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Article ; Online: Fresh insights into glucocorticoid-induced diabetes mellitus and new therapeutic directions.

Li, Jia-Xu / Cummins, Carolyn L

2022 Volume 18, Issue 9, Page(s) 540–557

Abstract: Glucocorticoid hormones were discovered to have use as potent anti-inflammatory and immunosuppressive therapeutics in the 1940s and their continued use and development have successfully revolutionized the management of acute and chronic inflammatory ... ...

Abstract	Glucocorticoid hormones were discovered to have use as potent anti-inflammatory and immunosuppressive therapeutics in the 1940s and their continued use and development have successfully revolutionized the management of acute and chronic inflammatory diseases. However, long-term use of glucocorticoids is severely hampered by undesirable metabolic complications, including the development of type 2 diabetes mellitus. These effects occur due to glucocorticoid receptor activation within multiple tissues, which results in inter-organ crosstalk that increases hepatic glucose production and inhibits peripheral glucose uptake. Despite the high prevalence of glucocorticoid-induced hyperglycaemia associated with their routine clinical use, treatment protocols for optimal management of the metabolic adverse effects are lacking or underutilized. The type, dose and potency of the glucocorticoid administered dictates the choice of hypoglycaemic intervention (non-insulin or insulin therapy) that should be provided to patients. The longstanding quest to identify dissociated glucocorticoid receptor agonists to separate the hyperglycaemic complications of glucocorticoids from their therapeutically beneficial anti-inflammatory effects is ongoing, with selective glucocorticoid receptor modulators in clinical testing. Promising areas of preclinical research include new mechanisms to disrupt glucocorticoid signalling in a tissue-selective manner and the identification of novel targets that can selectively dissociate the effects of glucocorticoids. These research arms share the ultimate goal of achieving the anti-inflammatory actions of glucocorticoids without the metabolic consequences.
MeSH term(s)	Anti-Inflammatory Agents/adverse effects ; Diabetes Mellitus, Type 2/drug therapy ; Glucocorticoids/adverse effects ; Humans ; Immunosuppressive Agents/pharmacology ; Receptors, Glucocorticoid/metabolism
Chemical Substances	Anti-Inflammatory Agents ; Glucocorticoids ; Immunosuppressive Agents ; Receptors, Glucocorticoid
Language	English
Publishing date	2022-05-18
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2489381-X
ISSN	1759-5037 ; 1759-5029
ISSN (online)	1759-5037
ISSN	1759-5029
DOI	10.1038/s41574-022-00683-6
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Article ; Online: Regulation of Alternative Splicing by Steroid Hormones.

Le Billan, Florian / Umogbai, Gloria / Cummins, Carolyn L

Endocrinology

2023 Volume 164, Issue 7

Abstract: Steroid hormone signaling pathways are critical for organismal development and act through binding to nuclear receptors (NRs) driving transcriptional regulation. In this review, we summarize evidence for another-underrated-mechanism of action for steroid ...

Abstract	Steroid hormone signaling pathways are critical for organismal development and act through binding to nuclear receptors (NRs) driving transcriptional regulation. In this review, we summarize evidence for another-underrated-mechanism of action for steroid hormones: their ability to modulate the alternative splicing of pre-messenger RNA. Thirty years ago, pioneering studies used in vitro transfection of plasmids expressing alternative exons under the control of hormone-responsive promoters in cell lines. These studies demonstrated that steroid hormones binding to their NRs affected both gene transcription and alternative splicing outcomes. The advent of exon arrays and next-generation sequencing has allowed researchers to observe the effect of steroid hormones at the whole-transcriptome level. These studies demonstrate that steroid hormones regulate alternative splicing in a time-, gene-, and tissue-specific manner. We provide examples of the mechanisms by which steroid hormones regulate alternative splicing including 1) recruitment of dual-function proteins that behave as coregulators and splicing factors, 2) transcriptional regulation of splicing factor levels, 3) the alternative splicing of splicing factors or transcription factors that feed-forward regulate steroid hormone signaling, and 4) regulation of elongation rate. Experiments performed in vivo and in cancer cell lines highlight that steroid hormone-mediated alternative splicing occurs both in physiological and pathophysiologic states. Studying the effect of steroid hormones on alternative splicing is a fruitful avenue for research that should be exploited to discover new targets for therapeutic intervention.
MeSH term(s)	Alternative Splicing ; Transcription Factors ; Hormones ; Gene Expression Regulation ; Steroids/pharmacology ; Receptors, Cytoplasmic and Nuclear ; RNA Splicing Factors
Chemical Substances	Transcription Factors ; Hormones ; Steroids ; Receptors, Cytoplasmic and Nuclear ; RNA Splicing Factors
Language	English
Publishing date	2023-05-24
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqad081
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Article ; Online: Quantification of Oxysterol Nuclear Receptor Ligands by LC/MS/MS.

