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Article ; Online: The Potential Role of Osteopontin and Furin in Worsening Disease Outcomes in COVID-19 Patients with Pre-Existing Diabetes.

Adu-Agyeiwaah, Yvonne / Grant, Maria B / Obukhov, Alexander G

2020 Volume 9, Issue 11

Abstract: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing coronavirus disease 2019 (COVID-19) pandemic, with more than 50 million cases reported globally. Findings have consistently identified an increased severity of ... ...

Abstract	The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing coronavirus disease 2019 (COVID-19) pandemic, with more than 50 million cases reported globally. Findings have consistently identified an increased severity of SARS-CoV-2 infection in individuals with diabetes. Osteopontin, a cytokine-like matrix-associated phosphoglycoprotein, is elevated in diabetes and drives the expression of furin, a proprotein convertase implicated in the proteolytic processing and activation of several precursors, including chemokines, growth factors, hormones, adhesion molecules, and receptors. Elevated serum furin is a signature of diabetes mellitus progression and is associated with a dysmetabolic phenotype and increased risk of diabetes-linked premature mortality. Additionally, furin plays an important role in enhancing the infectivity of SARS-CoV-2 by promoting its entry and replication in the host cell. Here, we hypothesize that diabetes-induced osteopontin and furin protein upregulation results in worse outcomes in diabetic patients with SARS-CoV-2 infection owing to the roles of these protein in promoting viral infection and increasing metabolic dysfunction. Thus, targeting the osteopontin-furin axis may be a plausible strategy for reducing mortality in SARS-CoV-2 patients with diabetes.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; COVID-19/epidemiology ; COVID-19/mortality ; COVID-19/virology ; Child ; Child, Preschool ; Comorbidity ; Diabetes Mellitus/blood ; Diabetes Mellitus/epidemiology ; Female ; Furin/blood ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Osteopontin/blood ; Renin-Angiotensin System ; SARS-CoV-2/metabolism ; SARS-CoV-2/pathogenicity ; Severity of Illness Index ; Up-Regulation ; Virulence ; Young Adult
Chemical Substances	Osteopontin (106441-73-0) ; Furin (EC 3.4.21.75)
Language	English
Publishing date	2020-11-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9112528
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Article: Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model.

Prasad, Ram / Adu-Agyeiwaah, Yvonne / Floyd, Jason L / Asare-Bediako, Bright / Li Calzi, Sergio / Chakraborty, Dibyendu / Harbour, Angela / Rohella, Aayush / Busik, Julia V / Li, Qiuhong / Grant, Maria B

Journal of clinical medicine

2023 Volume 12, Issue 5

Abstract: Intestinal lymphatic, known as lacteal, plays a critical role in maintaining intestinal homeostasis by regulating several key functions, including the absorption of dietary lipids, immune cell trafficking, and interstitial fluid balance in the gut. The ... ...

Abstract	Intestinal lymphatic, known as lacteal, plays a critical role in maintaining intestinal homeostasis by regulating several key functions, including the absorption of dietary lipids, immune cell trafficking, and interstitial fluid balance in the gut. The absorption of dietary lipids relies on lacteal integrity, mediated by button-like and zipper-like junctions. Although the intestinal lymphatic system is well studied in many diseases, including obesity, the contribution of lacteals to the gut-retinal axis in type 1 diabetes (T1D) has not been examined. Previously, we showed that diabetes induces a reduction in intestinal angiotensin-converting enzyme 2 (ACE2), leading to gut barrier disruption. However, when ACE2 levels are maintained, a preservation of gut barrier integrity occurs, resulting in less systemic inflammation and a reduction in endothelial cell permeability, ultimately retarding the development of diabetic complications, such as diabetic retinopathy. Here, we examined the impact of T1D on intestinal lymphatics and circulating lipids and tested the impact of intervention with ACE-2-expressing probiotics on key aspects of gut and retinal function.
Language	English
Publishing date	2023-02-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm12051771
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Article ; Online: Intravitreal Administration of AAV2-SIRT1 Reverses Diabetic Retinopathy in a Mouse Model of Type 2 Diabetes.

