222 results on '"Stuart Maudsley"'
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2. Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities
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Gerd Schreurs, Stuart Maudsley, Cynthia Nast, Marleen Praet, Sylvina Da Silva Fernandes, Peter Boor, Patrick D’Haese, Marc E. De Broe, and Benjamin A. Vervaet
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Medicine ,Science - Abstract
Abstract CINAC-patients present renal proximal tubular cell lysosomal lesions which are also observed in patients experiencing calcineurin inhibitor (CNI) nephrotoxicity, suggesting that CINAC is a toxin-induced nephropathy. An alternative hypothesis advocates chronic dehydration as a major etiological factor for CINAC. Here, we evaluated histological and molecular changes in dehydrated versus toxin exposed rats. Wistar rats were divided in 3 groups. Group 1 (n = 6) had free access to drinking water (control group). Group 2 (n = 8) was water deprived for 10 h per 24 h, 5 days/week and placed in an incubator (37 °C) for 30 min/h during water deprivation. Group 3 (n = 8) underwent daily oral gavage with cyclosporine (40 mg/kg body weight). After 28 days, renal function, histopathology and proteomic signatures were analysed. Cyclosporine-treated rats developed focal regions of atrophic proximal tubules with associated tubulo-interstitial fibrosis. PASM staining revealed enlarged argyrophilic granules in affected proximal tubules, identified as lysosomes by immunofluorescent staining. Electron microscopy confirmed the enlarged and dysmorphic phenotype of the lysosomes. Overall, these kidney lesions resemble those that have been previously documented in farmers with CINAC. Dehydration resulted in none of the above histopathological features. Proteomic analysis revealed that dehydration and cyclosporine both induce injury pathways, yet of a clear distinct nature with a signature of toxicity only for the cyclosporine group. In conclusion, both cyclosporine and dehydration are injurious to the kidney. However, dehydration alone does not result in kidney histopathology as observed in CINAC patients, whereas cyclosporine administration does. The histopathological analogy between CINAC and calcineurin inhibitor nephrotoxicity in rats and humans supports the involvement of an as-yet-unidentified environmental toxin in CINAC etiology.
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- 2023
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3. Editorial: Macromolecular interactions in signaling pathways: from classical approaches to virtual reality
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Marcello Leopoldo, Marialessandra Contino, Stuart Maudsley, and Milka Vrecl
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GPCRs ,signal transduction ,protein-protein interactions ,dimerization ,internalization ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Published
- 2024
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4. GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process
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Stuart Maudsley, Claudia Schrauwen, İrem Harputluoğlu, Deborah Walter, Hanne Leysen, and Patricia McDonald
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GPR19 ,receptor ,aging ,stress ,damage ,DNA ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
G protein-coupled receptors (GPCRs) play a significant role in controlling biological paradigms such as aging and aging-related disease. We have previously identified receptor signaling systems that are specifically associated with controlling molecular pathologies associated with the aging process. Here, we have identified a pseudo-orphan GPCR, G protein-coupled receptor 19 (GPR19), that is sensitive to many molecular aspects of the aging process. Through an in-depth molecular investigation process that involved proteomic, molecular biological, and advanced informatic experimentation, this study found that the functionality of GPR19 is specifically linked to sensory, protective, and remedial signaling systems associated with aging-related pathology. This study suggests that the activity of this receptor may play a role in mitigating the effects of aging-related pathology by promoting protective and remedial signaling systems. GPR19 expression variation demonstrates variability in the molecular activity in this larger process. At low expression levels in HEK293 cells, GPR19 expression regulates signaling paradigms linked with stress responses and metabolic responses to these. At higher expression levels, GPR19 expression co-regulates systems involved in sensing and repairing DNA damage, while at the highest levels of GPR19 expression, a functional link to processes of cellular senescence is seen. In this manner, GPR19 may function as a coordinator of aging-associated metabolic dysfunction, stress response, DNA integrity management, and eventual senescence.
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- 2023
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5. The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer’s Disease
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Wayne Chadwick, Stuart Maudsley, William Hull, Enes Havolli, Eugene Boshoff, Mark D. W. Hill, Pascal J. D. Goetghebeur, David C. Harrison, Sohaib Nizami, David C. Bedford, Gareth Coope, Katia Real, Christoph Thiemermann, Peter Maycox, Mark Carlton, and Sarah L. Cole
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sporadic Alzheimer’s disease ,D-galactose ,cognitive deficits ,neurodegeneration ,advanced glycation end products ,oxidative stress ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Sporadic Alzheimer’s disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.
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- 2023
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6. A Proteomic Screen to Unravel the Molecular Pathways Associated with Warfarin-Induced or TNAP-Inhibited Arterial Calcification in Rats
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Britt Opdebeeck, Ellen Neven, Stuart Maudsley, Hanne Leysen, Deborah Walter, Hilde Geryl, Patrick C. D’Haese, and Anja Verhulst
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arterial media calcification ,tissue non-specific alkaline phosphatase ,inflammation ,lipid/glucose homeostasis ,mitochondrial pathway ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Arterial media calcification refers to the pathological deposition of calcium phosphate crystals in the arterial wall. This pathology is a common and life-threatening complication in chronic kidney disease, diabetes and osteoporosis patients. Recently, we reported that the use of a TNAP inhibitor, SBI-425, attenuated arterial media calcification in a warfarin rat model. Employing a high-dimensionality unbiased proteomic approach, we also investigated the molecular signaling events associated with blocking arterial calcification through SBI-425 dosing. The remedial actions of SBI-425 were strongly associated with (i) a significant downregulation of inflammatory (acute phase response signaling) and steroid/glucose nuclear receptor signaling (LXR/RXR signaling) pathways and (ii) an upregulation of mitochondrial metabolic pathways (TCA cycle II and Fatty Acid β-oxidation I). Interestingly, we previously demonstrated that uremic toxin-induced arterial calcification contributes to the activation of the acute phase response signaling pathway. Therefore, both studies suggest a strong link between acute phase response signaling and arterial calcification across different conditions. The identification of therapeutic targets in these molecular signaling pathways may pave the way to novel therapies against the development of arterial media calcification.
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- 2023
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7. Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process
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Stuart Maudsley, Deborah Walter, Claudia Schrauwen, Nore Van Loon, İrem Harputluoğlu, Julia Lenaerts, and Patricia McDonald
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GPR19 ,GPCR ,aging ,therapeutics ,longevity ,stress ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
G protein-coupled receptors (GPCRs) represent one of the most functionally diverse classes of transmembrane proteins. GPCRs and their associated signaling systems have been linked to nearly every physiological process. They also constitute nearly 40% of the current pharmacopeia as direct targets of remedial therapies. Hence, their place as a functional nexus in the interface between physiological and pathophysiological processes suggests that GPCRs may play a central role in the generation of nearly all types of human disease. Perhaps one mechanism through which GPCRs can mediate this pivotal function is through the control of the molecular aging process. It is now appreciated that, indeed, many human disorders/diseases are induced by GPCR signaling processes linked to pathological aging. Here we discuss one such novel member of the GPCR family, GPR19, that may represent an important new target for novel remedial strategies for the aging process. The molecular signaling pathways (metabolic control, circadian rhythm regulation and stress responsiveness) associated with this recently characterized receptor suggest an important role in aging-related disease etiology.
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- 2022
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8. G Protein-Coupled Receptor Systems and Their Role in Cellular Senescence
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Paula Santos-Otte, Hanne Leysen, Jaana van Gastel, Jhana O. Hendrickx, Bronwen Martin, and Stuart Maudsley
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Biotechnology ,TP248.13-248.65 - Abstract
Aging is a complex biological process that is inevitable for nearly all organisms. Aging is the strongest risk factor for development of multiple neurodegenerative disorders, cancer and cardiovascular disorders. Age-related disease conditions are mainly caused by the progressive degradation of the integrity of communication systems within and between organs. This is in part mediated by, i) decreased efficiency of receptor signaling systems and ii) an increasing inability to cope with stress leading to apoptosis and cellular senescence. Cellular senescence is a natural process during embryonic development, more recently it has been shown to be also involved in the development of aging disorders and is now considered one of the major hallmarks of aging. G-protein-coupled receptors (GPCRs) comprise a superfamily of integral membrane receptors that are responsible for cell signaling events involved in nearly every physiological process. Recent advances in the molecular understanding of GPCR signaling complexity have expanded their therapeutic capacity tremendously. Emerging data now suggests the involvement of GPCRs and their associated proteins in the development of cellular senescence. With the proven efficacy of therapeutic GPCR targeting, it is reasonable to now consider GPCRs as potential platforms to control cellular senescence and the consequently, age-related disorders. Keywords: G protein-coupled receptors (GPCRs), Aging, Cellular senescence, β-Arrestin, G protein-coupled receptor kinase interacting protein 2 (GIT2)
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- 2019
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9. The Relaxin-3 Receptor, RXFP3, Is a Modulator of Aging-Related Disease
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Hanne Leysen, Deborah Walter, Lore Clauwaert, Lieselot Hellemans, Jaana van Gastel, Lakshmi Vasudevan, Bronwen Martin, and Stuart Maudsley
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relaxin-family peptide receptor 3 ,aging ,G-protein-coupled receptors ,DNA ,damage ,GIT2 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
During the aging process our body becomes less well equipped to deal with cellular stress, resulting in an increase in unrepaired damage. This causes varying degrees of impaired functionality and an increased risk of mortality. One of the most effective anti-aging strategies involves interventions that combine simultaneous glucometabolic support with augmented DNA damage protection/repair. Thus, it seems prudent to develop therapeutic strategies that target this combinatorial approach. Studies have shown that the ADP-ribosylation factor (ARF) GTPase activating protein GIT2 (GIT2) acts as a keystone protein in the aging process. GIT2 can control both DNA repair and glucose metabolism. Through in vivo co-regulation analyses it was found that GIT2 forms a close coexpression-based relationship with the relaxin-3 receptor (RXFP3). Cellular RXFP3 expression is directly affected by DNA damage and oxidative stress. Overexpression or stimulation of this receptor, by its endogenous ligand relaxin 3 (RLN3), can regulate the DNA damage response and repair processes. Interestingly, RLN3 is an insulin-like peptide and has been shown to control multiple disease processes linked to aging mechanisms, e.g., anxiety, depression, memory dysfunction, appetite, and anti-apoptotic mechanisms. Here we discuss the molecular mechanisms underlying the various roles of RXFP3/RLN3 signaling in aging and age-related disorders.