Magomedova, Lilia / Cummins, Carolyn L

Methods in molecular biology (Clifton, N.J.)

2019 Volume 1951, Page(s) 1–14

Abstract: Oxidative derivatives of cholesterol such as 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 25-hydroxycholesterol, and (25S),26-hydroxycholesterol are endogenous ligands for the liver X receptors (LXRα and LXRβ). The LXRs are nuclear hormone ... ...

Abstract	Oxidative derivatives of cholesterol such as 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 25-hydroxycholesterol, and (25S),26-hydroxycholesterol are endogenous ligands for the liver X receptors (LXRα and LXRβ). The LXRs are nuclear hormone receptors known as "intracellular cholesterol sensors" because of their ability to bind to and be activated by oxysterols at circulating concentrations. Oxysterols are expressed in a tissue-specific manner and are generally at least 10
MeSH term(s)	Animals ; Chromatography, Liquid ; Humans ; Ligands ; Mice ; Oxysterols/blood ; Oxysterols/isolation & purification ; Oxysterols/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Solid Phase Extraction ; Tandem Mass Spectrometry
Chemical Substances	Ligands ; Oxysterols ; Receptors, Cytoplasmic and Nuclear
Language	English
Publishing date	2019-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9130-3_1
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Article ; Online: Beyond the Foam Cell: The Role of LXRs in Preventing Atherogenesis.

Rasheed, Adil / Cummins, Carolyn L

International journal of molecular sciences

2018 Volume 19, Issue 8

Abstract: Atherosclerosis is a chronic condition associated with cardiovascular disease. While largely identified by the accumulation of lipid-laden foam cells within the aorta later on in life, atherosclerosis develops over several stages and decades. During ... ...

Abstract	Atherosclerosis is a chronic condition associated with cardiovascular disease. While largely identified by the accumulation of lipid-laden foam cells within the aorta later on in life, atherosclerosis develops over several stages and decades. During atherogenesis, various cell types of the aorta acquire a pro-inflammatory phenotype that initiates the cascade of signaling events facilitating the formation of these foam cells. The liver X receptors (LXRs) are nuclear receptors that upon activation induce the expression of transporters responsible for promoting cholesterol efflux. In addition to promoting cholesterol removal from the arterial wall, LXRs have potent anti-inflammatory actions via the transcriptional repression of key pro-inflammatory cytokines. These beneficial functions sparked an interest in the potential to target LXRs and the development of agonists as anti-atherogenic agents. These early studies focused on mediating the contributions of macrophages to the underlying pathogenesis. However, further evidence has since demonstrated that LXRs reduce atherosclerosis through their actions in multiple cell types apart from those monocytes/macrophages that infiltrate the lesion. LXRs and their target genes have profound effects on multiple other cells types of the hematopoietic system. Furthermore, LXRs can also mediate dysfunction within vascular cell types of the aorta including endothelial and smooth muscle cells. Taken together, these studies demonstrate the whole-body benefits of LXR activation with respect to anti-atherogenesis, and that LXRs remain a viable target for the treatment of atherosclerosis, with a reach which extends beyond plaque macrophages.
MeSH term(s)	Animals ; Atherosclerosis/metabolism ; Atherosclerosis/pathology ; Cholesterol/metabolism ; Foam Cells/metabolism ; Foam Cells/pathology ; Humans ; Liver X Receptors/metabolism ; Macrophages/metabolism ; Macrophages/pathology ; Myocytes, Smooth Muscle/metabolism ; Myocytes, Smooth Muscle/pathology
Chemical Substances	Liver X Receptors ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2018-08-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms19082307
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Article ; Online: Getting the Skinny on Follistatin and Fat

Li, Jia-Xu / Cummins, Carolyn L

Endocrinology

2017 Volume 158, Issue 5, Page(s) 1109–1112

Language	English
Publishing date	2017-05-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/en.2017-00223
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Article: Glucocorticoids and Metabolic Control.