Adu-Agyeiwaah, Yvonne / Vieira, Cristiano P / Asare-Bediako, Bright / Li Calzi, Sergio / DuPont, Mariana / Floyd, Jason / Boye, Sanford / Chiodo, Vince / Busik, Julia V / Grant, Maria B

Translational vision science & technology

2023 Volume 12, Issue 4, Page(s) 20

Abstract: Purpose: The expression of silent information regulator (SIRT) 1 is reduced in diabetic retinopathy (DR). Previous studies showed that alterations in SIRT1 messenger RNA (mRNA) and protein expression are implicated in progressive inflammation and ... ...

Abstract	Purpose: The expression of silent information regulator (SIRT) 1 is reduced in diabetic retinopathy (DR). Previous studies showed that alterations in SIRT1 messenger RNA (mRNA) and protein expression are implicated in progressive inflammation and formation of retinal acellular capillaries. Treatment with the SIRT1 agonist, SRT1720, improved visual response by restoration of a- and b-wave responses on electroretinogram scotopic measurements in diabetic (db/db) mice. In this study, we investigated the effects of intravitreal SIRT1 delivery on diabetic retinal pathology. Methods: Nine-month-old db/db mice received one intravitreal injection of either AAV2-SIRT1 or AAV2-GFP control virus, and after 3 months, electroretinography and optomotor responses were measured. Their eyes were then removed and analyzed by immunohistochemistry and flow cytometry. Results: SIRT1 mRNA and protein levels were increased following AAV2-SIRT1 administration compared to control virus AAV2-GFP injected mice. IBA1+ and caspase 3 expression were decreased in retinas of db/db mice injected with AAV2-SIRT1, and reductions in scotopic a- and b-waves and high spatial frequency in optokinetic response were prevented. Retinal hypoxia inducible factor 1α (HIF-1α) protein levels were reduced in the AAV2-SIRT1-injected mice compared to control-injected mice. Using flow cytometry to assess changes in intracellular HIF-1α levels, endothelial cells (CD31+) from AAV-2 SIRT1 injected mice demonstrated reduced HIF-1α expression compared to db/db mice injected with the control virus. Conclusions: Intravitreal AAV2-SIRT1 delivery increased retina SIRT1 and transduced neural and endothelial cells, thus reversing functional damage and improving overall visual function. Translational relevance: AAV2-SIRT1 gene therapy represents a beneficial approach for the treatment of chronic retinal conditions such as DR.
MeSH term(s)	Mice ; Animals ; Diabetic Retinopathy/genetics ; Diabetic Retinopathy/therapy ; Sirtuin 1/genetics ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/therapy ; Endothelial Cells/metabolism ; Disease Models, Animal ; RNA, Messenger
Chemical Substances	Sirtuin 1 (EC 3.5.1.-) ; RNA, Messenger ; Sirt1 protein, mouse (EC 3.5.1.-)
Language	English
Publishing date	2023-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2674602-5
ISSN	2164-2591 ; 2164-2591
ISSN (online)	2164-2591
ISSN	2164-2591
DOI	10.1167/tvst.12.4.20
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Article ; Online: Cholesterol crystal formation is a unifying pathogenic mechanism in the development of diabetic retinopathy.

Hammer, Sandra S / Dorweiler, Tim F / McFarland, Delaney / Adu-Agyeiwaah, Yvonne / Mast, Natalia / El-Darzi, Nicole / Fortmann, Seth D / Nooti, Sunil / Agrawal, Devendra K / Pikuleva, Irina A / Abela, George S / Grant, Maria B / Busik, Julia V

Diabetologia

2023 Volume 66, Issue 9, Page(s) 1705–1718

Abstract: Aims/hypothesis: Hyper-reflective crystalline deposits found in retinal lesions have been suggested to predict the progression of diabetic retinopathy, but the nature of these structures remains unknown.: Methods: Scanning electron microscopy and ... ...