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- 2022
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10. GPCRs Are Optimal Regulators of Complex Biological Systems and Orchestrate the Interface between Health and Disease
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Hanne Leysen, Deborah Walter, Bregje Christiaenssen, Romi Vandoren, İrem Harputluoğlu, Nore Van Loon, and Stuart Maudsley
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dimensionality ,G protein-coupled receptor ,network ,pharmacology ,precision ,quantitative ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
GPCRs arguably represent the most effective current therapeutic targets for a plethora of diseases. GPCRs also possess a pivotal role in the regulation of the physiological balance between healthy and pathological conditions; thus, their importance in systems biology cannot be underestimated. The molecular diversity of GPCR signaling systems is likely to be closely associated with disease-associated changes in organismal tissue complexity and compartmentalization, thus enabling a nuanced GPCR-based capacity to interdict multiple disease pathomechanisms at a systemic level. GPCRs have been long considered as controllers of communication between tissues and cells. This communication involves the ligand-mediated control of cell surface receptors that then direct their stimuli to impact cell physiology. Given the tremendous success of GPCRs as therapeutic targets, considerable focus has been placed on the ability of these therapeutics to modulate diseases by acting at cell surface receptors. In the past decade, however, attention has focused upon how stable multiprotein GPCR superstructures, termed receptorsomes, both at the cell surface membrane and in the intracellular domain dictate and condition long-term GPCR activities associated with the regulation of protein expression patterns, cellular stress responses and DNA integrity management. The ability of these receptorsomes (often in the absence of typical cell surface ligands) to control complex cellular activities implicates them as key controllers of the functional balance between health and disease. A greater understanding of this function of GPCRs is likely to significantly augment our ability to further employ these proteins in a multitude of diseases.
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- 2021
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11. Endothelial Contribution to Warfarin-Induced Arterial Media Calcification in Mice
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Geoffrey Van den Bergh, Sofie De Moudt, Astrid Van den Branden, Ellen Neven, Hanne Leysen, Stuart Maudsley, Guido R. Y. De Meyer, Patrick D’Haese, and Anja Verhulst
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vascular calcification ,endothelial cells ,vascular smooth muscle cells ,nitric oxide ,organ baths ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Arterial media calcification (AMC) is predominantly regulated by vascular smooth muscle cells (VSMCs), which transdifferentiate into pro-calcifying cells. In contrast, there is little evidence for endothelial cells playing a role in the disease. The current study investigates cellular functioning and molecular pathways underlying AMC, respectively by, an ex vivo isometric organ bath set-up to explore the interaction between VSMCs and ECs and quantitative proteomics followed by functional pathway interpretation. AMC development, which was induced in mice by dietary warfarin administration, was proved by positive Von Kossa staining and a significantly increased calcium content in the aorta compared to that of control mice. The ex vivo organ bath set-up showed calcified aortic segments to be significantly more sensitive to phenylephrine induced contraction, compared to control segments. This, together with the fact that calcified segments as compared to control segments, showed a significantly smaller contraction in the absence of extracellular calcium, argues for a reduced basal NO production in the calcified segments. Moreover, proteomic data revealed a reduced eNOS activation to be part of the vascular calcification process. In summary, this study identifies a poor endothelial function, next to classic pro-calcifying stimuli, as a possible initiator of arterial calcification.
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- 2021
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12. GRK5 – A Functional Bridge Between Cardiovascular and Neurodegenerative Disorders
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Jhana O. Hendrickx, Jaana van Gastel, Hanne Leysen, Paula Santos-Otte, Richard T. Premont, Bronwen Martin, and Stuart Maudsley
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G-protein coupled receptor kinase 5 ,aging ,cardiovascular disease ,neurodegeneration ,GRK5 interactors ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Complex aging-triggered disorders are multifactorial programs that comprise a myriad of alterations in interconnected protein networks over a broad range of tissues. It is evident that rather than being randomly organized events, pathophysiologies that possess a strong aging component such as cardiovascular diseases (hypertensions, atherosclerosis, and vascular stiffening) and neurodegenerative conditions (dementia, Alzheimer’s disease, mild cognitive impairment, Parkinson’s disease), in essence represent a subtly modified version of the intricate molecular programs already in place for normal aging. To control such multidimensional activities there are layers of trophic protein control across these networks mediated by so-called “keystone” proteins. We propose that these “keystones” coordinate and interconnect multiple signaling pathways to control whole somatic activities such as aging-related disease etiology. Given its ability to control multiple receptor sensitivities and its broad protein-protein interactomic nature, we propose that G protein coupled receptor kinase 5 (GRK5) represents one of these key network controllers. Considerable data has emerged, suggesting that GRK5 acts as a bridging factor, allowing signaling regulation in pathophysiological settings to control the connectivity between both the cardiovascular and neurophysiological complications of aging.
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- 2018
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13. β-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets for Complex Age-Related Disorders
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Jaana van Gastel, Jhana O. Hendrickx, Hanne Leysen, Paula Santos-Otte, Louis M. Luttrell, Bronwen Martin, and Stuart Maudsley
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β-arrestin signaling ,ligand ‘bias’ ,GPCRs ,age-related disorders ,precision ,tailored efficacy ,Therapeutics. Pharmacology ,RM1-950 - Abstract
G protein coupled receptors (GPCRs) were first characterized as signal transducers that elicit downstream effects through modulation of guanine (G) nucleotide-binding proteins. The pharmacotherapeutic exploitation of this signaling paradigm has created a drug-based field covering nearly 50% of the current pharmacopeia. Since the groundbreaking discoveries of the late 1990s to the present day, it is now clear however that GPCRs can also generate productive signaling cascades through the modulation of β-arrestin functionality. β-Arrestins were first thought to only regulate receptor desensitization and internalization – exemplified by the action of visual arrestin with respect to rhodopsin desensitization. Nearly 20 years ago, it was found that rather than controlling GPCR signal termination, productive β-arrestin dependent GPCR signaling paradigms were highly dependent on multi-protein complex formation and generated long-lasting cellular effects, in contrast to G protein signaling which is transient and functions through soluble second messenger systems. β-Arrestin signaling was then first shown to activate mitogen activated protein kinase signaling in a G protein-independent manner and eventually initiate protein transcription – thus controlling expression patterns of downstream proteins. While the possibility of developing β-arrestin biased or functionally selective ligands is now being investigated, no additional research has been performed on its possible contextual specificity in treating age-related disorders. The ability of β-arrestin-dependent signaling to control complex and multidimensional protein expression patterns makes this therapeutic strategy feasible, as treating complex age-related disorders will likely require therapeutics that can exert network-level efficacy profiles. It is our understanding that therapeutically targeting G protein-independent effectors such as β-arrestin will aid in the development of precision medicines with tailored efficacy profiles for disease/age-specific contextualities.
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- 2018
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14. Effects of Detergent on α-Synuclein Structure: A Native MS-Ion Mobility Study
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Rani Moons, Renate van der Wekken-de Bruijne, Stuart Maudsley, Filip Lemière, Anne-Marie Lambeir, and Frank Sobott
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ion mobility ,mass spectrometry ,α-synuclein ,intrinsically disordered protein ,detergent micelles ,membrane interaction ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The intrinsically disordered protein α-synuclein plays a major role in Parkinson’s disease. The protein can oligomerize resulting in the formation of various aggregated species in neuronal cells, leading to neurodegeneration. The interaction of α-synuclein with biological cell membranes plays an important role for specific functions of α-synuclein monomers, e.g., in neurotransmitter release. Using different types of detergents to mimic lipid molecules present in biological membranes, including the presence of Ca2+ ions as an important structural factor, we aimed to gain an understanding of how α-synuclein interacts with membrane models and how this affects the protein conformation and potential oligomerization. We investigated detergent binding stoichiometry, affinity and conformational changes of α-synuclein taking detergent concentration, different detergent structures and charges into account. With native nano-electrospray ionization ion mobility-mass spectrometry, we were able to detect unique conformational patterns resulting from binding of specific detergents to α-synuclein. Our data demonstrate that α-synuclein monomers can interact with detergent molecules irrespective of their charge, that protein-micelle interactions occur and that micelle properties are an important factor.
