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Article ; Online: GDF15 is a dynamic biomarker of the integrated stress response in the central nervous system.

Asundi, Jyoti / Zhang, Chunlian / Donnelly-Roberts, Diana / Solorio, Josè Zavala / Challagundla, Malleswari / Connelly, Caitlin / Boch, Christina / Chen, Jun / Richter, Mario / Maneshi, Mohammad Mehdi / Swensen, Andrew M / Lebon, Lauren / Schiffmann, Raphael / Sanyal, Subhabrata / Sidrauski, Carmela / Kolumam, Ganesh / Baruch, Amos

CNS neuroscience & therapeutics

2024 Volume 30, Issue 2, Page(s) e14600

Abstract: Aim: Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS).: Methods: We determined GDF15 levels utilizing in vitro and in vivo neuronal systems ... ...

Abstract	Aim: Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS). Methods: We determined GDF15 levels utilizing in vitro and in vivo neuronal systems wherein the ISR was activated. Primarily, we used the murine model of vanishing white matter disease (VWMD), a neurological disease driven by persistent ISR in the CNS, to establish a link between levels of GDF15 in the cerebrospinal fluid (CSF) and ISR gene expression signature in the CNS. GDF15 was also determined in the CSF of VWM patients. Results: GDF15 expression was increased concomitant to ISR activation in stress-induced primary astrocytes as well as in retinal ganglion cells following optic nerve crush, while treatment with 2Bact, a specific eIF2B activator, suppressed both the ISR and GDF15. In the VWMD model, CSF GDF15 levels corresponded with the magnitude of the ISR and were reduced by 2BAct. In VWM patients, mean CSF GDF15 was elevated >20-fold as compared to healthy controls, whereas plasma GDF15 was undifferentiated. Conclusions: These data suggest that CSF GDF15 is a dynamic marker of ISR activation in the CNS and may serve as a pharmacodynamic biomarker for ISR-modulating therapies.
MeSH term(s)	Humans ; Mice ; Animals ; Growth Differentiation Factor 15/genetics ; Leukoencephalopathies/genetics ; Central Nervous System/metabolism ; Eukaryotic Initiation Factor-2B/genetics ; Eukaryotic Initiation Factor-2B/metabolism ; Biomarkers
Chemical Substances	Growth Differentiation Factor 15 ; Eukaryotic Initiation Factor-2B ; Biomarkers ; GDF15 protein, human
Language	English
Publishing date	2024-02-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2423461-8
ISSN	1755-5949 ; 1755-5930
ISSN (online)	1755-5949
ISSN	1755-5930
DOI	10.1111/cns.14600
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Zs.A 4537: Show issues

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Article ; Online: Nicotinic acetylcholine receptors as therapeutic targets: Emerging frontiers in basic research and clinical science--Editorial Comments.

Dani, John A / Donnelly-Roberts, Diana / Bertrand, Daniel

Biochemical pharmacology

2015 Volume 97, Issue 4, Page(s) 351

MeSH term(s)	Drug Design ; Drug Discovery ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/metabolism ; Receptors, Nicotinic/metabolism ; Signal Transduction/physiology ; Substance-Related Disorders/drug therapy ; Substance-Related Disorders/metabolism
Chemical Substances	Receptors, Nicotinic
Language	English
Publishing date	2015-10-15
Publishing country	England
Document type	Editorial
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2015.06.004
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Zs.A 19: Show issues

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Article ; Online: Small Molecule Phenotypic Screen Identifies Novel Regulators of LDLR Expression.

Krishnan, Navasona / Chen, Xiaoying / Donnelly-Roberts, Diana / Mohler, Eric G / Holtzman, David M / Gopalakrishnan, Sujatha M

ACS chemical biology

2020 Volume 15, Issue 12, Page(s) 3262–3274

Abstract: Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The current treatment options for AD are limited to ameliorating cognitive decline temporarily and not reversing or preventing the progression of ... ...

