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Short Amylin Receptor Antagonist Peptides Improve Memory Deficits In Alzheimer’S Disease Mouse Model, Rania Soudy, Ryoichi Kimura, Aarti Patel, Wen Fu, Kamaljit Kaur, David Westaway, Jing Yang, Jack Jhamandas 2019 University of Alberta

Short Amylin Receptor Antagonist Peptides Improve Memory Deficits In Alzheimer’S Disease Mouse Model, Rania Soudy, Ryoichi Kimura, Aarti Patel, Wen Fu, Kamaljit Kaur, David Westaway, Jing Yang, Jack Jhamandas

Pharmacy Faculty Articles and Research

Recent evidence supports involvement of amylin and the amylin receptor in the pathogenesis of Alzheimer’s disease (AD). We have previously shown that amylin receptor antagonist, AC253, improves spatial memory in AD mouse models. Herein, we generated and screened a peptide library and identified two short sequence amylin peptides (12–14 aa) that are proteolytically stable, brain penetrant when administered intraperitoneally, neuroprotective against Aβ toxicity and restore diminished levels of hippocampal long term potentiation in AD mice. Systemic administration of the peptides for five weeks in aged 5XFAD mice improved spatial memory, reduced amyloid plaque burden, and neuroinflammation. The common ...


Phosphoramide Mustard Exposure Induces Dna Adduct Formation And The Dna Damage Repair Response In Rat Ovarian Granulosa Cells, Shanthi Ganesan, Aileen F. Keating 2019 Iowa State University

Phosphoramide Mustard Exposure Induces Dna Adduct Formation And The Dna Damage Repair Response In Rat Ovarian Granulosa Cells, Shanthi Ganesan, Aileen F. Keating

Aileen Keating

Phosphoramide mustard (PM), the ovotoxic metabolite of the anti-cancer agent cyclophosphamide (CPA), destroys rapidly dividing cells by forming NOR-G-OH, NOR-G and G-NOR-G adducts with DNA, potentially leading to DNA damage. A previous study demonstrated that PM induces ovarian DNA damage in rat ovaries. To investigate whether PM induces DNA adduct formation, DNA damage and induction of the DNA repair response, rat spontaneously immortalized granulosa cells (SIGCs) were treated with vehicle control (1% DMSO) or PM (3 or 6 μM) for 24 or 48 h. Cell viability was reduced (P < 0.05) after 48 h of exposure to 3 or 6 μM PM. The NOR-G-OH DNA adduct was detected after 24 h of 6 μM PM exposure, while the more cytotoxic G-NOR-G DNA adduct was formed after 48 h by exposure to both PM concentrations. Phosphorylated H2AX (γH2AX), a marker of DNA double stranded break occurrence, was also increased by PM exposure, coincident with DNA adduct formation. Additionally, induction of genes (Atm, Parp1, Prkdc, Xrcc6, and Brca1) and proteins (ATM, γH2AX, PARP-1, PRKDC, XRCC6, and BRCA1) involved in DNA repair were observed in both a time- and dose-dependent manner. These data support that PM induces DNA adduct formation in ovarian granulosa cells, induces DNA damage and elicits the ovarian DNA repair response.


Protective Role For Ovarian Glutathione S-Transferase Isoform Pi During 7,12-Dimethylbenz[A]Anthracene-Induced Ovotoxicity, Poulomi Bhattacharya, Aileen F. Keating 2019 Iowa State University

Protective Role For Ovarian Glutathione S-Transferase Isoform Pi During 7,12-Dimethylbenz[A]Anthracene-Induced Ovotoxicity, Poulomi Bhattacharya, Aileen F. Keating

Aileen Keating

7,12-dimethylbenz[a]anthracene (DMBA) destroys ovarian follicles at all developmental stages. This study investigated a role for the glutathione S-transferase (Gst) isoforms alpha (a), mu (m) and pi (p) and the transcription factors, Ahr and Nrf2, during DMBA-induced ovotoxicity, and their regulation by phosphatidylinositol-3 kinase (PI3K) signaling. Negative regulation of JNK by GSTP during DMBA exposure was also studied. Post-natal day (PND) 4 Fischer 344 rat ovaries were exposed to vehicle control (1% DMSO) ± DMBA (1 μM) or vehicle control (1% DMSO) ± LY294002 (PI3K inhibitor; 20 μM) for 1, 2, 4, or 6 days. Total RNA or protein was ...


