, hematocrit, chemistry, and renal histology were assessed on sacrifice days 1, 3, 7 and 30 post-DU-dosing. Dose related increases in serum and kidney uranium were noted. DU concentration peaked day 1 in the kidney and days 3-7, in the serum. Dose-related elevations of Cr and BUN concentrations were seen on days 3 and 7. A decline in serum albumin coincided with Cr and BUN suggesting protein losing nephropathy. Dose related acute tubular necrosis and proliferative glomulonephritis were seen. Tubular regeneration in low d...
Nanoscale Research Letters, 2014
Due to the many beneficial properties combined from both poly(lactic-co-glycolic acid) (PLGA) nan... more Due to the many beneficial properties combined from both poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and liposomes, lipid-PLGA hybrid NPs have been intensively studied as cancer drug delivery systems, bio-imaging agent carriers, as well as antigen delivery vehicles. However, the impact of lipid composition on the performance of lipid-PLGA hybrid NPs as a delivery system has not been well investigated. In this study, the influence of lipid composition on the stability of the hybrid NPs and in vitro antigen release from NPs under different conditions was examined. The uptake of hybrid NPs with various surface charges by dendritic cells (DCs) was carefully studied. The results showed that PLGA NPs enveloped by a lipid shell with more positive surface charges could improve the stability of the hybrid NPs, enable better controlled release of antigens encapsulated in PLGA NPs, as well as enhance uptake of NPs by DC.
Toxicology, 2012
The current Organisation for Economic Cooperation and Development (OECD) guidelines for evaluatin... more The current Organisation for Economic Cooperation and Development (OECD) guidelines for evaluating organophosphorus-induced delayed neuropathy (OPIDN) require the observation of dosed animals over several days and the sacrifice of 48 hens. Adhering to these protocols in tests with enantiomers is difficult because large quantities of the compound are needed and many animals must be utilized. Thus, developing an in vitro screening protocol to evaluate chiral organophosphorus pesticides (OPs) that can induce delayed neuropathy is important. This work aimed to evaluate, in blood and brain samples from hens, human blood, and human cell culture samples, the potential of the enantiomeric forms of methamidophos to induce acetylcholinesterase (AChE) inhibition and/or delayed neurotoxicity. Calpain activation was also evaluated in the hen brain and SH-SY5Y human neuroblastoma cells. The ratio between the inhibition of neuropathy target esterase (NTE) and AChE activities by the methamidophos enantiomers was evaluated as a possible indicator of the enantiomers' abilities to induce OPIDN. The (−)-methamidophos exhibited an IC 50 value approximately 6 times greater than that of the (+)-methamidophos for the lymphocyte NTE (LNTE) of hens, and (+)-methamidophos exhibited an IC 50 value approximately 7 times larger than that of the (−)-methamidophos for the hen brain AChE. The IC 50 values were 7 times higher for the human erythrocyte AChE and 5 times higher for AChE in the SH-SY5Y human neuroblastoma cells. Considering the esterases inhibition and calpain results, (+)-methamidophos would be expected to have a greater ability to induce OPIDN than the (−)-methamidophos in humans and in hens.
Toxicological Sciences, 2005
Signaling through neurotrophic receptors is necessary for differentiation and survival of the dev... more Signaling through neurotrophic receptors is necessary for differentiation and survival of the developing nervous system. The present study examined the effects of the organic mercury compound thimerosal on nerve growth factor signal transduction and cell death in a human neuroblastoma cell line (SH-SY5Y cells). Following exposure to 100 ng/ml NGF and increasing concentrations of thimerosal (1 nM-10 mM), we measured the activation of TrkA, MAPK, and PKC-d. In controls, the activation of TrkA MAPK and PKC-d peaked after 5 min of exposure to NGF and then decreased but was still detectable at 60 min. Concurrent exposure to increasing concentrations of thimerosal and NGF for 5 min resulted in a concentration-dependent decrease in TrkA and MAPK phosphorylation, which was evident at 50 nM for TrkA and 100 nM for MAPK. Cell viability was assessed by the LDH assay. Following 24-h exposure to increasing concentrations of thimerosal, the EC 50 for cell death in the presence or absence of NGF was 596 nM and 38.7 nM, respectively. Following 48-h exposure to increasing concentrations of thimerosal, the EC 50 for cell death in the presence and absence of NGF was 105 nM and 4.35 nM, respectively. This suggests that NGF provides protection against thimerosal cytotoxicity. To determine if apoptotic versus necrotic cell death was occurring, oligonucleosomal fragmented DNA was quantified by ELISA. Control levels of fragmented DNA were similar in both the presence and absence of NGF. With and without NGF, thimerosal caused elevated levels of fragmented DNA appearing at 0.01 mM (apoptosis) to decrease at concentrations >1 mM (necrosis). These data demonstrate that thimerosal could alter NGF-induced signaling in neurotrophin-treated cells at concentrations lower than those responsible for cell death.