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- 2020
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15. Alternative Splicing of Neuronal Differentiation Factor TRF2 Regulated by HNRNPH1/H2
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Ioannis Grammatikakis, Peisu Zhang, Amaresh C. Panda, Jiyoung Kim, Stuart Maudsley, Kotb Abdelmohsen, Xiaoling Yang, Jennifer L. Martindale, Omar Motiño, Emmette R. Hutchison, Mark P. Mattson, and Myriam Gorospe
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TRF2 ,TRF2-S ,HNRNPH ,alternative splicing ,mRNA ,ribonucleoprotein complex ,Biology (General) ,QH301-705.5 - Abstract
During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels. Accordingly, HNRNPH levels decline while TRF2-S levels increase during neuronal differentiation. In addition, CRISPR/Cas9-mediated deletion of hnRNPH2 selectively accelerates the NGF-triggered differentiation of rat pheochromocytoma cells into neurons. In sum, HNRNPH is a splicing regulator of Trf2 pre-mRNA that prevents the expression of TRF2-S, a factor implicated in neuronal differentiation.
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- 2016
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16. Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus
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Zongyang Mou, Thomas M. Hyde, Barbara K. Lipska, Keri Martinowich, Peter Wei, Chiew-Jen Ong, Lindsay A. Hunter, Gladys I. Palaguachi, Eva Morgun, Rujia Teng, Chen Lai, Tania A. Condarco, Andrew P. Demidowich, Amanda J. Krause, Leslie J. Marshall, Karin Haack, V. Saroja Voruganti, Shelley A. Cole, Nancy F. Butte, Anthony G. Comuzzie, Michael A. Nalls, Alan B. Zonderman, Andrew B. Singleton, Michele K. Evans, Bronwen Martin, Stuart Maudsley, Jack W. Tsao, Joel E. Kleinman, Jack A. Yanovski, and Joan C. Han
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Mou et al. show that brain-derived neurotrophic factor (BDNF) rs12291063 minor C allele disrupts binding and transactivation by the transcriptional regulator ,heterogeneous nuclear ribonucleoprotein D0B ,and it is associated with lower ventromedial hypothalamic BDNF expression and obesity. BDNF augmentation may be specifically beneficial for treating obesity in individuals with the CC genotype ,Biology (General) ,QH301-705.5 - Abstract
Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.
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- 2015
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17. Sclerostin as Regulatory Molecule in Vascular Media Calcification and the Bone–Vascular Axis
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Annelies De Maré, Stuart Maudsley, Abdelkrim Azmi, Jhana O. Hendrickx, Britt Opdebeeck, Ellen Neven, Patrick C D’Haese, and Anja Verhulst
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chronic kidney disease ,vascular calcification ,bone disease ,mineral abnormalities ,rat model ,Medicine - Abstract
Sclerostin is a well-known inhibitor of bone formation that acts on Wnt/β-catenin signaling. This manuscript considers the possible role of sclerostin in vascular calcification, a process that shares many similarities with physiological bone formation. Rats were exposed to a warfarin-containing diet to induce vascular calcification. Vascular smooth muscle cell transdifferentiation, vascular calcification grade, and bone histomorphometry were examined. The presence and/or production of sclerostin was investigated in serum, aorta, and bone. Calcified human aortas were investigated to substantiate clinical relevance. Warfarin-exposed rats developed vascular calcifications in a time-dependent manner which went along with a progressive increase in serum sclerostin levels. Both osteogenic and adipogenic pathways were upregulated in calcifying vascular smooth muscle cells, as well as sclerostin mRNA and protein levels. Evidence for the local vascular action of sclerostin was found both in human and rat calcified aortas. Warfarin exposure led to a mildly decreased bone and mineralized areas. Osseous sclerostin production and bone turnover did not change significantly. This study showed local production of sclerostin in calcified vessels, which may indicate a negative feedback mechanism to prevent further calcification. Furthermore, increased levels of serum sclerostin, probably originating from excessive local production in calcified vessels, may contribute to the linkage between vascular pathology and impaired bone mineralization.
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- 2019
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18. G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes
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Hanne Leysen, Jaana van Gastel, Jhana O. Hendrickx, Paula Santos-Otte, Bronwen Martin, and Stuart Maudsley
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G protein-coupled receptor (GPCR) ,aging ,DNA damage ,β-arrestin ,G protein-coupled receptor kinase (GRK) ,interactome ,G protein-coupled receptor kinase interacting protein 2 (GIT2) ,ataxia telangiectasia mutated (ATM) ,clock proteins ,energy metabolism ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
G protein-coupled receptors (GPCRs) and their associated proteins represent one of the most diverse cellular signaling systems involved in both physiological and pathophysiological processes. Aging represents perhaps the most complex biological process in humans and involves a progressive degradation of systemic integrity and physiological resilience. This is in part mediated by age-related aberrations in energy metabolism, mitochondrial function, protein folding and sorting, inflammatory activity and genomic stability. Indeed, an increased rate of unrepaired DNA damage is considered to be one of the ‘hallmarks’ of aging. Over the last two decades our appreciation of the complexity of GPCR signaling systems has expanded their functional signaling repertoire. One such example of this is the incipient role of GPCRs and GPCR-interacting proteins in DNA damage and repair mechanisms. Emerging data now suggest that GPCRs could function as stress sensors for intracellular damage, e.g., oxidative stress. Given this role of GPCRs in the DNA damage response process, coupled to the effective history of drug targeting of these receptors, this suggests that one important future activity of GPCR therapeutics is the rational control of DNA damage repair systems.
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- 2018
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19. Long-term artificial sweetener acesulfame potassium treatment alters neurometabolic functions in C57BL/6J mice.
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Wei-na Cong, Rui Wang, Huan Cai, Caitlin M Daimon, Morten Scheibye-Knudsen, Vilhelm A Bohr, Rebecca Turkin, William H Wood, Kevin G Becker, Ruin Moaddel, Stuart Maudsley, and Bronwen Martin
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Medicine ,Science - Abstract
With the prevalence of obesity, artificial, non-nutritive sweeteners have been widely used as dietary supplements that provide sweet taste without excessive caloric load. In order to better understand the overall actions of artificial sweeteners, especially when they are chronically used, we investigated the peripheral and central nervous system effects of protracted exposure to a widely used artificial sweetener, acesulfame K (ACK). We found that extended ACK exposure (40 weeks) in normal C57BL/6J mice demonstrated a moderate and limited influence on metabolic homeostasis, including altering fasting insulin and leptin levels, pancreatic islet size and lipid levels, without affecting insulin sensitivity and bodyweight. Interestingly, impaired cognitive memory functions (evaluated by Morris Water Maze and Novel Objective Preference tests) were found in ACK-treated C57BL/6J mice, while no differences in motor function and anxiety levels were detected. The generation of an ACK-induced neurological phenotype was associated with metabolic dysregulation (glycolysis inhibition and functional ATP depletion) and neurosynaptic abnormalities (dysregulation of TrkB-mediated BDNF and Akt/Erk-mediated cell growth/survival pathway) in hippocampal neurons. Our data suggest that chronic use of ACK could affect cognitive functions, potentially via altering neuro-metabolic functions in male C57BL/6J mice.
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- 2013
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20. VennPlex--a novel Venn diagram program for comparing and visualizing datasets with differentially regulated datapoints.
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Huan Cai, Hongyu Chen, Tie Yi, Caitlin M Daimon, John P Boyle, Chris Peers, Stuart Maudsley, and Bronwen Martin
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Medicine ,Science - Abstract
With the development of increasingly large and complex genomic and proteomic data sets, an enhancement in the complexity of available Venn diagram analytical programs is becoming increasingly important. Current freely available Venn diagram programs often fail to represent extra complexity among datasets, such as regulation pattern differences between different groups. Here we describe the development of VennPlex, a program that illustrates the often diverse numerical interactions among multiple, high-complexity datasets, using up to four data sets. VennPlex includes versatile output features, where grouped data points in specific regions can be easily exported into a spreadsheet. This program is able to facilitate the analysis of two to four gene sets and their corresponding expression values in a user-friendly manner. To demonstrate its unique experimental utility we applied VennPlex to a complex paradigm, i.e. a comparison of the effect of multiple oxygen tension environments (1-20% ambient oxygen) upon gene transcription of primary rat astrocytes. VennPlex accurately dissects complex data sets reliably into easily identifiable groups for straightforward analysis and data output. This program, which is an improvement over currently available Venn diagram programs, is able to rapidly extract important datasets that represent the variety of expression patterns available within the data sets, showing potential applications in fields like genomics, proteomics, and bioinformatics.