Abstract	Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The current treatment options for AD are limited to ameliorating cognitive decline temporarily and not reversing or preventing the progression of dementia. Hence, more effective therapeutic strategies are needed to combat this devastating disease. The low-density lipoprotein receptor has been shown to modulate the neuronal metabolism of cholesterol and apolipoprotein E, a major genetic risk factor for AD. LDLR overexpression in mice has been shown to increase amyloid-β clearance and reduce amyloid deposition. We conducted a phenotypic screen to identify novel signaling pathways and targets that regulate LDLR expression in glial cells using an annotated compound library of approximately 29 000 compounds. The screen identified novel targets such as polo like kinase 1 (PLK1), activin receptor like kinase 5 (ALK5), and serotonin transporter (SERT). We used genetic, chemical biology and pathway analysis to confirm the target hypothesis. This work highlights that phenotypic screening is a promising strategy to identify novel mechanisms and targets for therapeutic intervention of complex neurodegenerative disorders.
MeSH term(s)	Alzheimer Disease/pathology ; Gene Knockdown Techniques ; Humans ; RNA, Small Interfering/genetics ; Receptors, LDL/drug effects ; Receptors, LDL/metabolism ; Reproducibility of Results ; Small Molecule Libraries/pharmacology
Chemical Substances	LDLR protein, human ; RNA, Small Interfering ; Receptors, LDL ; Small Molecule Libraries
Language	English
Publishing date	2020-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.0c00851
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Article ; Online: Nicotinic acetylcholine receptors as therapeutic targets: emerging frontiers in basic research and clinical science--editorial comments.

Dani, John A / Donnelly-Roberts, Diana / Bertrand, Daniel

Biochemical pharmacology

2013 Volume 86, Issue 8, Page(s) 1041

MeSH term(s)	Animals ; Central Nervous System/cytology ; Central Nervous System/physiology ; Cholinergic Agents/pharmacology ; Neurons/physiology ; Nicotinic Antagonists/pharmacology ; Receptors, Nicotinic/chemistry ; Receptors, Nicotinic/metabolism ; Signal Transduction/physiology
Chemical Substances	Cholinergic Agents ; Nicotinic Antagonists ; Receptors, Nicotinic
Language	English
Publishing date	2013-10-15
Publishing country	England
Document type	Editorial ; Introductory Journal Article
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2013.05.002
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Zs.A 19: Show issues

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Article ; Online: NRF2 activator A-1396076 ameliorates inflammation in autoimmune disease models by inhibiting antigen dependent T cell activation.

Goess, Christian / Terrillon, Sonia / Mayo, Martha / Bousquet, Peter / Wallace, Craig / Hart, Michelle / Mathieu, Suzanne / Twomey, Rachel / Donnelly-Roberts, Diana / Namovic, Marian / Jung, Paul / Hu, Min / Richardson, Paul / Esbenshade, Tim / Cuff, Carolyn A

Journal of translational autoimmunity

2020 Volume 4, Page(s) 100079

Abstract: Nuclear factor (erythroid-derived 2) like 2 (NRF2) is a nuclear transcription factor activated in response to oxidative stress that induces a gene program that dampens inflammation and can limit cell damage that perpetuates the inflammatory response. We ... ...

Abstract	Nuclear factor (erythroid-derived 2) like 2 (NRF2) is a nuclear transcription factor activated in response to oxidative stress that induces a gene program that dampens inflammation and can limit cell damage that perpetuates the inflammatory response. We have identified A-1396076, a potent and selective NRF2 activator with demonstrated KEAP1 binding and modulation of cellular NRF2 mediated effects.
Language	English
Publishing date	2020-12-23
Publishing country	Netherlands
Document type	Journal Article
ISSN	2589-9090
ISSN (online)	2589-9090
DOI	10.1016/j.jtauto.2020.100079
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Article ; Online: High throughput functional assays for P2X receptors.

Namovic, Marian T / Jarvis, Michael F / Donnelly-Roberts, Diana

Current protocols in pharmacology

2012 Volume Chapter 9, Page(s) Unit 9.15.

Abstract: Adenosine triphosphate (ATP) activates two receptor superfamilies, metabotropic P2Y and ionotropic P2X receptors. The P2X receptors are nonselective cation channels that are widely expressed on excitable cells including neurons, glia, and smooth muscle ... ...