Magomedova, Lilia / Cummins, Carolyn L

Handbook of experimental pharmacology

2016 Volume 233, Page(s) 73–93

Abstract: In response to stress, the central nervous system initiates a signaling cascade, which leads to the production of glucocorticoids (GCs). GCs act through the glucocorticoid receptor (GR) to coordinate the appropriate cellular response with the primary ... ...

Abstract	In response to stress, the central nervous system initiates a signaling cascade, which leads to the production of glucocorticoids (GCs). GCs act through the glucocorticoid receptor (GR) to coordinate the appropriate cellular response with the primary goal of mobilizing the storage forms of carbon precursors to generate a continuous glucose supply for the brain. Although GCs are critical for maintaining energy homeostasis, excessive GC stimulation leads to a number of undesirable side effects, including hyperglycemia, insulin resistance, fatty liver, obesity, and muscle wasting leading to severe metabolic dysfunction. Summarized below are the diverse metabolic roles of glucocorticoids in energy homeostasis and dysregulation, focusing specifically on glucose, lipid, and protein metabolism.
MeSH term(s)	Adipose Tissue/metabolism ; Animals ; Energy Metabolism/drug effects ; Glucocorticoids/pharmacology ; Glucose/metabolism ; Humans ; Lipid Metabolism/drug effects ; Liver/metabolism ; Muscle, Skeletal/metabolism ; Pancreas/metabolism ; Proteins/metabolism
Chemical Substances	Glucocorticoids ; Proteins ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2016
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	0171-2004
ISSN	0171-2004
DOI	10.1007/164_2015_1
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Article ; Online: Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells.

Rasheed, Adil / Tsai, Ricky / Cummins, Carolyn L

Journal of the American Heart Association

2018 Volume 7, Issue 10

Abstract: Background: The liver X receptors (LXRs; α/β) are nuclear receptors known to regulate cholesterol homeostasis and the production of select hematopoietic populations. The objective of this study was to determine the importance of LXRs and a high-fat high- ...

Abstract	Background: The liver X receptors (LXRs; α/β) are nuclear receptors known to regulate cholesterol homeostasis and the production of select hematopoietic populations. The objective of this study was to determine the importance of LXRs and a high-fat high-cholesterol diet on global hematopoiesis, with special emphasis on endothelial progenitor cells (EPCs), a vasoreparative cell type that is derived from bone marrow hematopoietic stem cells. Methods and results: Wild-type and LXR double-knockout ( Conclusions: LXRs are crucial for maintaining the balance of hematopoietic cells in a hypercholesterolemic environment and for mitigating the negative effects of cholesterol on EPC differentiation/secretome changes that promote monocyte-endothelial adhesion.
MeSH term(s)	Animals ; Antigens, CD/metabolism ; Cadherins/metabolism ; Cell Adhesion ; Cell Lineage ; Cells, Cultured ; Cholesterol, Dietary ; Diet, High-Fat ; Disease Models, Animal ; Endothelial Progenitor Cells/metabolism ; Endothelial Progenitor Cells/pathology ; Genotype ; Hematopoiesis ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/pathology ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Hypercholesterolemia/blood ; Hypercholesterolemia/metabolism ; Hypercholesterolemia/pathology ; Liver X Receptors/deficiency ; Liver X Receptors/genetics ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Vascular Endothelial Growth Factor Receptor-2/metabolism
Chemical Substances	Antigens, CD ; Cadherins ; Cholesterol, Dietary ; Liver X Receptors ; Nr1h2 protein, mouse ; Nr1h3 protein, mouse ; cadherin 5 ; Kdr protein, mouse (EC 2.7.10.1) ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1)
Language	English
Publishing date	2018-05-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2653953-6
ISSN	2047-9980 ; 2047-9980
ISSN (online)	2047-9980
ISSN	2047-9980
DOI	10.1161/JAHA.117.007787
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Article ; Online: Essential role of STAT-3 dependent NF-κB activation on IL-6-mediated downregulation of hepatic transporters.