Mechanisms Of Ovarian Atresia Induced By Xenobiotic Exposures, Jason W. Ross, Aileen F. Keating 2019 Iowa State University

Mechanisms Of Ovarian Atresia Induced By Xenobiotic Exposures, Jason W. Ross, Aileen F. Keating

Aileen Keating

The focus of this chapter is the mechanisms of apoptosis that occur during “normal” (physiologically-induced) or “abnormal” (chemical- or pathology-induced) attrition of ovarian oocytes. One of the primary functions of the ovary is development and maturation of oocytes, which occur within a follicular structure. During fetal development of the ovary, primordial germ cells (oogonia) are formed and become oocytes when they stop dividing, and are arrested at the diplotene stage (prophase) of the first meiotic division. At this stage the oocyte is surrounded by a single layer of flattened somatic cells (pre-granulosa cells) and a basement membrane to form primordial ...


Ovarian Expressed Microsomal Epoxide Hydrolase: Role In Detoxification Of 4-Vinylcyclohexene Diepoxide And Regulation By Phosphatidylinositol-3 Kinase Signaling, Poulomi Bhattacharya, Nivedita Sen, Patricia B. Hoyer, Aileen F. Keating 2019 Iowa State University

Ovarian Expressed Microsomal Epoxide Hydrolase: Role In Detoxification Of 4-Vinylcyclohexene Diepoxide And Regulation By Phosphatidylinositol-3 Kinase Signaling, Poulomi Bhattacharya, Nivedita Sen, Patricia B. Hoyer, Aileen F. Keating

Aileen Keating

4-vinylcyclohexene diepoxide (VCD) is a metabolite of 4-vinylcyclohexene (VCH) which has the potential to be formed in the ovary through CYP2E1 activity. VCD specifically destroys primordial and small primary follicles in the rodent ovary. Mouse ovaries exposed to VCD demonstrate increased mRNA and protein expression of microsomal epoxide hydrolase (mEH), and an inactive tetrol metabolite (4-(1,2-dihydroxy)ethyl-1,2-dihydroxycyclohexane) can be formed in mouse ovarian follicles, potentially through detoxification action of mEH. In contrast, mEH can bioactivate another ovotoxic chemical, 7,12-dimethylbenz[a]anthracene (DMBA) to a more toxic compound, DMBA-3,4-diol-1,2-epoxide. Thus, the present study evaluated a ...


Glutathione S-Transferase Class Mu Regulation Of Apoptosis Signal-Regulating Kinase 1 Protein During Vcd-Induced Ovotoxicity In Neonatal Rat Ovaries, Poulomi Bhattacharya, Jill A. Madden, Nivedita Sen, Patricia B. Hoyer, Aileen F. Keating 2019 Iowa State University

Glutathione S-Transferase Class Mu Regulation Of Apoptosis Signal-Regulating Kinase 1 Protein During Vcd-Induced Ovotoxicity In Neonatal Rat Ovaries, Poulomi Bhattacharya, Jill A. Madden, Nivedita Sen, Patricia B. Hoyer, Aileen F. Keating

Aileen Keating

4-vinylcyclohexene diepoxide (VCD) destroys ovarian primordial and small primary follicles via apoptosis. In mice, VCD exposure induces ovarian mRNA expression of glutathione S-transferase (GST) family members, including isoform mu (Gstm). Extra-ovarian GSTM negatively regulates pro-apoptotic apoptosis signal-related kinase 1 (ASK1) through protein complex formation, which dissociates during stress, thereby initiating ASK1-induced apoptosis. The present study investigated the ovarian response of Gstm mRNA and protein to VCD. Induction of Ask1 mRNA at VCD-induced follicle loss onset was determined. Ovarian GSTM:ASK1 protein complex formation was investigated and VCD exposure effects thereon evaluated. Phosphatidylinositol-3 kinase (PI3K) regulation of GSTM protein was also ...


Disruption Of Female Reproductive Function By Endotoxins, K. L. Bidne, M. J. Dickson, J. W. Ross, L. H. Baumgard, A. F. Keating 2019 Iowa State University

Disruption Of Female Reproductive Function By Endotoxins, K. L. Bidne, M. J. Dickson, J. W. Ross, L. H. Baumgard, A. F. Keating

Aileen Keating

Endotoxemia can be caused by obesity, environmental chemical exposure, abiotic stressors, and bacterial infection. Circumstances that deleteriously impact intestinal barrier integrity can induce endotoxemia and controlled experiments have identified negative impacts of lipopolysaccharide (LPS; an endotoxin mimetic) on folliculogenesis, puberty onset, estrus behavior, ovulation, meiotic competence, luteal function and ovarian steroidogenesis. In addition, neonatal LPS exposures have transgenerational female reproductive impacts, raising concern about early life contacts to this endogenous reproductive toxicant. Aims of this review are to identify physiological stressors causing endotoxemia, to highlight potential mechanism(s) by which LPS compromises female reproduction, and identify knowledge gaps regarding how ...