Abstract	Aims/hypothesis: Hyper-reflective crystalline deposits found in retinal lesions have been suggested to predict the progression of diabetic retinopathy, but the nature of these structures remains unknown. Methods: Scanning electron microscopy and immunohistochemistry were used to identify cholesterol crystals (CCs) in human donor, pig and mouse tissue. The effects of CCs were analysed in bovine retinal endothelial cells in vitro and in db/db mice in vivo using quantitative RT-PCR, bulk RNA sequencing, and cell death and permeability assays. Cholesterol homeostasis was determined using Results: We identified hyper-reflective crystalline deposits in human diabetic retina as CCs. Similarly, CCs were found in the retina of a diabetic mouse model and a high-cholesterol diet-fed pig model. Cell culture studies demonstrated that treatment of retinal cells with CCs can recapitulate all major pathogenic mechanisms leading to diabetic retinopathy, including inflammation, cell death and breakdown of the blood-retinal barrier. Fibrates, statins and α-cyclodextrin effectively dissolved CCs present in in vitro models of diabetic retinopathy, and prevented CC-induced endothelial pathology. Treatment of a diabetic mouse model with α-cyclodextrin reduced cholesterol levels and CC formation in the retina, and prevented diabetic retinopathy. Conclusions/interpretation: We established that cholesterol accumulation and CC formation are a unifying pathogenic mechanism in the development of diabetic retinopathy.
MeSH term(s)	Animals ; Cattle ; Mice ; Humans ; Swine ; Diabetic Retinopathy/metabolism ; alpha-Cyclodextrins/adverse effects ; alpha-Cyclodextrins/metabolism ; Endothelial Cells/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Retina/metabolism ; Disease Models, Animal ; Cholesterol/metabolism
Chemical Substances	alpha-Cyclodextrins ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2023-06-14
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-023-05949-w
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Article ; Online: Hematopoietic Cells Influence Vascular Development in the Retina.

Asare-Bediako, Bright / Adu-Agyeiwaah, Yvonne / Abad, Antonio / Li Calzi, Sergio / Floyd, Jason L / Prasad, Ram / DuPont, Mariana / Asare-Bediako, Richmond / Bustelo, Xose R / Grant, Maria B

Cells

2022 Volume 11, Issue 20

Abstract: Hematopoietic cells play a crucial role in the adult retina in health and disease. Monocytes, macrophages, microglia and myeloid angiogenic cells (MACs) have all been implicated in retinal pathology. However, the role that hematopoietic cells play in ... ...

Abstract	Hematopoietic cells play a crucial role in the adult retina in health and disease. Monocytes, macrophages, microglia and myeloid angiogenic cells (MACs) have all been implicated in retinal pathology. However, the role that hematopoietic cells play in retinal development is understudied. The temporal changes in recruitment of hematopoietic cells into the developing retina and the phenotype of the recruited cells are not well understood. In this study, we used the hematopoietic cell-specific protein Vav1 to track and investigate hematopoietic cells in the developing retina. By flow cytometry and immunohistochemistry, we show that hematopoietic cells are present in the retina as early as P0, and include microglia, monocytes and MACs. Even before the formation of retinal blood vessels, hematopoietic cells localize to the inner retina where they eventually form networks that intimately associate with the developing vasculature. Loss of Vav1 lead to a reduction in the density of medium-sized vessels and an increased inflammatory response in retinal astrocytes. When pups were subjected to oxygen-induced retinopathy, hematopoietic cells maintained a close association with the vasculature and occasionally formed 'frameworks' for the generation of new vessels. Our study provides further evidence for the underappreciated role of hematopoietic cells in retinal vasculogenesis and the formation of a healthy retina.
MeSH term(s)	Animals ; Animals, Newborn ; Retina/metabolism ; Retinal Vessels/metabolism ; Oxygen/metabolism ; Microglia
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2022-10-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11203207
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Article ; Online: Tribbles Homolog 3 Mediates the Development and Progression of Diabetic Retinopathy.

Pitale, Priyamvada M / Saltykova, Irina V / Adu-Agyeiwaah, Yvonne / Li Calzi, Sergio / Satoh, Takashi / Akira, Shizuo / Gorbatyuk, Oleg / Boulton, Michael E / Pardue, Machelle T / Garvey, W Timothy / Athar, Mohammad / Grant, Maria B / Gorbatyuk, Marina S

Diabetes

2021 Volume 70, Issue 8, Page(s) 1738–1753

Abstract: The current understanding of the molecular pathogenesis of diabetic retinopathy does not provide a mechanistic link between early molecular changes and the subsequent progression of the disease. In this study, we found that human diabetic retinas ... ...