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- 2013
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21. Textrous!: extracting semantic textual meaning from gene sets.
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Hongyu Chen, Bronwen Martin, Caitlin M Daimon, Sana Siddiqui, Louis M Luttrell, and Stuart Maudsley
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Medicine ,Science - Abstract
The un-biased and reproducible interpretation of high-content gene sets from large-scale genomic experiments is crucial to the understanding of biological themes, validation of experimental data, and the eventual development of plans for future experimentation. To derive biomedically-relevant information from simple gene lists, a mathematical association to scientific language and meaningful words or sentences is crucial. Unfortunately, existing software for deriving meaningful and easily-appreciable scientific textual 'tokens' from large gene sets either rely on controlled vocabularies (Medical Subject Headings, Gene Ontology, BioCarta) or employ Boolean text searching and co-occurrence models that are incapable of detecting indirect links in the literature. As an improvement to existing web-based informatic tools, we have developed Textrous!, a web-based framework for the extraction of biomedical semantic meaning from a given input gene set of arbitrary length. Textrous! employs natural language processing techniques, including latent semantic indexing (LSI), sentence splitting, word tokenization, parts-of-speech tagging, and noun-phrase chunking, to mine MEDLINE abstracts, PubMed Central articles, articles from the Online Mendelian Inheritance in Man (OMIM), and Mammalian Phenotype annotation obtained from Jackson Laboratories. Textrous! has the ability to generate meaningful output data with even very small input datasets, using two different text extraction methodologies (collective and individual) for the selecting, ranking, clustering, and visualization of English words obtained from the user data. Textrous!, therefore, is able to facilitate the output of quantitatively significant and easily appreciable semantic words and phrases linked to both individual gene and batch genomic data.
- Published
- 2013
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22. Altered lipid and salt taste responsivity in ghrelin and GOAT null mice.
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Huan Cai, Wei-Na Cong, Caitlin M Daimon, Rui Wang, Matthias H Tschöp, Jean Sévigny, Bronwen Martin, and Stuart Maudsley
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Medicine ,Science - Abstract
Taste perception plays an important role in regulating food preference, eating behavior and energy homeostasis. Taste perception is modulated by a variety of factors, including gastric hormones such as ghrelin. Ghrelin can regulate growth hormone release, food intake, adiposity, and energy metabolism. Octanoylation of ghrelin by ghrelin O-acyltransferase (GOAT) is a specific post-translational modification which is essential for many biological activities of ghrelin. Ghrelin and GOAT are both widely expressed in many organs including the gustatory system. In the current study, overall metabolic profiles were assessed in wild-type (WT), ghrelin knockout (ghrelin(-/-)), and GOAT knockout (GOAT(-/-)) mice. Ghrelin(-/-) mice exhibited decreased food intake, increased plasma triglycerides and increased ketone bodies compared to WT mice while demonstrating WT-like body weight, fat composition and glucose control. In contrast GOAT(-/-) mice exhibited reduced body weight, adiposity, resting glucose and insulin levels compared to WT mice. Brief access taste behavioral tests were performed to determine taste responsivity in WT, ghrelin(-/-) and GOAT(-/-) mice. Ghrelin and GOAT null mice possessed reduced lipid taste responsivity. Furthermore, we found that salty taste responsivity was attenuated in ghrelin(-/-) mice, yet potentiated in GOAT(-/-) mice compared to WT mice. Expression of the potential lipid taste regulators Cd36 and Gpr120 were reduced in the taste buds of ghrelin and GOAT null mice, while the salt-sensitive ENaC subunit was increased in GOAT(-/-) mice compared with WT mice. The altered expression of Cd36, Gpr120 and ENaC may be responsible for the altered lipid and salt taste perception in ghrelin(-/-) and GOAT(-/-) mice. The data presented in the current study potentially implicates ghrelin signaling activity in the modulation of both lipid and salt taste modalities.
- Published
- 2013
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23. Altered hypothalamic protein expression in a rat model of Huntington's disease.
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Wei-na Cong, Huan Cai, Rui Wang, Caitlin M Daimon, Stuart Maudsley, Kerstin Raber, Fabio Canneva, Stephan von Hörsten, and Bronwen Martin
- Subjects
Medicine ,Science - Abstract
Huntington's disease (HD) is a neurodegenerative disorder, which is characterized by progressive motor impairment and cognitive alterations. Changes in energy metabolism, neuroendocrine function, body weight, euglycemia, appetite function, and circadian rhythm can also occur. It is likely that the locus of these alterations is the hypothalamus. We used the HD transgenic (tg) rat model bearing 51 CAG repeats, which exhibits similar HD symptomology as HD patients to investigate hypothalamic function. We conducted detailed hypothalamic proteome analyses and also measured circulating levels of various metabolic hormones and lipids in pre-symptomatic and symptomatic animals. Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1). In addition, there are significant alterations in various circulating metabolic hormones and lipids in pre-symptomatic animals including, insulin, leptin, triglycerides and HDL, before any motor or cognitive alterations are apparent. These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction. Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD.
- Published
- 2012
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24. VENNTURE--a novel Venn diagram investigational tool for multiple pharmacological dataset analysis.
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Bronwen Martin, Wayne Chadwick, Tie Yi, Sung-Soo Park, Daoyuan Lu, Bin Ni, Shekhar Gadkaree, Kathleen Farhang, Kevin G Becker, and Stuart Maudsley
- Subjects
Medicine ,Science - Abstract
As pharmacological data sets become increasingly large and complex, new visual analysis and filtering programs are needed to aid their appreciation. One of the most commonly used methods for visualizing biological data is the Venn diagram. Currently used Venn analysis software often presents multiple problems to biological scientists, in that only a limited number of simultaneous data sets can be analyzed. An improved appreciation of the connectivity between multiple, highly-complex datasets is crucial for the next generation of data analysis of genomic and proteomic data streams. We describe the development of VENNTURE, a program that facilitates visualization of up to six datasets in a user-friendly manner. This program includes versatile output features, where grouped data points can be easily exported into a spreadsheet. To demonstrate its unique experimental utility we applied VENNTURE to a highly complex parallel paradigm, i.e. comparison of multiple G protein-coupled receptor drug dose phosphoproteomic data, in multiple cellular physiological contexts. VENNTURE was able to reliably and simply dissect six complex data sets into easily identifiable groups for straightforward analysis and data output. Applied to complex pharmacological datasets, VENNTURE's improved features and ease of analysis are much improved over currently available Venn diagram programs. VENNTURE enabled the delineation of highly complex patterns of dose-dependent G protein-coupled receptor activity and its dependence on physiological cellular contexts. This study highlights the potential for such a program in fields such as pharmacology, genomics, and bioinformatics.
- Published
- 2012
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25. Aging and Bone Health in Individuals with Developmental Disabilities
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Joan Jasien, Caitlin M. Daimon, Stuart Maudsley, Bruce K. Shapiro, and Bronwen Martin
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Low bone mass density (BMD), a classical age-related health issue and a known health concern for fair skinned, thin, postmenopausal Caucasian women, is found to be common among individuals with developmental/intellectual disabilities (D/IDs). It is the consensus that BMD is decreased in both men and women with D/ID. Maintaining good bone health is important for this population as fractures could potentially go undetected in nonverbal individuals, leading to increased morbidity and a further loss of independence. This paper provides a comprehensive overview of bone health of adults with D/ID, their risk of fractures, and how this compares to the general aging population. We will specifically focus on the bone health of two common developmental disabilities, Down syndrome (DS) and cerebral palsy (CP), and will discuss BMD and fracture rates in these complex populations. Gaining a greater understanding of how bone health is affected in individuals with D/ID could lead to better customized treatments for these specific populations.
- Published
- 2012
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26. Plasma BDNF is associated with age-related white matter atrophy but not with cognitive function in older, non-demented adults.
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Ira Driscoll, Bronwen Martin, Yang An, Stuart Maudsley, Luigi Ferrucci, Mark P Mattson, and Susan M Resnick
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Medicine ,Science - Abstract
Brain derived neurotrophic factor (BDNF) seems to be involved in regulation of synaptic plasticity and neurogenesis. BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether BDNF plasma concentration was associated with rates of age-related change in cognitive performance (n = 429) and regional brain volume (n = 59). Plasma BDNF levels, which were significantly higher in females (p0.05). Sex differences in the relationship between BDNF and the trajectories of regional brain volume changes were observed for the whole brain and frontal white matter volumes (p
- Published
- 2012
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27. Correction: Altered Hypothalamic Protein Expression in a Rat Model of Huntington's Disease.
