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BIO 300, a Nanosuspension of Genistein, Mitigates Radiation-Induced Erectile Dysfunction and Sensitizes Human Prostate Cancer Xenografts to Radiation Therapy.
Jackson IL, Pavlovic R, Alexander AA, Connors CQ, Newman D, Mahmood J, Eley J, Harvey AJ, Kaytor MD, Vujaskovic Z
(2019) Int J Radiat Oncol Biol Phys 105: 400-409
MeSH Terms: Animals, Blood Pressure, Disease Models, Animal, Drugs, Investigational, Erectile Dysfunction, Fibrosis, Genistein, Male, Mice, Mice, Nude, Nanoparticles, Penile Erection, Penis, Prostate, Radiation Injuries, Experimental, Radiation-Protective Agents, Random Allocation, Rats, Rats, Sprague-Dawley, Regional Blood Flow, Suspensions, Transplantation, Heterologous
Show Abstract · Added March 30, 2020
PURPOSE - To assess whether BIO 300, a synthetic genistein nanosuspension, improves the therapeutic index in prostate cancer treatment by preventing radiation-induced erectile dysfunction (ED) without reducing tumor radiosensitivity.
METHODS AND MATERIALS - Male Sprague-Dawley rats were exposed to 25 Gy of 220-kV prostate-confined x-rays. Animals were randomized to receive sham radiation therapy (RT), RT alone, RT with daily BIO 300 at 2 experimental dosing regimens, or RT with daily genistein. Erectile response was evaluated over time. Penile shaft tissue was harvested for histologic analyses. Murine xenograft studies using prostate cancer cell lines determined the effects of BIO 300 dosing on RT efficacy.
RESULTS - Prostate-confined RT significantly decreased apomorphine-induced erectile response (P < .05 vs sham RT). Erection frequency in animals receiving prophylactic treatment with BIO 300 starting 3 days before RT was similar to sham controls after RT. Treatment with synthetic genistein did not mitigate loss in erectile frequency. At week 14, post-RT treatment with BIO 300 resulted in significantly higher quality of erectile function compared with both the RT arm and the RT arm receiving genistein starting 3 days before irradiation (P < .05). In hormone-sensitive and insensitive prostate tumor-bearing mice, BIO 300 administration did not negatively affect radiation-induced tumor growth delay.
CONCLUSIONS - BIO 300 prevents radiation-induced ED, measured by erection frequency, erectile function, and erection quality, when administered 3 days before RT and continued daily for up to 14 weeks. Data also suggest that BIO 300 administered starting 2 hours after RT mitigates radiation-induced ED. Data provide strong nonclinical evidence to support clinical translation of BIO 300 for mitigation of ED while maintaining treatment response to RT.
Copyright © 2019. Published by Elsevier Inc.
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Mechanistic identification of biofluid metabolite changes as markers of acetaminophen-induced liver toxicity in rats.
Pannala VR, Vinnakota KC, Rawls KD, Estes SK, O'Brien TP, Printz RL, Papin JA, Reifman J, Shiota M, Young JD, Wallqvist A
(2019) Toxicol Appl Pharmacol 372: 19-32
MeSH Terms: Acetaminophen, Animals, Biomarkers, Chemical and Drug Induced Liver Injury, Disease Models, Animal, Early Diagnosis, Liver, Male, Metabolomics, Predictive Value of Tests, Rats, Sprague-Dawley, Time Factors
Show Abstract · Added March 5, 2020
Acetaminophen (APAP) is the most commonly used analgesic and antipyretic drug in the world. Yet, it poses a major risk of liver injury when taken in excess of the therapeutic dose. Current clinical markers do not detect the early onset of liver injury associated with excess APAP-information that is vital to reverse injury progression through available therapeutic interventions. Hence, several studies have used transcriptomics, proteomics, and metabolomics technologies, both independently and in combination, in an attempt to discover potential early markers of liver injury. However, the casual relationship between these observations and their relation to the APAP mechanism of liver toxicity are not clearly understood. Here, we used Sprague-Dawley rats orally gavaged with a single dose of 2 g/kg of APAP to collect tissue samples from the liver and kidney for transcriptomic analysis and plasma and urine samples for metabolomic analysis. We developed and used a multi-tissue, metabolism-based modeling approach to integrate these data, characterize the effect of excess APAP levels on liver metabolism, and identify a panel of plasma and urine metabolites that are associated with APAP-induced liver toxicity. Our analyses, which indicated that pathways involved in nucleotide-, lipid-, and amino acid-related metabolism in the liver were most strongly affected within 10 h following APAP treatment, identified a list of potential metabolites in these pathways that could serve as plausible markers of APAP-induced liver injury. Our approach identifies toxicant-induced changes in endogenous metabolism, is applicable to other toxicants based on transcriptomic data, and provides a mechanistic framework for interpreting metabolite alterations.