Toxicological Sciences, 1998
spectrum of cholinergic effects. An approach similar to that developed for OP pesticides could be... more spectrum of cholinergic effects. An approach similar to that developed for OP pesticides could be used to determine if other classes or groups of pesticides that share structural and toxicological characteristics act by a common mechanism of toxicity or by distinct mechanisms,
Toxicological Sciences, 1996
Synthetic polyol-based lubricating oils containing 3% of either commercial tricresyl phosphate (T... more Synthetic polyol-based lubricating oils containing 3% of either commercial tricresyl phosphate (TCP), triphenylphosphorothionate (TPPT), or butylated triphenyl phosphate (BTP) additive were evaluated for neurotoxicity in the adult hen using clinical, biochemical, and neuropathological endpoints. Groups of 17-20 hens were administered the oils by oral gavage at a "limit dose" of 1 g/kg, 5 days a week for 13 weeks. A group of positive control hens was included which received 7.5 mg/kg of one isomer of TCP (tri-ort/jo-cresyl phosphate, TOCP) on the same regimen, with an additional oral dose of 500 mg/kg given 12 days before the end of the experiment A negative control group received saline. Neurotoxic esterase (NTE) activity in brain and spinal cord of hens dosed with the lubricating oils was not significantly different from saline controls after 6 weeks of treatment After 13 weeks of dosing, NTE was inhibited 23 to 34% in brains of lubricant-treated hens. Clinical assessments of walking ability did not indicate any differences between the negative control group and lubricant-treated hens. Moreover, neuropathological examination revealed no alterations indicative of organophosphorus-induced delayed neuropathy (OPIDN). In hens treated with the positive control, significant inhibition of NTE was observed in brain and spinal cord at both 6 and 13 weeks of dosing; this group also demonstrated clinical impairment and pathological lesions indicative of OPIDN. In conclusion, the results of the present study indicated that synthetic polyol-based lubricating oils containing up to 3% TCP, TPPT, or BTP had low neurotoxic potential and should not pose a hazard under realistic conditions of exposure, c 19% sodaj of Toxtotogj Commercial grade tricresyl phosphate (TCP) and other phosphorus compounds are used as additives in a variety of lubricating oils, including those with applications in jet aircraft engines. Tri-orr/io-cresyl phosphate (TOCP) is one of a number of organophosphorus compounds that are capable
Toxicological Sciences, 2010
Toxicity and integrity disruption in response to transport through the blood-brain barrier (BBB) ... more Toxicity and integrity disruption in response to transport through the blood-brain barrier (BBB) of the organophosphates malathion and malaoxon and heavy metal lead acetate were assessed in two in vitro barrier systems. One system was constructed using bovine brain microvascular endothelial cells (BMEC), while the other system was constructed with rat brain microvascular endothelial cells (RBE4); both were cocultured with rat astrocytes. We hypothesized that these models would respond differently to neurotoxic compounds. Concentrations of malathion, malaoxon, and lead acetate between 0.01mM and 1mM were assessed for their capacity to cause cytotoxicity to the astrocytes and endothelial cells utilized to construct the BBB systems, with the least cytotoxic concentrations chosen for transfer assessments of neurotoxicants through the barrier systems. Concentrations of malathion at 10mM, malaoxon at 1mM, and lead acetate at 1 and 10mM were selected. Lead concentrations were measured in media of the abluminal and luminal sides of both systems using graphite furnace atomic absorption at the beginning of the treatment (T0) and 14 h later (T14). Passage of organophosphate compounds was determined utilizing inhibition of acetylcholinesterase enzyme in a neuroblastoma cell line (SH-SY5Y) localized below the barrier system. Transendothelial electrical resistance was assessed as a measurement of integrity of the barrier systems, with baseline values higher with the RBE4-astrocyte system than with the BMECastrocyte system. Metabolic capability, as measured by esterase activity, was higher in BMECs, which were more likely to retain lead than RBE4 cells. Results suggest that differences in endothelial cell source can affect the outcome of studies on toxicant transfer through in vitro BBB systems.