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Wei-na Cong, Huan Cai, Rui Wang, Caitlin M. Daimon, Stuart Maudsley, Kerstin Raber, Fabio Canneva, Stephan von Hörsten, and Bronwen Martin
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Medicine ,Science - Published
- 2012
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28. Metabolic Context Regulates Distinct Hypothalamic Transcriptional Responses to Antiaging Interventions
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Alexis M. Stranahan, Bronwen Martin, Wayne Chadwick, Sung-Soo Park, Liyun Wang, Kevin G. Becker, William H. WoodIII, Yongqing Zhang, and Stuart Maudsley
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
The hypothalamus is an essential relay in the neural circuitry underlying energy metabolism that needs to continually adapt to changes in the energetic environment. The neuroendocrine control of food intake and energy expenditure is associated with, and likely dependent upon, hypothalamic plasticity. Severe disturbances in energy metabolism, such as those that occur in obesity, are therefore likely to be associated with disruption of hypothalamic transcriptomic plasticity. In this paper, we investigated the effects of two well-characterized antiaging interventions, caloric restriction and voluntary wheel running, in two distinct physiological paradigms, that is, diabetic (db/db) and nondiabetic wild-type (C57/Bl/6) animals to investigate the contextual sensitivity of hypothalamic transcriptomic responses. We found that, both quantitatively and qualitatively, caloric restriction and physical exercise were associated with distinct transcriptional signatures that differed significantly between diabetic and non-diabetic mice. This suggests that challenges to metabolic homeostasis regulate distinct hypothalamic gene sets in diabetic and non-diabetic animals. A greater understanding of how genetic background contributes to hypothalamic response mechanisms could pave the way for the development of more nuanced therapeutics for the treatment of metabolic disorders that occur in diverse physiological backgrounds.
- Published
- 2012
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29. Central Role of the EGF Receptor in Neurometabolic Aging
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Sana Siddiqui, Meng Fang, Bin Ni, Daoyuan Lu, Bronwen Martin, and Stuart Maudsley
- Subjects
Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
A strong connection between neuronal and metabolic health has been revealed in recent years. It appears that both normal and pathophysiological aging, as well as neurodegenerative disorders, are all profoundly influenced by this “neurometabolic” interface, that is, communication between the brain and metabolic organs. An important aspect of this “neurometabolic” axis that needs to be investigated involves an elucidation of molecular factors that knit these two functional signaling domains, neuronal and metabolic, together. This paper attempts to identify and discuss a potential keystone signaling factor in this “neurometabolic” axis, that is, the epidermal growth factor receptor (EGFR). The EGFR has been previously demonstrated to act as a signaling nexus for many ligand signaling modalities and cellular stressors, for example, radiation and oxidative radicals, linked to aging and degeneration. The EGFR is expressed in a wide variety of cells/tissues that pertain to the coordinated regulation of neurometabolic activity. EGFR signaling has been highlighted directly or indirectly in a spectrum of neurometabolic conditions, for example, metabolic syndrome, diabetes, Alzheimer’s disease, cancer, and cardiorespiratory function. Understanding the positioning of the EGFR within the neurometabolic domain will enhance our appreciation of the ability of this receptor system to underpin highly complex physiological paradigms such as aging and neurodegeneration.
- Published
- 2012
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30. GIT2 acts as a potential keystone protein in functional hypothalamic networks associated with age-related phenotypic changes in rats.
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Wayne Chadwick, Bronwen Martin, Megan C Chapter, Sung-Soo Park, Liyun Wang, Caitlin M Daimon, Randall Brenneman, and Stuart Maudsley
- Subjects
Medicine ,Science - Abstract
The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. Using novel combinatorial bioinformatics analyses, we were able to gain a better understanding of the proteomic and phenotypic changes that occur during the aging process and have potentially identified the G protein-coupled receptor/cytoskeletal-associated protein GIT2 as a vital integrator and modulator of the normal aging process.
- Published
- 2012
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31. Correction: VENNTURE–A Novel Venn Diagram Investigational Tool for Multiple Pharmacological Dataset Analysis.
- Author
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Bronwen Martin, Wayne Chadwick, Tie Yi, Sung-Soo Park, Daoyuan Lu, Bin Ni, Shekhar Gadkaree, Kathleen Farhang, Kevin G. Becker, and Stuart Maudsley
- Subjects
Medicine ,Science - Published
- 2012
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32. Amitriptyline-mediated cognitive enhancement in aged 3×Tg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity.
- Author
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Wayne Chadwick, Nick Mitchell, Jenna Caroll, Yu Zhou, Sung-Soo Park, Liyun Wang, Kevin G Becker, Yongqing Zhang, Elin Lehrmann, William H Wood, Bronwen Martin, and Stuart Maudsley
- Subjects
Medicine ,Science - Abstract
Approximately 35 million people worldwide suffer from Alzheimer's disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (Aβ) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3×TgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic Aβ monomer with a concomitant decrease in cytotoxic dimer Aβ load, compared to vehicle-treated 3×TgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD.
- Published
- 2011
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33. Multiple oxygen tension environments reveal diverse patterns of transcriptional regulation in primary astrocytes.
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Wayne Chadwick, John P Boyle, Yu Zhou, Liyun Wang, Sung-Soo Park, Bronwen Martin, Rui Wang, Kevin G Becker, William H Wood, Yongqing Zhang, Chris Peers, and Stuart Maudsley
- Subjects
Medicine ,Science - Abstract
The central nervous system normally functions at O(2) levels which would be regarded as hypoxic by most other tissues. However, most in vitro studies of neurons and astrocytes are conducted under hyperoxic conditions without consideration of O(2)-dependent cellular adaptation. We analyzed the reactivity of astrocytes to 1, 4 and 9% O(2) tensions compared to the cell culture standard of 20% O(2), to investigate their ability to sense and translate this O(2) information to transcriptional activity. Variance of ambient O(2) tension for rat astrocytes resulted in profound changes in ribosomal activity, cytoskeletal and energy-regulatory mechanisms and cytokine-related signaling. Clustering of transcriptional regulation patterns revealed four distinct response pattern groups that directionally pivoted around the 4% O(2) tension, or demonstrated coherent ascending/decreasing gene expression patterns in response to diverse oxygen tensions. Immune response and cell cycle/cancer-related signaling pathway transcriptomic subsets were significantly activated with increasing hypoxia, whilst hemostatic and cardiovascular signaling mechanisms were attenuated with increasing hypoxia. Our data indicate that variant O(2) tensions induce specific and physiologically-focused transcript regulation patterns that may underpin important physiological mechanisms that connect higher neurological activity to astrocytic function and ambient oxygen environments. These strongly defined patterns demonstrate a strong bias for physiological transcript programs to pivot around the 4% O(2) tension, while uni-modal programs that do not, appear more related to pathological actions. The functional interaction of these transcriptional 'programs' may serve to regulate the dynamic vascular responsivity of the central nervous system during periods of stress or heightened activity.
- Published
- 2011
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34. Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses.
- Author
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Wayne Chadwick, Yu Zhou, Sung-Soo Park, Liyun Wang, Nicholas Mitchell, Matthew D Stone, Kevin G Becker, Bronwen Martin, and Stuart Maudsley
- Subjects
Medicine ,Science - Abstract
Oxidative exposure of cells occurs naturally and may be associated with cellular damage and dysfunction. Protracted low level oxidative exposure can induce accumulated cell disruption, affecting multiple cellular functions. Accumulated oxidative exposure has also been proposed as one of the potential hallmarks of the physiological/pathophysiological aging process. We investigated the multifactorial effects of long-term minimal peroxide exposure upon SH-SY5Y neural cells to understand how they respond to the continued presence of oxidative stressors. We show that minimal protracted oxidative stresses induce complex molecular and physiological alterations in cell functionality. Upon chronic exposure to minimal doses of hydrogen peroxide, SH-SY5Y cells displayed a multifactorial response to the stressor. To fully appreciate the peroxide-mediated cellular effects, we assessed these adaptive effects at the genomic, proteomic and cellular signal processing level. Combined analyses of these multiple levels of investigation revealed a complex cellular adaptive response to the protracted peroxide exposure. This adaptive response involved changes in cytoskeletal structure, energy metabolic shifts towards glycolysis and selective alterations in transmembrane receptor activity. Our analyses of the global responses to chronic stressor exposure, at multiple biological levels, revealed a viable neural phenotype in-part reminiscent of aged or damaged neural tissue. Our paradigm indicates how cellular physiology can subtly change in different contexts and potentially aid the appreciation of stress response adaptations.
- Published
- 2010
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35. Ghrelin is produced in taste cells and ghrelin receptor null mice show reduced taste responsivity to salty (NaCl) and sour (citric acid) tastants.