Involvement Of A Volatile Metabolite During Phosphoramide Mustard-Induced Ovotoxicity, Jill A. Madden, Patricia B. Hoyer, Patrick J. Devine, Aileen F. Keating 2019 Iowa State University

Involvement Of A Volatile Metabolite During Phosphoramide Mustard-Induced Ovotoxicity, Jill A. Madden, Patricia B. Hoyer, Patrick J. Devine, Aileen F. Keating

Aileen Keating

The finite ovarian follicle reserve can be negatively impacted by chemical exposures including the anti-neoplastic agent, cyclophosphamide (CPA). CPA requires bioactivation to phosphoramide mustard (PM) to elicit its therapeutic effects however; in addition to being the tumor-targeting metabolite, PM is also ovotoxic. In addition, PM can break down to a cytotoxic, volatile metabolite, chloroethylaziridine (CEZ). The aim of this study was initially to characterize PMinduced ovotoxicity in growing follicles. Using PND4 Fisher 344 rats, ovaries were cultured for 4 days before being exposed once to PM (10 or 30 μM). Following eight additional days in culture, relative to control (1 ...


Impact Of 7,12-Dimethylbenz[A]Anthracene Exposure On Connexin Gap Junction Proteins In Cultured Rat Ovaries, Shanthi Ganesan, Aileen F. Keating 2019 Iowa State University

Impact Of 7,12-Dimethylbenz[A]Anthracene Exposure On Connexin Gap Junction Proteins In Cultured Rat Ovaries, Shanthi Ganesan, Aileen F. Keating

Aileen Keating

7,12-dimethylbenz[a]anthracene (DMBA) destroys ovarian follicles in a concentration-dependent manner. The impact of DMBA on connexin (CX) proteins that mediate communication between follicular cell types along with pro-apoptotic factors p53 and Bax were investigated. Postnatal day (PND) 4 Fisher 344 rat ovaries were cultured for 4 days in vehicle medium (1% DMSO) followed by a single exposure to vehicle control (1% DMSO) or DMBA (12.5 nM or 75 nM) and cultured for 4 or 8 days. RT-PCR was performed to quantify Cx37, Cx43, p53 and Bax mRNA level. Western blotting and immunofluorescence staining were performed to determine ...


Acute 7,12-Dimethylbenz[A]Anthracene Exposure Causes Differential Concentration-Dependent Follicle Depletion And Gene Expression In Neonatal Rat Ovaries, Jill A. Madden, Patricia B. Hoyer, Patrick J. Devine, Aileen F. Keating 2019 Iowa State University

Acute 7,12-Dimethylbenz[A]Anthracene Exposure Causes Differential Concentration-Dependent Follicle Depletion And Gene Expression In Neonatal Rat Ovaries, Jill A. Madden, Patricia B. Hoyer, Patrick J. Devine, Aileen F. Keating

Aileen Keating

Chronic exposure to the polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA), generated during combustion of organic matter including cigarette smoke, depletes all ovarian follicle types in the mouse and rat, and in vitro models mimic this effect. To investigate the mechanisms involved in follicular depletion during acute DMBA exposure, two concentrations of DMBA at which follicle depletion has (75 nM) and has not (12.5 nM) been observed were investigated. Postnatal day four F344 rat ovaries were maintained in culture for four days before a single exposure to vehicle control (1% DMSO; CT) or DMBA (12 nM; low-concentration or ...


Enhanced Susceptibility Of Ovaries From Obese Mice To 7,12-Dimethylbenz[A]Anthracene-Induced Dna Damage, Shanthi Ganesan, Jackson Nteeba, Aileen F. Keating 2019 Iowa State University

Enhanced Susceptibility Of Ovaries From Obese Mice To 7,12-Dimethylbenz[A]Anthracene-Induced Dna Damage, Shanthi Ganesan, Jackson Nteeba, Aileen F. Keating

Aileen Keating

7,12-dimethylbenz[a]anthracene (DMBA) depletes ovarian follicles and induces DNA damage in extra-ovarian tissues, thus, we investigated ovarian DMBA-induced DNA damage. Additionally, since obesity is associated with increased offspring birth defect incidence, we hypothesized that a DMBA-induced DNA damage response (DDR) is compromised in ovaries from obese females. Wild type (lean) non agouti (a/a) and KK.Cg-Ay/J heterozygote (obese) mice were dosed with sesame oil or DMBA (1mg/kg; intraperitoneal injection) at 18 wks of age, for 14 days. Total ovarian RNA and protein were isolated and abundance of Ataxia telangiectasia mutated (Atm), X-ray repair complementing defective ...