Toxicologic Pathology, 2005
Adult male Long-Evans rats were exposed to 2 neurotoxic organophosphates in a setting of chronic ... more Adult male Long-Evans rats were exposed to 2 neurotoxic organophosphates in a setting of chronic stress, over a 63-day period. The organophosphates were tri- ortho-tolyl phosphate (TOTP) administered in 14 gavage doses of 75, 150 or 300 mg/kg, and chlorpyrifos, given in two 60 mg/kg subcutaneous exposures. Corticosterone was added to the drinking water at 400 μg/ml, to model aspects of chronic stress. These compounds/dosages were administered individually and in combination, with appropriate controls, giving rise to 16 experimental groups. The major neuropathologic change was the presence of axonal degeneration progressing to myelinated fiber degeneration, mainly in distal regions of selected fiber tracts and peripheral nerve, seen in animals sacrificed on experimental day 63. The cervical spinal cord and medullary levels of the sensory gracile fasciculus were most prominently affected. This axonopathy/fiber degeneration was TOTP dose-related at the 300 and 150 mg/kg levels. There w...
![Research paper thumbnail of Corrigendum to “Chlorpyrifos Alters Functional Integrity and Structure of an In Vitro BBB Model: Co-Cultures of Bovine Endothelial Cells and Neonatal Rat Astrocytes” [NeuroToxicology 26 (2005) 77–88]](https://attachments.academia-assets.com/118651396/thumbnails/1.jpg)
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ACS Omega, 2019
In vitro experiments previously published demonstrated the ability of fullerenes to decrease the ... more In vitro experiments previously published demonstrated the ability of fullerenes to decrease the capability of organophosphorus (OP) compounds to inhibit acetylcholinesterase. Experiments described herein demonstrate molecular level affinity interactions between fullerenes and the OP test compound paraoxon with NMR spectroscopy. The calculated binding constant of 19 M −1 indicates that this binding was not covalent.
Inflammatory Bowel Diseases, 2019
BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) a... more BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) and ulcerative colitis (UC) that targets the lanthionine synthetase C-like 2 (LANCL2) pathway and immunometabolic mechanisms. Oral BT-11 was assessed for safety, tolerability, and pharmacokinetics (PK) in normal healthy volunteers (n = 70) in a randomized, double-blind, placebo-controlled trial. Subjects (n = 70) were randomly assigned to one of five single ascending dose cohorts (up to 100 mg/kg, p.o.) and three multiple ascending dose cohorts [up to 100 mg/kg daily (QD) for seven days, orally]. Safety and tolerability were assessed by adverse event (AE) reporting, vital signs, electrocardiogram, hematology, and clinical chemistry. BT-11 did not increase total or gastrointestinal AE rates, as compared with placebo, and no serious adverse events were observed. Oral BT-11 dosing does not result in any clinically significant findings by biochemistry, coagulation, electrocardiogram, hematolo...
MedChemComm, 2019
Iridium based antimicrobial agents have shown efficacy againstS. aureus, including MRSA, and appe... more Iridium based antimicrobial agents have shown efficacy againstS. aureus, including MRSA, and appear to be safe in mice.
Molecular Pharmaceutics, 2019
Adjuvants are a critical component for vaccines, especially for a poorly immunogenic antigen, suc... more Adjuvants are a critical component for vaccines, especially for a poorly immunogenic antigen, such as nicotine. However, the impact of adjuvant release rate from a vaccine formulation on its immunogenicity has not been well illustrated. In this study, we fabricated a series of hybridnanoparticle-based nicotine vaccines to study the impact of adjuvant release rate on their immunological efficacy. It was found that the nanovaccine with a medium or slow adjuvant release rate induced a significantly higher anti-nicotine antibody titer than that with a fast release rate. Furthermore, the medium and slow adjuvant release rates resulted in a significantly lower brain nicotine concentration than the fast release rate after nicotine challenge. All findings suggest that adjuvant release rate affects the immunological efficacy of nanoparticle-based nicotine vaccines, providing a potential strategy to rationally designing vaccine formulations against psychoactive drugs or even other antigens. The hybrid-nanoparticle-based nicotine vaccine with an optimized adjuvant release rate can be a promising next-generation immunotherapeutic candidate against nicotine.