Copyright © 2019 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Preparation, preliminary pharmacokinetic and brain targeting study of metformin encapsulated W/O/W composite submicron emulsions promoted by borneol.
Hong L, Li X, Bao Y, Duvall CL, Zhang C, Chen W, Peng C
(2019) Eur J Pharm Sci 133: 160-166
MeSH Terms: Animals, Brain, Camphanes, Drug Compounding, Drug Delivery Systems, Drug Liberation, Emulsions, Female, Hypoglycemic Agents, Male, Metformin, Rats, Sprague-Dawley
Show Abstract · Added April 10, 2019
Metformin hydrochloride (Met) is the first-line drug to treat type 2 diabetes and has shown high efficiency in reducing Alzheimer's disease in recent studies. Herein, a borneol W/O/W composite submicron emulsion containing Met (B-Met-W/O/W SE) was prepared, expecting longer in-vivo circulation time, better bioavailability and brain targeting of Met drug. In the optimized formulation, the mean droplets size, polydispersity index and encapsulation efficiency of the composite were 386.5 nm, 0.219 and 87.26%, respectively. FTIR analysis confirmed that Met interacted with carriers in B-Met-W/O/W SE. Compared with Met free drug, in-vitro release of Met in B-Met-W/O/W SE delivery system was much slower. In pharmacokinetic studies in rats, the AUC, MRT and t of the B-Met-W/O/W SE system were respectively 1.27, 2.49 and 4.02-fold higher than Met free drug system. The drug-targeting index of B-Met-W/O/W SE system to the brain tissue was also higher than that of Met free drug system and Met-W/O/W SE system. These results indicated that B-Met-W/O/W SE drug delivery system is a promising candidate in treating clinical Alzheimer's disease.
Copyright © 2019 Elsevier B.V. All rights reserved.
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12 MeSH Terms
Phenotypes of primary retinal macroglia: Implications for purification and culture conditions.
Backstrom JR, Sheng J, Fischer RA, Sappington RM, Rex TS
(2019) Exp Eye Res 182: 85-92
MeSH Terms: Animals, Astrocytes, Cell Communication, Cell Culture Techniques, Cell Differentiation, Culture Media, Neuroglia, Phenotype, Rats, Rats, Sprague-Dawley, Retina, Retinal Neurons
Show Abstract · Added April 2, 2019
Many neurodegenerations, including those of the visual system, have complex etiologies that include roles for both neurons and glia. In the retina there is evidence that retinal astrocytes play an important role in neurodegeneration. There are several approaches for isolating and growing primary retinal astrocytes, however, they often lead to different results. In this study, we examined the influence of culture conditions on phenotypic maturation of primary, purified retinal glia. We compared retinal astrocytes and Müller glia purified by immunomagnetic separation, as differentiation between these astrocyte subtypes is critical and immuno-based methods are the standard practice of purification. We found that while time in culture impacts the health and phenotype of both astrocytes and Müller glia, the phenotypic maturation of retinal astrocytes was most impacted by serum factors. These factors appeared to actively regulate intermediate filament phenotypes in a manner consistent with the induction of astrocyte-mesenchymal transition (AMT). This propensity for retinal astrocytes to shift along an AMT continuum should be considered when interpreting resulting data. Our goal is that this study will help standardize the field so that studies are replicable, comparable, and as accurate as possible for subsequent interpretation of findings.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N-(2-(1 H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962).