Abstract	Adenosine triphosphate (ATP) activates two receptor superfamilies, metabotropic P2Y and ionotropic P2X receptors. The P2X receptors are nonselective cation channels that are widely expressed on excitable cells including neurons, glia, and smooth muscle cells. The protocols in this unit are useful for evaluating ligands that interact with P2X receptors on native cells or that are cloned and expressed in recombinant heterologous cell systems. Calcium imaging methods are described for the pharmacological characterization of fast or slowly desensitizing P2X receptors. While these methods are readily applicable to a wide variety of ligand-gated ion channels, the protocols provided herein detail how they can be used to measure activation of homomeric P2X3 (fast desensitizing) and heteromeric P2X2/3 (slowly desensitizing) receptors. Appropriate agonists and/or calcium dyes can be substituted to assess activity at other P2X receptor subtypes. An additional protocol is provided for measuring P2X7 receptor-mediated pore formation in THP-1, a native human acute monocytic leukemia cell line that can be used to study homomeric P2X7 (non-desensitizing) receptors that are expressed on macrophages and microglial cells.
MeSH term(s)	Astrocytoma/metabolism ; Buffers ; Calcium/metabolism ; Fluorometry/methods ; Humans ; Indicators and Reagents/pharmacology ; Purinergic P2X Receptor Agonists/pharmacology ; Purinergic P2X Receptor Antagonists/pharmacology ; Receptors, Purinergic P2X2/metabolism ; Tumor Cells, Cultured
Chemical Substances	Buffers ; Indicators and Reagents ; Purinergic P2X Receptor Agonists ; Purinergic P2X Receptor Antagonists ; Receptors, Purinergic P2X2 ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2012-06
Publishing country	United States
Document type	Journal Article
ISSN	1934-8290
ISSN (online)	1934-8290
DOI	10.1002/0471141755.ph0915s57
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Article ; Online: Losartan improves renal function and pathology in obese ZSF-1 rats.

Su, Zhi / Widomski, Deborah / Nikkel, Arthur / Leys, Laura / Namovic, Marian / Donnelly-Roberts, Diana / Gopalakrishnan, Murali / McGaraughty, Steve

Journal of basic and clinical physiology and pharmacology

2018 Volume 29, Issue 3, Page(s) 281–290

Abstract: Background: Losartan, a blocker of the angiotensin II type I receptor, is an important part of the standard of care for diabetic nephropathy (DN). The obese ZSF-1 rats display many aspects of the clinical features of human Type II DN. The current study ... ...

Abstract	Background: Losartan, a blocker of the angiotensin II type I receptor, is an important part of the standard of care for diabetic nephropathy (DN). The obese ZSF-1 rats display many aspects of the clinical features of human Type II DN. The current study was designed to examine the treatment effects of losartan on obese ZSF-1 rats and to evaluate the impact of the onset of dosing on efficacy. Methods: The rats (7-10 weeks) underwent a right uninephrectomy (Unx) or sham surgery. Losartan (3, 10, 30 mg/kg) was dosed 3 or 9 weeks post-Unx and continued for 12 weeks. Results: Treatment with losartan reduced urinary protein excretion and blood lipids (triglyceride and cholesterol) dose-dependently in both studies. The glomerular filtration rate (GFR) was significantly lower in obese ZSF-1 rats compared with those in lean rats, and losartan was efficacious against this endpoint, in particular with the earlier onset of treatment. Losartan also decreased tubulointerstitial fibrosis, and similar to GFR, earlier treatment conferred beneficial actions even at the lowest dose of 3 mg/kg. Several urinary biomarkers were elevated in the obese ZSF-1 rats, but the levels of sTNFR1, TIMP-1, L-FABP and KIM-1 were the only markers decreased by losartan. Conclusions: Losartan was renoprotective in the ZSF-1 rats with DN, improving both the pathological and functional parameters of the disease. Importantly, the data also highlight the importance of treatment at earlier stages of the disease for protecting against decline in the GFR and the development of fibrosis.
MeSH term(s)	Angiotensin II Type 1 Receptor Blockers/administration & dosage ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Animals ; Biomarkers/metabolism ; Cholesterol/blood ; Diabetes Mellitus, Experimental/complications ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/drug therapy ; Diabetic Nephropathies/prevention & control ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Glomerular Filtration Rate/drug effects ; Losartan/administration & dosage ; Losartan/pharmacology ; Male ; Obesity/drug therapy ; Rats ; Triglycerides/blood
Chemical Substances	Angiotensin II Type 1 Receptor Blockers ; Biomarkers ; Triglycerides ; Cholesterol (97C5T2UQ7J) ; Losartan (JMS50MPO89)
Language	English
Publishing date	2018-02-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1071737-7
ISSN	2191-0286 ; 0792-6855 ; 0334-1534
ISSN (online)	2191-0286
ISSN	0792-6855 ; 0334-1534
DOI	10.1515/jbcpp-2017-0157
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Zs.A 3207: Show issues

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Article ; Online: Nicotinic acetylcholine receptors as therapeutic targets: emerging frontiers in basic research and clinical science--Editorial Comments.