Biomaterials, 2018
Polyethylene glycol (PEG) has long been used in nanoparticle-based drug or vaccine delivery platf... more Polyethylene glycol (PEG) has long been used in nanoparticle-based drug or vaccine delivery platforms. In this study, nano-nicotine vaccines (NanoNicVac) were PEGylated to different degrees to investigate the impact of PEG on the immunological efficacy of the vaccine. Hybrid nanoparticles with various degrees of PEGylation (2.5%-30%) were assembled. It was found that 30% PEGylation resulted in a hybrid nanoparticle of a compromised core-shell structure. A higher concentration of PEG also led to a slower cellular uptake of hybrid nanoparticles by dendritic cells. However, increasing the quantity of the PEG could effectively reduce nanoparticle aggregation during storage and improve the stability of the hybrid nanoparticles. Subsequently, nicotine vaccines were synthesized by conjugating nicotine haptens to the differently PEGylated hybrid nanoparticles. In both in vitro and in vivo studies, it was found that a nicotine vaccine with 20% PEGylation (NanoNicVac 20.0) was significantly m...
Biomaterials, 2018
Current clinically-tested nicotine vaccines have yet shown enhanced smoking cessation efficacy du... more Current clinically-tested nicotine vaccines have yet shown enhanced smoking cessation efficacy due to their low immunogenicity. Achieving a sufficiently high immunogenicity is a necessity for establishing a clinically-viable nicotine vaccine. This study aims to facilitate the immunogenicity of a hybrid nanoparticle-based nicotine vaccine by rationally incorporating toll-like receptor (TLR)-based adjuvants, including monophosphoryl lipid A (MPLA), Resiquimod (R848), CpG oligodeoxynucleotide 1826 (CpG ODN 1826), and their combinations. The nanoparticle-delivered model adjuvant was found to be taken up more efficiently by dendritic cells than the free counterpart. Nanovaccine particles were transported to endosomal compartments upon cellular internalization. The incorporation of single or dual TLR adjuvants not only considerably increased total anti-nicotine IgG titers but also significantly affected IgG subtype distribution in mice. Particularly, the nanovaccines carrying MPLA+R848 or...
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology, Jul 1, 2017
Cerium oxide nanoparticles have widespread use in the materials industry, and have recently come ... more Cerium oxide nanoparticles have widespread use in the materials industry, and have recently come into consideration for biomedical use due to their potent regenerative antioxidant properties. Given that the brain is one of the most highly oxidative organs in the body, it is subject to some of the greatest levels of oxidative stress, particularly in neurodegenerative disease. Therefore, cerium oxide nanoparticles are currently being investigated for efficacy in several neurodegenerative disorders and have shown promising levels of neuroprotection. This review discusses the basis for cerium oxide nanoparticle use in neurodegenerative disease and its hypothesized mechanism of action. The review focuses on an up-to-date summary of in vivo work with cerium oxide nanoparticles in animal models of neurodegenerative disease. Additionally, we examine the current state of information regarding biodistribution, toxicity, and safety for cerium oxide nanoparticles at the in vivo level. Finally, ...
Biomaterials, 2017
A lipid-polymeric hybrid nanoparticle-based next-generation nicotine nanovaccine was rationalized... more A lipid-polymeric hybrid nanoparticle-based next-generation nicotine nanovaccine was rationalized in this study to combat nicotine addiction. A series of nanovaccines, which had nicotine-haptens localized on carrier protein (LPKN), nanoparticle surface (LPNK), or both (LPNKN), were designed to study the impact of hapten localization on their immunological efficacy. All three nanovaccines were efficiently taken up and processed by dendritic cells. LPNKN induced a significantly higher immunogenicity against nicotine and a significantly lower anti-carrier protein antibody level compared to LPKN and LPNK. Meanwhile, it was found that the anti-nicotine antibodies elicited by LPKN and LPNKN bind nicotine stronger than those elicited by LPKN, and LPNK and LPNKN resulted in a more balanced Th1-Th2 immunity than LPKN. Moreover, LPNKN exhibited the best ability to block nicotine from entering the brain of mice. Collectively, the results demonstrated that the immunological efficacy of the hybr...