Abstract	The current understanding of the molecular pathogenesis of diabetic retinopathy does not provide a mechanistic link between early molecular changes and the subsequent progression of the disease. In this study, we found that human diabetic retinas overexpressed TRIB3 and investigated the role of TRIB3 in diabetic retinal pathobiology in mice. We discovered that TRIB3 controlled major molecular events in early diabetic retinas via HIF1α-mediated regulation of retinal glucose flux, reprogramming cellular metabolism, and governing of inflammatory gene expression. These early molecular events further defined the development of neurovascular deficit observed in mice with diabetic retinopathy. TRIB3 ablation in the streptozotocin-induced mouse model led to significant retinal ganglion cell survival and functional restoration accompanied by a dramatic reduction in pericyte loss and acellular capillary formation. Under hypoxic conditions, TRIB3 contributed to advanced proliferative stages by significant upregulation of GFAP and VEGF expression, thus controlling gliosis and aberrant vascularization in oxygen-induced retinopathy mouse retinas. Overall, our data reveal that TRIB3 is a master regulator of diabetic retinal pathophysiology that may accelerate the onset and progression of diabetic retinopathy to proliferative stages in humans and present TRIB3 as a potentially novel therapeutic target for diabetic retinopathy.
MeSH term(s)	Animals ; Capillaries/metabolism ; Capillaries/pathology ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetic Retinopathy/genetics ; Diabetic Retinopathy/metabolism ; Diabetic Retinopathy/pathology ; Disease Progression ; Humans ; Mice ; Pericytes/metabolism ; Pericytes/pathology ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Retina/metabolism ; Retina/pathology
Chemical Substances	Cell Cycle Proteins ; Repressor Proteins ; TRIB3 protein, human ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db20-1268
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Article ; Online: Depleting hypothalamic somatostatinergic neurons recapitulates diabetic phenotypes in mouse brain, bone marrow, adipose and retina.

Huang, Chao / Rosencrans, Robert F / Bugescu, Raluca / Vieira, Cristiano P / Hu, Ping / Adu-Agyeiwaah, Yvonne / Gamble, Karen L / Longhini, Ana Leda F / Fuller, Patrick M / Leinninger, Gina M / Grant, Maria B

Diabetologia

2021 Volume 64, Issue 11, Page(s) 2575–2588

Abstract: Aims/hypothesis: Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive ...

Abstract	Aims/hypothesis: Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. Methods: The present data show that leptin receptor-deficient (db/db) mice exhibit reduced hypothalamic SST neurons, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus delivery of diphtheria toxin subunit A (DTA) driven by an SST-cre system to deplete these neurons in Sst Results: SST-DTA mice exhibit enhanced hypothalamic c-Fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed haematopoiesis, generating excess granulocyte-monocyte progenitors and increased proinflammatory (C-C chemokine receptor type 2; CCR2 Conclusions/interpretation: The isolated reduction in hypothalamic SST neurons was able to recapitulate several hallmark features of type 2 diabetes in disease-relevant tissues.
MeSH term(s)	Adipose Tissue/metabolism ; Animals ; Bone Marrow/metabolism ; Brain/metabolism ; Diabetes Mellitus, Type 2/diagnosis ; Diabetes Mellitus, Type 2/metabolism ; Diphtheria Toxin/toxicity ; Electroretinography ; Flow Cytometry ; Hypothalamus/metabolism ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Neurons/metabolism ; Real-Time Polymerase Chain Reaction ; Retina/metabolism ; Somatostatin/metabolism
Chemical Substances	Diphtheria Toxin ; Somatostatin (51110-01-1)
Language	English
Publishing date	2021-08-24
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-021-05549-6
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Article ; Online: Characterizing the Retinal Phenotype in the High-Fat Diet and Western Diet Mouse Models of Prediabetes.

Asare-Bediako, Bright / Noothi, Sunil K / Li Calzi, Sergio / Athmanathan, Baskaran / Vieira, Cristiano P / Adu-Agyeiwaah, Yvonne / Dupont, Mariana / Jones, Bryce A / Wang, Xiaoxin X / Chakraborty, Dibyendu / Levi, Moshe / Nagareddy, Prabhakara R / Grant, Maria B

Cells

2020 Volume 9, Issue 2

Abstract: We sought to delineate the retinal features associated with the high-fat diet (HFD) mouse, a widely used model of obesity. C57BL/6 mice were fed either a high-fat (60% fat; HFD) or low-fat (10% fat; LFD) diet for up to 12 months. The effect of HFD on ... ...