- Author
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Yu-Kyong Shin, Bronwen Martin, Wook Kim, Caitlin M White, Sunggoan Ji, Yuxiang Sun, Roy G Smith, Jean Sévigny, Matthias H Tschöp, Stuart Maudsley, and Josephine M Egan
- Subjects
Medicine ,Science - Abstract
The gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved.Using immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present within the taste buds of the tongue. Prepro-ghrelin, prohormone convertase 1/3 (PC 1/3), ghrelin, its cognate receptor (GHSR), and ghrelin-O-acyltransferase (GOAT , the enzyme that activates ghrelin) are expressed in Type I, II, III and IV taste cells of mouse taste buds. In addition, ghrelin and GHSR co-localize in the same taste cells, suggesting that ghrelin works in an autocrine manner in taste cells. To determine a role for ghrelin in modifying taste perception, we performed taste behavioral tests using GHSR null mice. GHSR null mice exhibited significantly reduced taste responsivity to sour (citric acid) and salty (sodium chloride) tastants.These findings suggest that ghrelin plays a local modulatory role in determining taste bud signaling and function and could be a novel mechanism for the modulation of salty and sour taste responsivity.
- Published
- 2010
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36. Circulating brain-derived neurotrophic factor and indices of metabolic and cardiovascular health: data from the Baltimore Longitudinal Study of Aging.
- Author
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Erin Golden, Ana Emiliano, Stuart Maudsley, B Gwen Windham, Olga D Carlson, Josephine M Egan, Ira Driscoll, Luigi Ferrucci, Bronwen Martin, and Mark P Mattson
- Subjects
Medicine ,Science - Abstract
Besides its well-established role in nerve cell survival and adaptive plasticity, brain-derived neurotrophic factor (BDNF) is also involved in energy homeostasis and cardiovascular regulation. Although BDNF is present in the systemic circulation, it is unknown whether plasma BDNF correlates with circulating markers of dysregulated metabolism and an adverse cardiovascular profile.To determine whether circulating BDNF correlates with indices of metabolic and cardiovascular health, we measured plasma BDNF levels in 496 middle-age and elderly subjects (mean age approximately 70), in the Baltimore Longitudinal Study of Aging. Linear regression analysis revealed that plasma BDNF is associated with risk factors for cardiovascular disease and metabolic syndrome, regardless of age. In females, BDNF was positively correlated with BMI, fat mass, diastolic blood pressure, total cholesterol, and LDL-cholesterol, and inversely correlated with folate. In males, BDNF was positively correlated with diastolic blood pressure, triglycerides, free thiiodo-thyronine (FT3), and bioavailable testosterone, and inversely correlated with sex-hormone binding globulin, and adiponectin.Plasma BDNF significantly correlates with multiple risk factors for metabolic syndrome and cardiovascular dysfunction. Whether BDNF contributes to the pathogenesis of these disorders or functions in adaptive responses to cellular stress (as occurs in the brain) remains to be determined.
- Published
- 2010
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37. Complex and Multidimensional Lipid Raft Alterations in a Murine Model of Alzheimer's Disease
- Author
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Wayne Chadwick, Randall Brenneman, Bronwen Martin, and Stuart Maudsley
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Geriatrics ,RC952-954.6 - Abstract
Various animal models of Alzheimer's disease (AD) have been created to assist our appreciation of AD pathophysiology, as well as aid development of novel therapeutic strategies. Despite the discovery of mutated proteins that predict the development of AD, there are likely to be many other proteins also involved in this disorder. Complex physiological processes are mediated by coherent interactions of clusters of functionally related proteins. Synaptic dysfunction is one of the hallmarks of AD. Synaptic proteins are organized into multiprotein complexes in high-density membrane structures, known as lipid rafts. These microdomains enable coherent clustering of synergistic signaling proteins. We have used mass analytical techniques and multiple bioinformatic approaches to better appreciate the intricate interactions of these multifunctional proteins in the 3xTgAD murine model of AD. Our results show that there are significant alterations in numerous receptor/cell signaling proteins in cortical lipid rafts isolated from 3xTgAD mice.
- Published
- 2010
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38. Gonadal transcriptome alterations in response to dietary energy intake: sensing the reproductive environment.
- Author
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Bronwen Martin, Michele Pearson, Randall Brenneman, Erin Golden, William Wood, Vinayakumar Prabhu, Kevin G Becker, Mark P Mattson, and Stuart Maudsley
- Subjects
Medicine ,Science - Abstract
Reproductive capacity and nutritional input are tightly linked and animals' specific responses to alterations in their physical environment and food availability are crucial to ensuring sustainability of that species. We have assessed how alterations in dietary energy intake (both reductions and excess), as well as in food availability, via intermittent fasting (IF), affect the gonadal transcriptome of both male and female rats. Starting at four months of age, male and female rats were subjected to a 20% or 40% caloric restriction (CR) dietary regime, every other day feeding (IF) or a high fat-high glucose (HFG) diet for six months. The transcriptional activity of the gonadal response to these variations in dietary energy intake was assessed at the individual gene level as well as at the parametric functional level. At the individual gene level, the females showed a higher degree of coherency in gonadal gene alterations to CR than the males. The gonadal transcriptional and hormonal response to IF was also significantly different between the male and female rats. The number of genes significantly regulated by IF in male animals was almost 5 times greater than in the females. These IF males also showed the highest testosterone to estrogen ratio in their plasma. Our data show that at the level of gonadal gene responses, the male rats on the IF regime adapt to their environment in a manner that is expected to increase the probability of eventual fertilization of females that the males predict are likely to be sub-fertile due to their perception of a food deficient environment.
- Published
- 2009
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39. iTRAQ analysis of complex proteome alterations in 3xTgAD Alzheimer's mice: understanding the interface between physiology and disease.
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Bronwen Martin, Randall Brenneman, Kevin G Becker, Marjan Gucek, Robert N Cole, and Stuart Maudsley
- Subjects
Medicine ,Science - Abstract
Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with accumulation of amyloid beta-peptide, synaptic degeneration and the death of neurons in the hippocampus, and temporal, parietal and frontal lobes of the cerebral cortex. Analysis of postmortem brain tissue from AD patients can provide information on molecular alterations present at the end of the disease process, but cannot discriminate between changes that are specifically involved in AD versus those that are simply a consequence of neuronal degeneration. Animal models of AD provide the opportunity to elucidate the molecular changes that occur in brain cells as the disease process is initiated and progresses. To this end, we used the 3xTgAD mouse model of AD to gain insight into the complex alterations in proteins that occur in the hippocampus and cortex in AD. The 3xTgAD mice express mutant presenilin-1, amyloid precursor protein and tau, and exhibit AD-like amyloid and tau pathology in the hippocampus and cortex, and associated cognitive impairment. Using the iTRAQ stable-isotope-based quantitative proteomic technique, we performed an in-depth proteomic analysis of hippocampal and cortical tissue from 16 month old 3xTgAD and non-transgenic control mice. We found that the most important groups of significantly altered proteins included those involved in synaptic plasticity, neurite outgrowth and microtubule dynamics. Our findings have elucidated some of the complex proteome changes that occur in a mouse model of AD, which could potentially illuminate novel therapeutic avenues for the treatment of AD and other neurodegenerative disorders.
- Published
- 2008
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40. Conserved and differential effects of dietary energy intake on the hippocampal transcriptomes of females and males.
- Author
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Bronwen Martin, Michele Pearson, Randall Brenneman, Erin Golden, Alex Keselman, Titilola Iyun, Olga D Carlson, Josephine M Egan, Kevin G Becker, William Wood, Vinayakumar Prabhu, Rafael de Cabo, Stuart Maudsley, and Mark P Mattson
- Subjects
Medicine ,Science - Abstract
The level of dietary energy intake influences metabolism, reproductive function, the development of age-related diseases, and even cognitive behavior. Because males and females typically play different roles in the acquisition and allocation of energy resources, we reasoned that dietary energy intake might differentially affect the brains of males and females at the molecular level. To test this hypothesis, we performed a gene array analysis of the hippocampus in male and female rats that had been maintained for 6 months on either ad libitum (control), 20% caloric restriction (CR), 40% CR, intermittent fasting (IF) or high fat/high glucose (HFG) diets. These diets resulted in expected changes in body weight, and circulating levels of glucose, insulin and leptin. However, the CR diets significantly increased the size of the hippocampus of females, but not males. Multiple genes were regulated coherently in response to energy restriction diets in females, but not in males. Functional physiological pathway analyses showed that the 20% CR diet down-regulated genes involved in glycolysis and mitochondrial ATP production in males, whereas these metabolic pathways were up-regulated in females. The 40% CR diet up-regulated genes involved in glycolysis, protein deacetylation, PGC-1alpha and mTor pathways in both sexes. IF down-regulated many genes in males including those involved in protein degradation and apoptosis, but up-regulated many genes in females including those involved in cellular energy metabolism, cell cycle regulation and protein deacetylation. Genes involved in energy metabolism, oxidative stress responses and cell death were affected by the HFG diet in both males and females. The gender-specific molecular genetic responses of hippocampal cells to variations in dietary energy intake identified in this study may mediate differential behavioral responses of males and females to differences in energy availability.