Biomaterials, Nov 18, 2016
Owing to the urgent need for more effective treatment against nicotine addiction, a hybrid nanopa... more Owing to the urgent need for more effective treatment against nicotine addiction, a hybrid nanoparticle-based nicotine vaccine (NanoNiccine) was developed in this study. NanoNiccine was composed of a poly(lactide-co-glycolide) acid (PLGA) core, keyhole limpet hemocyanin (KLH) as an adjuvant protein enclosed within the PLGA core, a lipid layer, and nicotine haptens conjugated to the outer surface of the lipid layer. In contrast to the traditional nicotine vaccine, NanoNiccine is not a nicotine-protein conjugate vaccine. Instead, the nicotine hapten and protein are separately located in the nanostructure to minimize antibody production towards KLH. The cellular uptake study demonstrated that NanoNiccine was ideal for internalization and processing by dendritic cells (DCs). Mice immunized with NanoNiccine produced much lower IgG level against KLH as compared to that immunized with the traditional nicotine-KLH (Nic-KLH) vaccine. In addition, NanoNiccine achieved up to a 400% higher tite...
International Journal of Toxicology, 2016
Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn’s... more Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn’s disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/d. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/d for 14 days (n = 10 rats dosed/group). Treated and control rats were observed for behavioral detriments, and blood and tissues were collected for clinical pathology and histopathological examination. A functional observational battery demonstrated no differences between treated and control groups over multiple times of observation for quantal, categorical, and continuous end points, including posture, in cage activity, approach, response to touch, weight, grip strength, body temperature, and time on a rotarod. Histopathological examination of the brain, kidney, liver, adrenal g...
Acta biomaterialia, 2015
Lipid-polymer hybrid nanoparticles (NPs), consisting of a polymeric core and a lipid shell, have ... more Lipid-polymer hybrid nanoparticles (NPs), consisting of a polymeric core and a lipid shell, have been intensively examined as delivery systems for cancer drugs, imaging agents, and vaccines. For applications in vaccine particularly, the hybrid NPs need to be able to protect the enclosed antigens during circulation, easily be up-taken by dendritic cells, and possess good stability for prolonged storage. However, the influence of lipid composition on the performance of hybrid NPs has not been well studied. In this study, we demonstrate that higher concentrations of cholesterol in the lipid layer enable slower and more controlled antigen release from lipid-poly(lactide-co-glycolide) acid (lipid-PLGA) NPs in human serum and phosphate buffered saline (PBS). Higher concentrations of cholesterol also promoted in vitro cellular uptake of hybrid NPs, improved the stability of the lipid layer, and protected the integrity of the hybrid structure during long-term storage. However, stabilized hy...
Toxicologic pathology, 2007
Military use of depleted uranium (DU) has renewed interest in the toxicology of this metal. In th... more Military use of depleted uranium (DU) has renewed interest in the toxicology of this metal. In this study, the nephrotoxicity of single exposure DU was assessed with and without pre-exposure stress. Adult male Sprague-Dawley rats (n=288) were administered a single IM dose of 0, 0.1, 0.3 or 1.0 mg/kg DU. Corticosterone concentrations (ng/ml, mean+/-SD) were 763.65+/-130.94 and 189.80+/-90.81 for swim stressed and unstressed rats. Serum and kidney uranium concentration, hematocrit, chemistry, and renal histology were assessed on sacrifice days 1, 3, 7 and 30 post-DU-dosing. Dose related increases in serum and kidney uranium were noted. DU concentration peaked day 1 in the kidney and days 3-7, in the serum. Dose-related elevations of Cr and BUN concentrations were seen on days 3 and 7. A decline in serum albumin coincided with Cr and BUN suggesting protein losing nephropathy. Dose related acute tubular necrosis and proliferative glomulonephritis were seen. Tubular regeneration in low d...
Nanoscale Research Letters, 2014
Due to the many beneficial properties combined from both poly(lactic-co-glycolic acid) (PLGA) nan... more Due to the many beneficial properties combined from both poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and liposomes, lipid-PLGA hybrid NPs have been intensively studied as cancer drug delivery systems, bio-imaging agent carriers, as well as antigen delivery vehicles. However, the impact of lipid composition on the performance of lipid-PLGA hybrid NPs as a delivery system has not been well investigated. In this study, the influence of lipid composition on the stability of the hybrid NPs and in vitro antigen release from NPs under different conditions was examined. The uptake of hybrid NPs with various surface charges by dendritic cells (DCs) was carefully studied. The results showed that PLGA NPs enveloped by a lipid shell with more positive surface charges could improve the stability of the hybrid NPs, enable better controlled release of antigens encapsulated in PLGA NPs, as well as enhance uptake of NPs by DC.