Abstract	We sought to delineate the retinal features associated with the high-fat diet (HFD) mouse, a widely used model of obesity. C57BL/6 mice were fed either a high-fat (60% fat; HFD) or low-fat (10% fat; LFD) diet for up to 12 months. The effect of HFD on body weight and insulin resistance were measured. The retina was assessed by electroretinogram (ERG), fundus photography, permeability studies, and trypsin digests for enumeration of acellular capillaries. The HFD cohort experienced hypercholesterolemia when compared to the LFD cohort, but not hyperglycemia. HFD mice developed a higher body weight (60.33 g vs. 30.17g,
MeSH term(s)	Animals ; Body Weight ; Diabetes Mellitus, Type 2/physiopathology ; Diabetic Retinopathy/physiopathology ; Diet, Fat-Restricted ; Diet, High-Fat ; Diet, Western ; Disease Models, Animal ; Electroretinography ; Insulin Resistance ; Mice ; Mice, Inbred C57BL ; Obesity/physiopathology ; Phenotype ; Prediabetic State/physiopathology ; Retina/physiopathology
Language	English
Publishing date	2020-02-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9020464
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Article ; Online: Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes.

Prasad, Ram / Floyd, Jason L / Dupont, Mariana / Harbour, Angela / Adu-Agyeiwaah, Yvonne / Asare-Bediako, Bright / Chakraborty, Dibyendu / Kichler, Kara / Rohella, Aayush / Li Calzi, Sergio / Lammendella, Regina / Wright, Justin / Boulton, Michael E / Oudit, Gavin Y / Raizada, Mohan K / Stevens, Bruce R / Li, Qiuhong / Grant, Maria B

Circulation research

2022 Volume 132, Issue 1, Page(s) e1–e21

Abstract: Background: We examined components of systemic and intestinal renin-angiotensin system on gut barrier permeability, glucose homeostasis, systemic inflammation, and progression of diabetic retinopathy (DR) in human subjects and mice with type 1 diabetes ( ...

Abstract	Background: We examined components of systemic and intestinal renin-angiotensin system on gut barrier permeability, glucose homeostasis, systemic inflammation, and progression of diabetic retinopathy (DR) in human subjects and mice with type 1 diabetes (T1D). Methods: T1D individual with (n=18) and without (n=20) DR and controls (n=34) were examined for changes in gut-regulated components of the immune system, gut leakage markers (FABP2 [fatty acid binding protein 2] and peptidoglycan), and Ang II (angiotensin II); Results: T1D subjects exhibit elevations in gut-derived circulating immune cells (ILC1 cells) and higher gut leakage markers, which were positively correlated with plasma Ang II and DR severity. The LP-ACE2 prevention cohort and genetic overexpression of intestinal ACE2 preserved barrier integrity, reduced inflammatory response, improved hyperglycemia, and delayed development of DR. Improvements in glucose homeostasis were due to intestinal MasR activation, resulting in a GSK-3β (glycogen synthase kinase-3 beta)/c-Myc (cellular myelocytomatosis oncogene)-mediated decrease in intestinal glucose transporter expression. In the LP-ACE2 intervention cohort, gut barrier integrity was improved and DR reversed, but no improvement in hyperglycemia was observed. These data support that the beneficial effects of LP-ACE2 on DR are due to the action of ACE2, not improved glucose homeostasis. Conclusions: Dysregulated systemic and intestinal renin-angiotensin system was associated with worsening gut barrier permeability, gut-derived immune cell activation, systemic inflammation, and progression of DR in human subjects. In
MeSH term(s)	Animals ; Humans ; Mice ; Angiotensin-Converting Enzyme 2/metabolism ; Diabetes Mellitus, Type 1/complications ; Diabetes Mellitus, Type 1/metabolism ; Diabetic Retinopathy/prevention & control ; Glucose/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Hyperglycemia/complications ; Inflammation/metabolism ; Intestine, Small ; Peptide Fragments/metabolism ; Peptidyl-Dipeptidase A/genetics ; Renin-Angiotensin System/physiology
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Glucose (IY9XDZ35W2) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Peptide Fragments ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Ace2 protein, mouse (EC 3.4.17.23)
Language	English
Publishing date	2022-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.122.322003
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Article ; Online: Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction.

Hammer, Sandra S / Vieira, Cristiano P / McFarland, Delaney / Sandler, Maximilian / Levitsky, Yan / Dorweiler, Tim F / Lydic, Todd A / Asare-Bediako, Bright / Adu-Agyeiwaah, Yvonne / Sielski, Micheli S / Dupont, Mariana / Longhini, Ana Leda / Li Calzi, Sergio / Chakraborty, Dibyendu / Seigel, Gail M / Proshlyakov, Denis A / Grant, Maria B / Busik, Julia V

Diabetologia

2021 Volume 64, Issue 7, Page(s) 1674–1689

Abstract: Aims/hypothesis: Homo sapiens evolved under conditions of intermittent food availability and prolonged fasting between meals. Periods of fasting are important for recovery from meal-induced oxidative and metabolic stress, and tissue repair. Constant ... ...