- Published
- 2008
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41. The TM2.50 Aspartate of the TM1‐2‐7 Hydrogen‐Bond Network Modulates Signaling Bias Effects in G Protein‐Coupled Receptor 19 (GPR19)
- Author
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Deborah Walter, Hanne Leysen, Bregje Christiaenssen, and Stuart Maudsley
- Subjects
Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
42. Making biomedical sciences publications more accessible for machines
- Author
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Joris Van Meenen, Hanne Leysen, Hongyu Chen, Rudi Baccarne, Deborah Walter, Bronwen Martin, and Stuart Maudsley
- Subjects
Computer. Automation ,Philosophy ,History ,Biomedical Research ,Health (social science) ,Sociology ,Health Policy ,Pharmacology. Therapy ,Publications ,Documentation and information ,Humans ,Information Storage and Retrieval ,Education - Abstract
With the rapidly expanding catalogue of scientific publications, especially within the Biomedical Sciences field, it is becoming increasingly difficult for researchers to search for, read or even interpret emerging scientific findings. PubMed, just one of the current biomedical data repositories, comprises over 33 million citations for biomedical research, and over 2500 publications are added each day. To further strengthen the impact biomedical research, we suggest that there should be more synergy between publications and machines. By bringing machines into the realm of research and publication, we can greatly augment the assessment, investigation and cataloging of the biomedical literary corpus. The effective application of machine-based manuscript assessment and interpretation is now crucial, and potentially stands as the most effective way for researchers to comprehend and process the tsunami of biomedical data and literature. Many biomedical manuscripts are currently published online in poorly searchable document types, with figures and data presented in formats that are partially inaccessible to machine-based approaches. The structure and format of biomedical manuscripts should be adapted to facilitate machine-assisted interrogation of this important literary corpus. In this context, it is important to embrace the concept that biomedical scientists should also write manuscripts that can be read by machines. It is likely that an enhanced human-machine synergy in reading biomedical publications will greatly enhance biomedical data retrieval and reveal novel insights into complex datasets.
- Published
- 2022
43. Progression of established non-diabetic chronic kidney disease is halted by metformin treatment in rats
- Author
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Raphaëlle Corremans, Ellen Neven, Stuart Maudsley, Hanne Leysen, Marc E. De Broe, Patrick C. D’Haese, Benjamin A. Vervaet, and Anja Verhulst
- Subjects
Male ,Proteomics ,Adenine ,Metformin ,Rats ,Diabetes Mellitus, Type 2 ,Nephrology ,Animals ,Humans ,Diabetic Nephropathies ,Female ,Human medicine ,Canagliflozin ,Renal Insufficiency, Chronic ,Biology - Abstract
Current treatment strategies for chronic kidney disease (CKD) mainly focus on controlling risk factors. Metformin, a first-line drug for type-2 diabetes, exerts beneficial pleiotropic actions beyond its prescribed use and incipient data has revealed protective effects against the development of kidney impairment. This study evaluated the therapeutic efficacy of metformin and canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor recently approved by the United States Food and Drug Administration to treat diabetic nephropathy, in slowing the progression of established non-diabetic CKD. Rats with adenine-induced CKD were assigned to different treatment groups to receive either 200 mg/kg metformin, four or five weeks after the start of the adenine diet (established mild-moderate CKD), or 25 mg/kg canagliflozin four weeks after the start of the diet, by daily oral gavage administered during four weeks. Each treatment group was compared to a vehicle group. Chronic adenine dosing resulted in severe CKD in vehicle-treated rats as indicated by a marked rise in serum creatinine levels, a marked decrease in creatinine clearance, and a disturbed mineral metabolism. Metformin, but not canagliflozin, halted functional kidney decline. Additionally, kidneys of metformin-treated animals showed less interstitial area and inflammation as compared to the vehicle group. Proteomic analyses revealed that metformin’s kidney-protective effect was associated with the activation of the Hippo signaling pathway, a highly conserved multiprotein kinase cascade that controls tissue development, organ size, cell proliferation, and apoptosis. Thus, metformin demonstrated therapeutic efficacy by halting the progression of established CKD in a rat model.
- Published
- 2022
44. Systems Pharmacology: Enabling Multidimensional Therapeutics
- Author
-
Stuart Maudsley, Jaana van Gastel, Hanne Leysen, and Bronwen Martin
- Subjects
Management science ,Computer science ,Systems pharmacology - Published
- 2022
45. The RXFP3 receptor is functionally associated with cellular responses to oxidative stress and DNA damage
- Author
-
Hanne Leysen, Stuart Maudsley, Jaana van Gastel, Paula Santos-Otte, Jhana O. Hendrickx, Abdelkrim Azmi, and Bronwen Martin
- Subjects
Aging ,DNA damage ,medicine.disease_cause ,Receptors, G-Protein-Coupled ,GPCR ,medicine ,Humans ,Gene Regulatory Networks ,RNA, Messenger ,Receptor ,Biology ,G protein-coupled receptor ,Relaxin ,Felodipine ,Chemistry ,GTPase-Activating Proteins ,relaxin 3 ,Computational Biology ,Cell Biology ,Cell biology ,Oxidative Stress ,HEK293 Cells ,Gene Expression Regulation ,Phosphorylation ,Camptothecin ,Human medicine ,Topoisomerase I Inhibitors ,relaxin family peptide 3 receptor ,Relaxin-3 ,Oxidative stress ,Research Paper ,medicine.drug - Abstract
DNA damage response (DDR) processes, often caused by oxidative stress, are important in aging and -related disorders. We recently showed that G protein-coupled receptor (GPCR) kinase interacting protein 2 (GIT2) plays a key role in both DNA damage and oxidative stress. Multiple tissue analyses in GIT2KO mice demonstrated that GIT2 expression affects the GPCR relaxin family peptide 3 receptor (RXFP3), and is thus a therapeutically-targetable system. RXFP3 and GIT2 play similar roles in metabolic aging processes. Gaining a detailed understanding of the RXFP3-GIT2 functional relationship could aid the development of novel anti-aging therapies. We determined the connection between RXFP3 and GIT2 by investigating the role of RXFP3 in oxidative stress and DDR. Analyzing the effects of oxidizing (H2O2) and DNA-damaging (camptothecin) stressors on the interacting partners of RXFP3 using Affinity Purification-Mass Spectrometry, we found multiple proteins linked to DDR and cell cycle control. RXFP3 expression increased in response to DNA damage, overexpression, and Relaxin 3-mediated stimulation of RXFP3 reduced phosphorylation of DNA damage marker H2AX, and repair protein BRCA1, moderating DNA damage. Our data suggests an RXFP3-GIT2 system that could regulate cellular degradation after DNA damage, and could be a novel mechanism for mitigating the rate of age-related damage accumulation.
- Published
- 2019
46. The TRY‐motif in the Relaxin Family Peptide Receptor 3 (RXFP3) functions as a Molecular Switch Between DNA Damage Response and Cell Cycle Control
- Author
-
Jaana van Gastel, Hanne Leysen, Stuart Maudsley, Jens Van Turnhout, Bronwen Martin, Abdelkrim Azmi, Jasper Verswyvel, Laura Vangenechten, and Paula Santos-Otte
- Subjects
Relaxin ,Molecular switch ,Motif (narrative) ,Peptide receptor ,Chemistry ,DNA damage ,Cell cycle control ,Genetics ,Molecular Biology ,Biochemistry ,Biotechnology ,Cell biology - Published
- 2021
47. Image-guided phenotyping of ovariectomized mice: altered functional connectivity, cognition, myelination, and dopaminergic functionality
- Author
-
Jaana van Gastel, Rukun Hinz, Abdelkrim Azmi, Stuart Maudsley, Annemie Van der Linden, Charlotte Laloux, A. Langbeen, Peter E.J. Bols, Cynthia Anckaerts, Firat Kara, Valerie Leysen, Disha Shah, Pascal Simoens, Vincent Prevot, and Marleen Verhoye
- Subjects
0301 basic medicine ,Hypothalamo-Hypophyseal System ,Aging ,Ovariectomy ,Quantitative proteomics ,Population ,Gene Expression ,Pituitary-Adrenal System ,Cell Cycle Proteins ,Biology ,Proteomics ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,0302 clinical medicine ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,medicine ,Animals ,Cognitive Dysfunction ,education ,Cellular Senescence ,education.field_of_study ,Resting state fMRI ,medicine.diagnostic_test ,General Neuroscience ,Dopaminergic ,Receptors, Dopamine D3 ,Brain ,Membrane Proteins ,Cognition ,Magnetic resonance imaging ,Magnetic Resonance Imaging ,Mice, Inbred C57BL ,030104 developmental biology ,Female ,Human medicine ,Neurology (clinical) ,Geriatrics and Gerontology ,Functional magnetic resonance imaging ,Neuroscience ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
A large proportion of the population suffers from endocrine disruption, e.g., menopausal women, which might result in accelerated aging and a higher risk for developing cognitive disorders. Therefore, it is crucial to fully understand the impact of such disruptions on the brain to identify potential therapeutic strategies. Here, we show using resting-state functional magnetic resonance imaging that ovariectomy and consequent hypothalamus-pituitary-gonadal disruption result in the selective dysconnectivity of 2 discrete brain regions in mice. This effect coincided with cognitive deficits and an underlying pathological molecular phenotype involving an imbalance of neurodevelopmental/neurodegenerative signaling. Furthermore, this quantitative mass spectrometry proteomics-based analysis of molecular signaling patterns further identified a strong involvement of altered dopaminergic functionality (e.g., DAT and predicted upstream regulators DRD3, NR4A2), reproductive signaling (e.g., Srd5a2), rotatin expression (rttn), cellular aging (e.g., Rxfp3, Git2), myelination, and axogenesis (e.g., Nefl, Mag). With this, we have provided an improved understanding of the impact of hypothalamus-pituitary-gonadal dysfunction and highlighted the potential of using a highly translational magnetic resonance imaging technique for monitoring these effects on the brain.