Toxicology, 2012
The current Organisation for Economic Cooperation and Development (OECD) guidelines for evaluatin... more The current Organisation for Economic Cooperation and Development (OECD) guidelines for evaluating organophosphorus-induced delayed neuropathy (OPIDN) require the observation of dosed animals over several days and the sacrifice of 48 hens. Adhering to these protocols in tests with enantiomers is difficult because large quantities of the compound are needed and many animals must be utilized. Thus, developing an in vitro screening protocol to evaluate chiral organophosphorus pesticides (OPs) that can induce delayed neuropathy is important. This work aimed to evaluate, in blood and brain samples from hens, human blood, and human cell culture samples, the potential of the enantiomeric forms of methamidophos to induce acetylcholinesterase (AChE) inhibition and/or delayed neurotoxicity. Calpain activation was also evaluated in the hen brain and SH-SY5Y human neuroblastoma cells. The ratio between the inhibition of neuropathy target esterase (NTE) and AChE activities by the methamidophos enantiomers was evaluated as a possible indicator of the enantiomers' abilities to induce OPIDN. The (−)-methamidophos exhibited an IC 50 value approximately 6 times greater than that of the (+)-methamidophos for the lymphocyte NTE (LNTE) of hens, and (+)-methamidophos exhibited an IC 50 value approximately 7 times larger than that of the (−)-methamidophos for the hen brain AChE. The IC 50 values were 7 times higher for the human erythrocyte AChE and 5 times higher for AChE in the SH-SY5Y human neuroblastoma cells. Considering the esterases inhibition and calpain results, (+)-methamidophos would be expected to have a greater ability to induce OPIDN than the (−)-methamidophos in humans and in hens.
Toxicological Sciences, 2005
Signaling through neurotrophic receptors is necessary for differentiation and survival of the dev... more Signaling through neurotrophic receptors is necessary for differentiation and survival of the developing nervous system. The present study examined the effects of the organic mercury compound thimerosal on nerve growth factor signal transduction and cell death in a human neuroblastoma cell line (SH-SY5Y cells). Following exposure to 100 ng/ml NGF and increasing concentrations of thimerosal (1 nM-10 mM), we measured the activation of TrkA, MAPK, and PKC-d. In controls, the activation of TrkA MAPK and PKC-d peaked after 5 min of exposure to NGF and then decreased but was still detectable at 60 min. Concurrent exposure to increasing concentrations of thimerosal and NGF for 5 min resulted in a concentration-dependent decrease in TrkA and MAPK phosphorylation, which was evident at 50 nM for TrkA and 100 nM for MAPK. Cell viability was assessed by the LDH assay. Following 24-h exposure to increasing concentrations of thimerosal, the EC 50 for cell death in the presence or absence of NGF was 596 nM and 38.7 nM, respectively. Following 48-h exposure to increasing concentrations of thimerosal, the EC 50 for cell death in the presence and absence of NGF was 105 nM and 4.35 nM, respectively. This suggests that NGF provides protection against thimerosal cytotoxicity. To determine if apoptotic versus necrotic cell death was occurring, oligonucleosomal fragmented DNA was quantified by ELISA. Control levels of fragmented DNA were similar in both the presence and absence of NGF. With and without NGF, thimerosal caused elevated levels of fragmented DNA appearing at 0.01 mM (apoptosis) to decrease at concentrations >1 mM (necrosis). These data demonstrate that thimerosal could alter NGF-induced signaling in neurotrophin-treated cells at concentrations lower than those responsible for cell death.