Abstract	Aims/hypothesis: Homo sapiens evolved under conditions of intermittent food availability and prolonged fasting between meals. Periods of fasting are important for recovery from meal-induced oxidative and metabolic stress, and tissue repair. Constant high energy-density food availability in present-day society contributes to the pathogenesis of chronic diseases, including diabetes and its complications, with intermittent fasting (IF) and energy restriction shown to improve metabolic health. We have previously demonstrated that IF prevents the development of diabetic retinopathy in a mouse model of type 2 diabetes (db/db); however the mechanisms of fasting-induced health benefits and fasting-induced risks for individuals with diabetes remain largely unknown. Sirtuin 1 (SIRT1), a nutrient-sensing deacetylase, is downregulated in diabetes. In this study, the effect of SIRT1 stimulation by IF, fasting-mimicking cell culture conditions (FMC) or pharmacological treatment using SRT1720 was evaluated on systemic and retinal metabolism, systemic and retinal inflammation and vascular and bone marrow damage. Methods: The effects of IF were modelled in vivo using db/db mice and in vitro using bovine retinal endothelial cells or rat retinal neuroglial/precursor R28 cell line serum starved for 24 h. mRNA expression was analysed by quantitative PCR (qPCR). SIRT1 activity was measured via histone deacetylase activity assay. NR1H3 (also known as liver X receptor alpha [LXRα]) acetylation was measured via western blot analysis. Results: IF increased Sirt1 mRNA expression in mouse liver and retina when compared with non-fasted animals. IF also increased SIRT1 activity eightfold in mouse retina while FMC increased SIRT1 activity and expression in retinal endothelial cells when compared with control. Sirt1 expression was also increased twofold in neuronal retina progenitor cells (R28) after FMC treatment. Moreover, FMC led to SIRT1-mediated LXRα deacetylation and subsequent 2.4-fold increase in activity, as measured by increased mRNA expression of the genes encoding ATP-binding cassette transporter (Abca1 and Abcg1). These changes were reduced when retinal endothelial cells expressing a constitutively acetylated LXRα mutant were tested. Increased SIRT1/LXR/ABC-mediated cholesterol export resulted in decreased retinal endothelial cell cholesterol levels. Direct activation of SIRT1 by SRT1720 in db/db mice led to a twofold reduction of diabetes-induced inflammation in the retina and improved diabetes-induced visual function impairment, as measured by electroretinogram and optokinetic response. In the bone marrow, there was prevention of diabetes-induced myeloidosis and decreased inflammatory cytokine expression. Conclusions/interpretation: Taken together, activation of SIRT1 signalling by IF or through pharmacological activation represents an effective therapeutic strategy that provides a mechanistic link between the advantageous effects associated with fasting regimens and prevention of microvascular and bone marrow dysfunction in diabetes.
MeSH term(s)	Animals ; Cattle ; Cell Death/drug effects ; Cell Death/genetics ; Cells, Cultured ; Diabetes Mellitus, Experimental/complications ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/physiopathology ; Diabetes Mellitus, Experimental/therapy ; Diabetic Angiopathies/genetics ; Diabetic Angiopathies/metabolism ; Diabetic Angiopathies/prevention & control ; Fasting/physiology ; Gene Expression/drug effects ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Heterocyclic Compounds, 4 or More Rings/therapeutic use ; Hypoglycemic Agents/pharmacology ; Liver X Receptors/genetics ; Liver X Receptors/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Rats ; Retina/drug effects ; Retina/pathology ; Retinal Neurons/drug effects ; Retinal Neurons/metabolism ; Retinal Neurons/pathology ; Retinal Vessels/drug effects ; Retinal Vessels/metabolism ; Retinal Vessels/pathology ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Sirtuin 1/drug effects ; Sirtuin 1/genetics ; Sirtuin 1/metabolism
Chemical Substances	Heterocyclic Compounds, 4 or More Rings ; Hypoglycemic Agents ; Liver X Receptors ; SRT1720 ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2021-03-26
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-021-05431-5
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