Abualsunun, Walaa A / Sahin, Cigdem / Cummins, Carolyn L / Piquette-Miller, Micheline

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2019 Volume 143, Page(s) 105151

Abstract: IL-6 markedly decreases the expression of numerous hepatic transporters. We previously demonstrated that IL-6-mediated downregulation of transporters occurs through STAT3, with partial involvement of PXR. However, while IL-6-mediated induction of STAT3 ... ...

Abstract	IL-6 markedly decreases the expression of numerous hepatic transporters. We previously demonstrated that IL-6-mediated downregulation of transporters occurs through STAT3, with partial involvement of PXR. However, while IL-6-mediated induction of STAT3 occurs rapidly, repression of transporter expression is not observed until 6 h post-treatment. This temporal mismatch suggested that the downregulation of transporters following IL-6 at 6 h might require additional signaling downstream of STAT3. Since NF-κB has been implicated in endotoxin-mediated downregulation of transporters, we hypothesized that NF-κB may be similarly involved in suppressing transporter expression following IL-6. Our objective was to investigate whether IL-6-mediated changes in transporter expression occur through STAT3-dependent NF-κB activation, and whether PXR is involved. PXR null (-/-) or wild type (+/+) mice were pre-dosed with the NF-κB inhibitor PHA408 or vehicle 30 min prior to receiving a single dose of IL-6 or saline. Mice were euthanized after 6 h and transporter expression was analyzed using qRT-PCR. IL-6 imposed downregulation of Abcb1a, Abcb1b, Abcc3, Abcg2 and Cyp3a11 in both PXR (+/+) and PXR (-/-) mice, while downregulation of Abcb11, Abcc2, Slc10a1, and Slco2b1 was only significant in PXR (+/+) mice. PHA408 pretreatment fully inhibited NF-κB activation in PXR (+/+) but only partially inhibited NF-κB in PXR (-/-). Inhibition of NF-κB attenuated IL-6-mediated changes in transporters in PXR (+/+) mice. Transient transfection assays did not detect significant activation of human or mouse PXR by PHA408. Our findings suggest that IL-6 imposes significant downregulation of numerous ABC and SLC transporters in the liver via collaborative STAT3/NF-κB activation. Since drug transporters play an integral role in the pharmacokinetics of numerous clinically relevant drugs, understanding the signaling pathways involved in transporter regulation during inflammation will contribute to a better understanding of drug-disease interactions.
MeSH term(s)	Animals ; Down-Regulation ; Interleukin-6/blood ; Liver/metabolism ; Male ; Membrane Transport Proteins/genetics ; Mice, Inbred C57BL ; Mice, Knockout ; NF-kappa B/metabolism ; Pregnane X Receptor/genetics ; Pregnane X Receptor/metabolism ; STAT3 Transcription Factor/metabolism
Chemical Substances	Interleukin-6 ; Membrane Transport Proteins ; NF-kappa B ; Nr1i2 protein, mouse ; Pregnane X Receptor ; STAT3 Transcription Factor ; Stat3 protein, mouse ; interleukin-6, mouse
Language	English
Publishing date	2019-11-15
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2019.105151
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Article ; Online: Selective peroxisome proliferator-activated receptor-gamma modulator, INT131 exhibits anti-inflammatory effects in an EcoHIV mouse model.

Omeragic, Amila / Saikali, Michael F / Currier, Sydney / Volsky, David J / Cummins, Carolyn L / Bendayan, Reina

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2019 Volume 34, Issue 2, Page(s) 1996–2010

Abstract: Despite the use of antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments, that is, HIV-1-associated neurocognitive disorders remain prevalent potentially due to persistent viral replication, production of viral proteins, ... ...