Application Of Fraser’S “Practical” Ethic In Veterinary Practice, And Its Compatibility With A “One Welfare” Framework, Anne Fawcett, Siobhan Mullan, Paul McGreevy 2019 University of Sydney

Application Of Fraser’S “Practical” Ethic In Veterinary Practice, And Its Compatibility With A “One Welfare” Framework, Anne Fawcett, Siobhan Mullan, Paul Mcgreevy

Paul McGreevy, PhD

Ethically challenging situations are common in veterinary practice, and they may be a source of moral stress, which may in turn impact the welfare of veterinarians. Despite recognition of the importance of ethical reasoning, some veterinary students may struggle to apply theoretical ethical frameworks. Fraser developed a “practical” ethic consisting of four principles that can be applied to ethically challenging situations. We apply Fraser’s “practical” ethic to three cases that veterinarians may encounter: animal hoarding, animal neglect, and treatment of wildlife. We argue that Fraser’s “practical” ethic is consistent with a One Welfare framework, and may have increasing ...


The Impact Of Dietary Supplementation Of Arginine During Gestation In A Commercial Swine Herd: I. Gilt Reproductive Performance, Elizabeth A. Hines, Matthew R. Romoser, Zoë E. Kiefer, Aileen F. Keating, Lance H. Baumgard, Jarad Niemi, Nicholas K. Gabler, John F. Patience, Benjamin Haberl, Noel H. Williams, Brian J. Kerr, Kevin J. Touchette, Jason W. Ross 2019 Iowa State University

The Impact Of Dietary Supplementation Of Arginine During Gestation In A Commercial Swine Herd: I. Gilt Reproductive Performance, Elizabeth A. Hines, Matthew R. Romoser, Zoë E. Kiefer, Aileen F. Keating, Lance H. Baumgard, Jarad Niemi, Nicholas K. Gabler, John F. Patience, Benjamin Haberl, Noel H. Williams, Brian J. Kerr, Kevin J. Touchette, Jason W. Ross

Animal Science Publications

Supplemental Arg during gestation purportedly benefits fetal development. However, the benefits of a gestational Arg dietary strategy in commercial production are unclear. Therefore, objectives of this study examined Arg supplementation during different gestational stages and the effects on gilt reproductive performance. Pubertal gilts (n = 548) were allocated into four treatment groups: Control (n = 143; 0% supplemental Arg) or one of three supplemental Arg (1% as fed) treatments: from 15 to 45 d of gestation (n = 138; Early-Arg); from 15 d of gestation until farrowing (n = 139; Full-Arg); or from 85 d of gestation until farrowing (n = 128; Late-Arg). At farrowing ...


Ethical And Scientific Pitfalls Concerning Laboratory Research With Non-Human Primates, And Possible Solutions, Constança Carvalho, Augusta Gaspar, Andrew Knight, Luís Vicente 2019 University of Lisbon, Portugal

Ethical And Scientific Pitfalls Concerning Laboratory Research With Non-Human Primates, And Possible Solutions, Constança Carvalho, Augusta Gaspar, Andrew Knight, Luís Vicente

Andrew Knight, PhD

Basic and applied laboratory research, whenever intrusive or invasive, presents substantial ethical challenges for ethical committees, be it with human beings or with non-human animals. In this paper we discuss the use of non-human primates (NHPs), mostly as animal models, in laboratory based research. We examine the two ethical frameworks that support current legislation and guidelines: deontology and utilitarianism. While human based research is regulated under deontological principles, guidelines for laboratory animal research rely on utilitarianism. We argue that the utilitarian framework is inadequate for this purpose: on the one hand, it is almost impossible to accurately predict the benefits ...


Is Animal-Based Biomedical Research Being Used In Its Original Context?, Constança Carvalho, Daniel Alves, Andrew Knight, Luís Vicente 2019 University of Lisbon, Portugal

Is Animal-Based Biomedical Research Being Used In Its Original Context?, Constança Carvalho, Daniel Alves, Andrew Knight, Luís Vicente

Andrew Knight, PhD

No abstract provided.