Reed CW, Yohn SE, Washecheck JP, Roenfanz HF, Quitalig MC, Luscombe VB, Jenkins MT, Rodriguez AL, Engers DW, Blobaum AL, Conn PJ, Niswender CM, Lindsley CW
(2019) J Med Chem 62: 1690-1695
MeSH Terms: Allosteric Regulation, Animals, Anti-Anxiety Agents, Benzamides, Brain, Drug Discovery, Male, Mice, Inbred C57BL, Molecular Structure, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Structure-Activity Relationship, Triazoles
Show Abstract · Added March 3, 2020
Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC at minimum effective doses (MEDs) of 3 mg/kg in preclinical anxiety models.
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Glutamate-oxaloacetate transaminase activity promotes palmitate lipotoxicity in rat hepatocytes by enhancing anaplerosis and citric acid cycle flux.
Egnatchik RA, Leamy AK, Sacco SA, Cheah YE, Shiota M, Young JD
(2019) J Biol Chem 294: 3081-3090
MeSH Terms: Animals, Aspartate Aminotransferases, Cell Death, Cell Line, Citric Acid Cycle, Extracellular Space, Glutamine, Hepatocytes, Ketoglutaric Acids, Male, Oxidative Stress, Oxygen, Palmitates, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 28, 2019
Hepatocyte lipotoxicity is characterized by aberrant mitochondrial metabolism, which predisposes cells to oxidative stress and apoptosis. Previously, we reported that translocation of calcium from the endoplasmic reticulum to mitochondria of palmitate-treated hepatocytes activates anaplerotic flux from glutamine to α-ketoglutarate (αKG), which subsequently enters the citric acid cycle (CAC) for oxidation. We hypothesized that increased glutamine anaplerosis fuels elevations in CAC flux and oxidative stress following palmitate treatment. To test this hypothesis, primary rat hepatocytes or immortalized H4IIEC3 rat hepatoma cells were treated with lipotoxic levels of palmitate while modulating anaplerotic pathways leading to αKG. We found that culture media supplemented with glutamine, glutamate, or dimethyl-αKG increased palmitate lipotoxicity compared with media that lacked these anaplerotic substrates. Knockdown of glutamate-oxaloacetate transaminase activity significantly reduced the lipotoxic effects of palmitate, whereas knockdown of glutamate dehydrogenase (Glud1) had no effect on palmitate lipotoxicity. C flux analysis of H4IIEC3 cells co-treated with palmitate and the pan-transaminase inhibitor aminooxyacetic acid confirmed that reductions in lipotoxic markers were associated with decreases in anaplerosis, CAC flux, and oxygen consumption. Taken together, these results demonstrate that lipotoxic palmitate treatments enhance anaplerosis in cultured rat hepatocytes, causing a shift to aberrant transaminase metabolism that fuels CAC dysregulation and oxidative stress.
© 2019 Egnatchik et al.
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Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu).
Bollinger SR, Engers DW, Panarese JD, West M, Engers JL, Loch MT, Rodriguez AL, Blobaum AL, Jones CK, Thompson Gray A, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR
(2019) J Med Chem 62: 342-358
MeSH Terms: Allosteric Regulation, Amides, Animals, Brain, Catalepsy, Cytochrome P-450 CYP1A2, Half-Life, Haloperidol, Humans, Isoxazoles, Male, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This work describes the discovery and characterization of novel 6-(1 H-pyrazolo[4,3- b]pyridin-3-yl)amino-benzo[ d]isothiazole-3-carboxamides as mGlu PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu PAMs. From this work, 27o (VU6001376) was identified as a potent (EC = 50.1 nM, 50.5% GluMax) and selective mGlu PAM with an excellent rat DMPK profile ( in vivo rat CL = 3.1 mL/min/kg, t = 445 min, CYP1A2 IC > 30 μM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.