Abstract	Despite the use of antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments, that is, HIV-1-associated neurocognitive disorders remain prevalent potentially due to persistent viral replication, production of viral proteins, associated brain inflammation or in certain instances, antiretroviral neurotoxicity. Cellular targets in the brain include microglia which in response to infection release inflammatory markers and viral proteins. Evidence suggests that PPARγ agonists exert anti-inflammatory properties in neurological disorders. However, these agonists namely, thiazolidinediones have limited use in the clinic due to reported adverse side effects. INT131 is a novel non-thiazolidinedione compound that belongs to a new class of drugs known as selective PPARγ modulators. INT131 is considered to have a safer profile; however, its neuroprotective role in vivo is not known.The goal of this study was to examine the effect of INT131 in the context of EcoHIV-induced inflammation in vitro, in primary cultures of mouse glial cells and in vivo, in a mouse model of EcoHIV-associated brain inflammation, as well as characterize its pharmacokinetic properties and brain penetration. In primary cultures of glial cells and in the in vivo mouse model, EcoHIV exposure resulted in a significant elevation of inflammatory markers such as TNFα, IL-1β, CCL3, and C3 which were attenuated with INT131 treatment. Pharmacokinetic analyses revealed that INT131 penetrates into the brain with a brain to blood partition ratio Kp value of 8.5%. Overall, this is the first report to demonstrate that INT131 could be a potential candidate for the treatment of HIV-1-associated brain inflammation.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacokinetics ; Anti-Inflammatory Agents/pharmacology ; Cytokines/genetics ; Cytokines/metabolism ; Disease Models, Animal ; HIV Infections/drug therapy ; HIV Infections/genetics ; HIV Infections/metabolism ; HIV Infections/pathology ; HIV-1/genetics ; HIV-1/metabolism ; Inflammation/drug therapy ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/pathology ; Mice ; Neurocognitive Disorders/drug therapy ; Neurocognitive Disorders/genetics ; Neurocognitive Disorders/metabolism ; Neurocognitive Disorders/pathology ; Neuroglia/pathology ; PPAR gamma/agonists ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Quinolines/pharmacokinetics ; Quinolines/pharmacology ; Sulfonamides/pharmacokinetics ; Sulfonamides/pharmacology
Chemical Substances	Anti-Inflammatory Agents ; Cytokines ; INT 131 ; PPAR gamma ; Pparg protein, mouse ; Quinolines ; Sulfonamides
Language	English
Publishing date	2019-12-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201901874R
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: PGP-14 establishes a polar lipid permeability barrier within the C. elegans pharyngeal cuticle.

Kamal, Muntasir / Tokmakjian, Levon / Knox, Jessica / Han, Duhyun / Moshiri, Houtan / Magomedova, Lilia / Nguyen, Ken Cq / Zheng, Hong / Burns, Andrew R / Cooke, Brittany / Lacoste, Jessica / Yeo, May / Hall, David H / Cummins, Carolyn L / Roy, Peter J

PLoS genetics

2023 Volume 19, Issue 11, Page(s) e1011008

Abstract: The cuticles of ecdysozoan animals are barriers to material loss and xenobiotic insult. Key to this barrier is lipid content, the establishment of which is poorly understood. Here, we show that the p-glycoprotein PGP-14 functions coincidently with the ... ...

Abstract	The cuticles of ecdysozoan animals are barriers to material loss and xenobiotic insult. Key to this barrier is lipid content, the establishment of which is poorly understood. Here, we show that the p-glycoprotein PGP-14 functions coincidently with the sphingomyelin synthase SMS-5 to establish a polar lipid barrier within the pharyngeal cuticle of the nematode C. elegans. We show that PGP-14 and SMS-5 are coincidentally expressed in the epithelium that surrounds the anterior pharyngeal cuticle where PGP-14 localizes to the apical membrane. pgp-14 and sms-5 also peak in expression at the time of new cuticle synthesis. Loss of PGP-14 and SMS-5 dramatically reduces pharyngeal cuticle staining by Nile Red, a key marker of polar lipids, and coincidently alters the nematode's response to a wide-range of xenobiotics. We infer that PGP-14 exports polar lipids into the developing pharyngeal cuticle in an SMS-5-dependent manner to safeguard the nematode from environmental insult.
MeSH term(s)	Animals ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Cell Membrane/metabolism ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Lipids ; Permeability
Chemical Substances	Caenorhabditis elegans Proteins ; Lipids
Language	English
Publishing date	2023-11-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1011008
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