Critically Evaluating Animal Research, Andrew Knight 2019 University of Winchester

Critically Evaluating Animal Research, Andrew Knight

Andrew Knight, PhD

No abstract provided.


Contribution Of Animal Models To Contemporary Understanding Of Attention Deficit Hyperactivity Disorder, Constança Carvalho, Mariana Vieira Crespo, Luísa Ferreira Bastos, Andrew Knight, Luís Vincente 2019 University of Lisbon, Portugal

Contribution Of Animal Models To Contemporary Understanding Of Attention Deficit Hyperactivity Disorder, Constança Carvalho, Mariana Vieira Crespo, Luísa Ferreira Bastos, Andrew Knight, Luís Vincente

Andrew Knight, PhD

Attention Deficit Hyperactivity Disorder (ADHD) is a poorly understood neurodevelopmental disorder of multifactorial origin. Animal-based research has been used to investigate ADHD etiology, pathogenesis and treatment, but the efficacy of this research for patients has not yet been systematically evaluated. Such evaluation is important given the resource consumption and ethical concerns incurred by animal use.

We used the citation tracking facility within Web of Science to locate citations of original research papers on animal models related to ADHD published prior to 2010 identified in PubMed by relevant search terms. Human medical papers citing those animal studies were carefully analyzed by ...


Contribution Of Animal Models To Contemporary Understanding Of Attention Deficit Hyperactivity Disorder, Constança Carvalho, Mariana Vieira Crespo, Luísa Ferreira Bastos, Andrew Knight, Luís Vincente 2019 University of Lisbon, Portugal

Contribution Of Animal Models To Contemporary Understanding Of Attention Deficit Hyperactivity Disorder, Constança Carvalho, Mariana Vieira Crespo, Luísa Ferreira Bastos, Andrew Knight, Luís Vincente

Biomedicine and Animal Models in Research Collection

Attention Deficit Hyperactivity Disorder (ADHD) is a poorly understood neurodevelopmental disorder of multifactorial origin. Animal-based research has been used to investigate ADHD etiology, pathogenesis and treatment, but the efficacy of this research for patients has not yet been systematically evaluated. Such evaluation is important given the resource consumption and ethical concerns incurred by animal use.

We used the citation tracking facility within Web of Science to locate citations of original research papers on animal models related to ADHD published prior to 2010 identified in PubMed by relevant search terms. Human medical papers citing those animal studies were carefully analyzed by ...


Bias During The Evaluation Of Animal Studies, Andrew Knight 2019 Oxford Centre for Animal Ethics

Bias During The Evaluation Of Animal Studies, Andrew Knight

Andrew Knight, Ph.D.

My recent book entitled The Costs and Benefits of Animal Experiments seeks to answer a key question within animal ethics, namely: is animal experimentation ethically justifiable? Or, more precisely, is it justifiable within the utilitarian cost:benefit framework that fundamentally underpins most regulations governing animal experimentation? To answer this question I reviewed more than 500 scientific publications describing animal studies, animal welfare impacts, and alternative research, toxicity testing and educational methodologies. To minimise bias I focused primarily on large-scale systematic reviews that had examined the human clinical and toxicological utility of animal studies. Despite this, Dr. Susanne Prankel recently reviewed ...


Tracing Nutrient Sources To Lipid Production In Insects Using Stable Isotope (Δ13c, Δ2h) Tracers: Implications For Nutritional Physiology Of Migratory Species., Libesha Anparasan, Keith A. Hobson 2019 The University of Western Ontario

Tracing Nutrient Sources To Lipid Production In Insects Using Stable Isotope (Δ13c, Δ2h) Tracers: Implications For Nutritional Physiology Of Migratory Species., Libesha Anparasan, Keith A. Hobson

Western Research Forum

Using stable isotope measurements of insect tissues to determine origin and migratory patterns is well established. However, isotopically determining nutritional origins of lipids, the primary fuel of migration, has not been as thoroughly researched. We explored isotopic links between diet and stored lipids in laboratory raised True armyworm moths (Mythimna unipuncta) using δ13C and δ2H measurements. Pupae were randomly separated into four groups (n=20) and fed isotopically distinct nectar, each consisting of a combination of high δ13C (C4 sugar), or low δ13C (C3 sugar) carbohydrate, with high δ2H (deuterium ...


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