Donnelly-Roberts, Diana / Bertrand, Daniel / Gopalakrishnan, Murali

Biochemical pharmacology

2011 Volume 82, Issue 8, Page(s) 797

MeSH term(s)	Biomedical Research ; Clinical Medicine ; Congresses as Topic ; Drug Discovery ; Ligands ; Receptors, Nicotinic/metabolism ; Receptors, Nicotinic/physiology
Chemical Substances	Ligands ; Receptors, Nicotinic
Language	English
Publishing date	2011-10-15
Publishing country	England
Document type	Editorial
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2011.05.002
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Zs.A 19: Show issues

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Article ; Online: Therapeutic Potential of α7 Nicotinic Acetylcholine Receptors.

Bertrand, Daniel / Lee, Chih-Hung L / Flood, Dorothy / Marger, Fabrice / Donnelly-Roberts, Diana

Pharmacological reviews

2015 Volume 67, Issue 4, Page(s) 1025–1073

Abstract: Progress in the fields of neuroscience and molecular biology has identified the forebrain cholinergic system as being important in many higher order brain functions. Further analysis of the genes encoding the nicotinic acetylcholine receptors (nAChRs) ... ...

Abstract	Progress in the fields of neuroscience and molecular biology has identified the forebrain cholinergic system as being important in many higher order brain functions. Further analysis of the genes encoding the nicotinic acetylcholine receptors (nAChRs) has highlighted, in particular, the role of α7 nAChRs in these higher order brain functions as evidenced by their peculiar physiologic and pharmacological properties. As this receptor has gained the attention of scientists from academia and industry, our knowledge of its roles in various brain and bodily functions has increased immensely. We have also seen the development of small molecules that have further refined our understanding of the roles of α7 nAChRs, and these molecules have begun to be tested in clinical trials for several indications. Although a large body of data has confirmed a role of α7 nAChRs in cognition, the translation of small molecules affecting α7 nAChRs into therapeutics has to date only progressed to the stage of testing in clinical trials. Notably, however, most recent human genetic and biochemical studies are further underscoring the crucial role of α7 nAChRs and associated genes in multiple organ systems and disease states. The aim of this review is to discuss our current knowledge of α7 nAChRs and their relevance as a target in specific functional systems and disease states.
MeSH term(s)	Animals ; Brain/metabolism ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/physiopathology ; Humans ; Immune System Diseases/genetics ; Immune System Diseases/physiopathology ; Nervous System Diseases/genetics ; Nervous System Diseases/physiopathology ; Polymorphism, Single Nucleotide ; Signal Transduction ; Structure-Activity Relationship ; alpha7 Nicotinic Acetylcholine Receptor/genetics ; alpha7 Nicotinic Acetylcholine Receptor/metabolism
Chemical Substances	Chrna7 protein, human ; alpha7 Nicotinic Acetylcholine Receptor
Language	English
Publishing date	2015-10
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	209898-2
ISSN	1521-0081 ; 0031-6997
ISSN (online)	1521-0081
ISSN	0031-6997
DOI	10.1124/pr.113.008581
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Article ; Online: Nicotinic acetylcholine receptors as therapeutic targets: emerging frontiers in basic research and clinical science--editorial perspective.

Bertrand, Daniel / Gopalakrishnan, Murali / Donnelly-Roberts, Diana

Biochemical pharmacology

2009 Volume 78, Issue 7, Page(s) 657

MeSH term(s)	Animals ; Cholinergic Agents/pharmacology ; Cholinergic Agents/therapeutic use ; Drug Discovery ; Humans ; Protein Subunits/physiology ; Receptors, Nicotinic/physiology ; Research
Chemical Substances	Cholinergic Agents ; Protein Subunits ; Receptors, Nicotinic
Language	English
Publishing date	2009-10-01
Publishing country	England
Document type	Editorial
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2009.06.101
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