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Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
Shi CH, Rubel C, Soss SE, Sanchez-Hodge R, Zhang S, Madrigal SC, Ravi S, McDonough H, Page RC, Chazin WJ, Patterson C, Mao CY, Willis MS, Luo HY, Li YS, Stevens DA, Tang MB, Du P, Wang YH, Hu ZW, Xu YM, Schisler JC
(2018) PLoS Genet 14: e1007664
MeSH Terms: Animals, Behavior, Animal, CRISPR-Cas Systems, Cognition, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Inbred C57BL, Models, Molecular, Motor Activity, Mutagenesis, Site-Directed, Phenotype, Point Mutation, Protein Domains, Protein Multimerization, Rats, Rats, Sprague-Dawley, Spinocerebellar Ataxias, Ubiquitin-Protein Ligases
Show Abstract · Added March 26, 2019
CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.
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Alteration of BDNF in the medial prefrontal cortex and the ventral hippocampus impairs extinction of avoidance.
Rosas-Vidal LE, Lozada-Miranda V, Cantres-Rosario Y, Vega-Medina A, Melendez L, Quirk GJ
(2018) Neuropsychopharmacology 43: 2636-2644
MeSH Terms: Animals, Avoidance Learning, Brain-Derived Neurotrophic Factor, CRISPR-Cas Systems, Cell Line, Tumor, Extinction, Psychological, Hippocampus, Male, Neural Pathways, Neuronal Plasticity, Prefrontal Cortex, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 3, 2020
Brain-derived neurotrophic factor (BDNF) is critical for establishing activity-related neural plasticity. There is increasing interest in the mechanisms of active avoidance and its extinction, but little is known about the role of BDNF in these processes. Using the platform-mediated avoidance task combined with local infusions of an antibody against BDNF, we show that blocking BDNF in either prelimbic (PL) or infralimbic (IL) medial prefrontal cortex during extinction training impairs subsequent recall of extinction of avoidance, differing from extinction of conditioned freezing. By combining retrograde tracers with BDNF immunohistochemistry, we show that extinction of avoidance increases BDNF expression in ventral hippocampal (vHPC) neurons, but not amygdala neurons, projecting to PL and IL. Using the CRISPR/Cas9 system, we further show that reducing BDNF production in vHPC neurons impairs recall of avoidance extinction. Thus, the vHPC may mediate behavioral flexibility in avoidance by driving extinction-related plasticity via BDNFergic projections to both PL and IL. These findings add to the growing body of knowledge implicating the hippocampal-prefrontal pathway in anxiety-related disorders and extinction-based therapies.
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Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150 Deacetylation by Axonal HDAC1.
Pathak A, Stanley EM, Hickman FE, Wallace N, Brewer B, Li D, Gluska S, Perlson E, Fuhrmann S, Akassoglou K, Bronfman F, Casaccia P, Burnette DT, Carter BD
(2018) Dev Cell 46: 376-387.e7
MeSH Terms: Animals, Axonal Transport, Axons, Dynactin Complex, Histone Deacetylase 1, Microtubule-Associated Proteins, Neurons, Rats, Sprague-Dawley, Receptor, Nerve Growth Factor
Show Abstract · Added March 27, 2019
During development, neurons undergo apoptosis if they do not receive adequate trophic support from tissues they innervate or when detrimental factors activate the p75 neurotrophin receptor (p75NTR) at their axon ends. Trophic factor deprivation (TFD) or activation of p75NTR in distal axons results in a retrograde degenerative signal. However, the nature of this signal and the regulation of its transport are poorly understood. Here, we identify p75NTR intracellular domain (ICD) and histone deacetylase 1 (HDAC1) as part of a retrograde pro-apoptotic signal generated in response to TFD or ligand binding to p75NTR in sympathetic neurons. We report an unconventional function of HDAC1 in retrograde transport of a degenerative signal and its constitutive presence in sympathetic axons. HDAC1 deacetylates dynactin subunit p150, which enhances its interaction with dynein. These findings define p75NTR ICD as a retrograde degenerative signal and reveal p150 deacetylation as a unique mechanism regulating axonal transport.
Copyright © 2018 Elsevier Inc. All rights reserved.
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