Toxicological Sciences, 1998
spectrum of cholinergic effects. An approach similar to that developed for OP pesticides could be... more spectrum of cholinergic effects. An approach similar to that developed for OP pesticides could be used to determine if other classes or groups of pesticides that share structural and toxicological characteristics act by a common mechanism of toxicity or by distinct mechanisms,
Toxicological Sciences, 1996
Synthetic polyol-based lubricating oils containing 3% of either commercial tricresyl phosphate (T... more Synthetic polyol-based lubricating oils containing 3% of either commercial tricresyl phosphate (TCP), triphenylphosphorothionate (TPPT), or butylated triphenyl phosphate (BTP) additive were evaluated for neurotoxicity in the adult hen using clinical, biochemical, and neuropathological endpoints. Groups of 17-20 hens were administered the oils by oral gavage at a "limit dose" of 1 g/kg, 5 days a week for 13 weeks. A group of positive control hens was included which received 7.5 mg/kg of one isomer of TCP (tri-ort/jo-cresyl phosphate, TOCP) on the same regimen, with an additional oral dose of 500 mg/kg given 12 days before the end of the experiment A negative control group received saline. Neurotoxic esterase (NTE) activity in brain and spinal cord of hens dosed with the lubricating oils was not significantly different from saline controls after 6 weeks of treatment After 13 weeks of dosing, NTE was inhibited 23 to 34% in brains of lubricant-treated hens. Clinical assessments of walking ability did not indicate any differences between the negative control group and lubricant-treated hens. Moreover, neuropathological examination revealed no alterations indicative of organophosphorus-induced delayed neuropathy (OPIDN). In hens treated with the positive control, significant inhibition of NTE was observed in brain and spinal cord at both 6 and 13 weeks of dosing; this group also demonstrated clinical impairment and pathological lesions indicative of OPIDN. In conclusion, the results of the present study indicated that synthetic polyol-based lubricating oils containing up to 3% TCP, TPPT, or BTP had low neurotoxic potential and should not pose a hazard under realistic conditions of exposure, c 19% sodaj of Toxtotogj Commercial grade tricresyl phosphate (TCP) and other phosphorus compounds are used as additives in a variety of lubricating oils, including those with applications in jet aircraft engines. Tri-orr/io-cresyl phosphate (TOCP) is one of a number of organophosphorus compounds that are capable
Toxicological Sciences, 2010
Toxicity and integrity disruption in response to transport through the blood-brain barrier (BBB) ... more Toxicity and integrity disruption in response to transport through the blood-brain barrier (BBB) of the organophosphates malathion and malaoxon and heavy metal lead acetate were assessed in two in vitro barrier systems. One system was constructed using bovine brain microvascular endothelial cells (BMEC), while the other system was constructed with rat brain microvascular endothelial cells (RBE4); both were cocultured with rat astrocytes. We hypothesized that these models would respond differently to neurotoxic compounds. Concentrations of malathion, malaoxon, and lead acetate between 0.01mM and 1mM were assessed for their capacity to cause cytotoxicity to the astrocytes and endothelial cells utilized to construct the BBB systems, with the least cytotoxic concentrations chosen for transfer assessments of neurotoxicants through the barrier systems. Concentrations of malathion at 10mM, malaoxon at 1mM, and lead acetate at 1 and 10mM were selected. Lead concentrations were measured in media of the abluminal and luminal sides of both systems using graphite furnace atomic absorption at the beginning of the treatment (T0) and 14 h later (T14). Passage of organophosphate compounds was determined utilizing inhibition of acetylcholinesterase enzyme in a neuroblastoma cell line (SH-SY5Y) localized below the barrier system. Transendothelial electrical resistance was assessed as a measurement of integrity of the barrier systems, with baseline values higher with the RBE4-astrocyte system than with the BMECastrocyte system. Metabolic capability, as measured by esterase activity, was higher in BMECs, which were more likely to retain lead than RBE4 cells. Results suggest that differences in endothelial cell source can affect the outcome of studies on toxicant transfer through in vitro BBB systems.
Toxicologic Pathology, 2005
Adult male Long-Evans rats were exposed to 2 neurotoxic organophosphates in a setting of chronic ... more Adult male Long-Evans rats were exposed to 2 neurotoxic organophosphates in a setting of chronic stress, over a 63-day period. The organophosphates were tri- ortho-tolyl phosphate (TOTP) administered in 14 gavage doses of 75, 150 or 300 mg/kg, and chlorpyrifos, given in two 60 mg/kg subcutaneous exposures. Corticosterone was added to the drinking water at 400 μg/ml, to model aspects of chronic stress. These compounds/dosages were administered individually and in combination, with appropriate controls, giving rise to 16 experimental groups. The major neuropathologic change was the presence of axonal degeneration progressing to myelinated fiber degeneration, mainly in distal regions of selected fiber tracts and peripheral nerve, seen in animals sacrificed on experimental day 63. The cervical spinal cord and medullary levels of the sensory gracile fasciculus were most prominently affected. This axonopathy/fiber degeneration was TOTP dose-related at the 300 and 150 mg/kg levels. There w...