- Published
- 2019
48. G Protein-Coupled Receptor Systems and Their Role in Cellular Senescence
- Author
-
Hanne Leysen, Jhana O. Hendrickx, Paula Santos-Otte, Stuart Maudsley, Jaana van Gastel, and Bronwen Martin
- Subjects
Aging ,Review Article ,Disease ,Aging disorders ,Biochemistry ,vascular smooth muscle cells, (VSMC) ,cyclin-dependent kinase inhibitor 1, (cdkn1A/p21) ,0302 clinical medicine ,Structural Biology ,Hutchinson–Gilford progeria syndrome, (HGPS) ,purinergic receptors family, (P2Y) ,protein kinases, (PK) ,beta2-adrenergic receptor, (β2AR) ,Receptor ,endothelial cell differentiation gene, (Edg) ,nuclear factor kappa-light-chain-enhancer of activated B cells, (NF- κβ) ,senescence associated secretory phenotype, (SASP) ,0303 health sciences ,Relaxin family receptor 3, (RXFP3) ,tumor suppressor gene PTEN, (PTEN) ,transcription factor E2F3, (E2F3) ,Computer Science Applications ,Cell biology ,retinoblastoma, (RB) ,Chemistry ,030220 oncology & carcinogenesis ,G protein-coupled receptor kinase, (GRK) ,latent semantic indexing, (LSI) ,Lysophosphatidic acid, (LPA) ,G protein-coupled receptors (GPCRs) ,G protein-coupled receptor kinase interacting protein 2 (GIT2) ,mitogen-activated protein kinase, (MAPK) ,Regulator of G-protein signaling, (RGS) ,Engineering sciences. Technology ,AT1R blockers, (ARB) ,Biotechnology ,Cell signaling ,lcsh:Biotechnology ,renin-angiotensin system, (RAS) ,Biophysics ,Cellular senescence ,tumor suppressor protein 53, (p53) ,Biology ,03 medical and health sciences ,Cell surface receptor ,lcsh:TP248.13-248.65 ,angiotensin type 2 receptor, (AT2R) ,Genetics ,G protein-coupled receptor kinase interacting protein 2, (GIT2) ,Ataxia telangiectasia mutated, (ATM) ,Angiotensin II, (Ang II) ,030304 developmental biology ,G protein-coupled receptor ,inactive state, (R) ,angiotensin type 1 receptor, (AT1R) ,G protein-coupled receptors, (GPCRs) ,β-Arrestin ,ADP-ribosylation factor GTPase-activating protein, (Arf-GAP) ,cyclin-dependent kinase 2, (CDK2) ,Apoptosis ,transmembrane, (TM) ,stress-induced premature senescence, (SIPS) ,active state, (R*) - Abstract
Aging is a complex biological process that is inevitable for nearly all organisms. Aging is the strongest risk factor for development of multiple neurodegenerative disorders, cancer and cardiovascular disorders. Age-related disease conditions are mainly caused by the progressive degradation of the integrity of communication systems within and between organs. This is in part mediated by, i) decreased efficiency of receptor signaling systems and ii) an increasing inability to cope with stress leading to apoptosis and cellular senescence. Cellular senescence is a natural process during embryonic development, more recently it has been shown to be also involved in the development of aging disorders and is now considered one of the major hallmarks of aging. G-protein-coupled receptors (GPCRs) comprise a superfamily of integral membrane receptors that are responsible for cell signaling events involved in nearly every physiological process. Recent advances in the molecular understanding of GPCR signaling complexity have expanded their therapeutic capacity tremendously. Emerging data now suggests the involvement of GPCRs and their associated proteins in the development of cellular senescence. With the proven efficacy of therapeutic GPCR targeting, it is reasonable to now consider GPCRs as potential platforms to control cellular senescence and the consequently, age-related disorders., Graphical Abstract Unlabelled Image
- Published
- 2019
49. Aging-related modifications to G protein-coupled receptor signaling diversity
- Author
-
Bronwen Martin, Stuart Maudsley, Hanne Leysen, Laura Vangenechten, Louis M. Luttrell, Jaana van Gastel, and Jan Boddaert
- Subjects
0301 basic medicine ,Pharmacology ,Premature aging ,Aging ,Effector ,Pharmacology. Therapy ,SUPERFAMILY ,Computational biology ,Disease ,Biology ,G Protein-Coupled Receptor Signaling ,GPCR Signaling ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Humans ,Pharmacology (medical) ,G protein-coupled receptor ,Signal Transduction - Abstract
Aging is a highly complex molecular process, affecting nearly all tissue systems in humans and is the highest risk factor in developing neurodegenerative disorders such as Alzheimer & rsquo;s and Parkinson & rsquo;s disease, cardiovascular disease and Type 2 diabetes mellitus. The intense complexity of the aging process creates an incentive to develop more specific drugs that attenuate or even reverse some of the features of premature aging. As our current pharmacopeia is dominated by therapeutics that target members of the G protein-coupled receptor (GPCR) superfamily it may be prudent to search for effective anti-aging therapeutics in this fertile domain. Since the first demonstration of GPCR-based beta-arrestin signaling, it has become clear that an enhanced appreciation of GPCR signaling diversity may facilitate the creation of therapeutics with selective signaling activities. Such & lsquo;biased & rsquo; ligand signaling profiles can be effectively investigated using both standard molecular biological techniques as well as high-dimensionality data analyses. Through a more nuanced appreciation of the quantitative nature across the multiple dimensions of signaling bias that drugs possess, researchers may be able to further refine the efficacy of GPCR modulators to impact the complex aberrations that constitute the aging process. Identifying novel effector profiles could expand the effective pharmacopeia and assist in the design of precision medicines. This review discusses potential non-G protein effectors, and specifically their potential therapeutic suitability in aging and age-related disorders. (c) 2020 Published by Elsevier Inc.
- Published
- 2021
50. Effects of Detergent on α-Synuclein Structure: A Native MS-Ion Mobility Study
- Author
-
Frank Sobott, Anne-Marie Lambeir, Stuart Maudsley, Renate van der Wekken-de Bruijne, Rani Moons, and Filip Lemière
- Subjects
Models, Molecular ,0301 basic medicine ,Protein Conformation ,Micelle ,lcsh:Chemistry ,chemistry.chemical_compound ,0302 clinical medicine ,Protein structure ,Nanotechnology ,lcsh:QH301-705.5 ,Spectroscopy ,mass spectrometry ,Neurodegeneration ,General Medicine ,Computer Science Applications ,Chemistry ,Monomer ,Membrane ,alpha-Synuclein ,Protein Binding ,Spectrometry, Mass, Electrospray Ionization ,ligand binding ,Electrospray ionization ,Detergents ,electrospray ionization ,Models, Biological ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,ion mobility ,α-synuclein ,medicine ,Humans ,membrane interaction ,Molecule ,Physical and Theoretical Chemistry ,Biology ,Molecular Biology ,detergent micelles ,Organic Chemistry ,Biological membrane ,intrinsically disordered protein ,medicine.disease ,nervous system diseases ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,nervous system ,Biophysics ,Protein Multimerization ,030217 neurology & neurosurgery - Abstract
The intrinsically disordered protein &alpha, synuclein plays a major role in Parkinson&rsquo, s disease. The protein can oligomerize resulting in the formation of various aggregated species in neuronal cells, leading to neurodegeneration. The interaction of &alpha, synuclein with biological cell membranes plays an important role for specific functions of &alpha, synuclein monomers, e.g., in neurotransmitter release. Using different types of detergents to mimic lipid molecules present in biological membranes, including the presence of Ca2+ ions as an important structural factor, we aimed to gain an understanding of how &alpha, synuclein interacts with membrane models and how this affects the protein conformation and potential oligomerization. We investigated detergent binding stoichiometry, affinity and conformational changes of &alpha, synuclein taking detergent concentration, different detergent structures and charges into account. With native nano-electrospray ionization ion mobility-mass spectrometry, we were able to detect unique conformational patterns resulting from binding of specific detergents to &alpha, synuclein. Our data demonstrate that &alpha, synuclein monomers can interact with detergent molecules irrespective of their charge, that protein-micelle interactions occur and that micelle properties are an important factor.
- Published
- 2020
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