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Article ; Online: Molecular mechanisms associated with diabetic endothelial-erectile dysfunction.

Castela, Ângela / Costa, Carla

2016 Volume 13, Issue 5, Page(s) 266–274

Abstract: Erectile dysfunction (ED) is a common complication of diabetes, affecting up to 75% of all diabetic men. Although the aetiology of diabetic ED is multifactorial, endothelial dysfunction is recognized as a mainstay in the pathophysiology of the disease. ... ...

Abstract	Erectile dysfunction (ED) is a common complication of diabetes, affecting up to 75% of all diabetic men. Although the aetiology of diabetic ED is multifactorial, endothelial dysfunction is recognized as a mainstay in the pathophysiology of the disease. Endothelial dysfunction is induced by the detrimental actions of high glucose levels and increased oxidative stress on endothelial cells that make up the vascular lining. Besides directly injuring the endothelium, diabetes might also hamper vascular repair mechanisms of angiogenesis and vasculogenesis. These states exacerbate and maintain endothelial dysfunction, impairing vasorelaxation events and cavernosal blood perfusion, which are crucial for normal erectile function.
MeSH term(s)	Animals ; Diabetes Mellitus/blood ; Diabetes Mellitus/epidemiology ; Diabetes Mellitus/physiopathology ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/pathology ; Endothelium, Vascular/physiopathology ; Erectile Dysfunction/blood ; Erectile Dysfunction/epidemiology ; Erectile Dysfunction/physiopathology ; Humans ; Male ; Oxidative Stress/physiology ; Penile Erection/physiology
Language	English
Publishing date	2016-02-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2493737-X
ISSN	1759-4820 ; 1759-4812
ISSN (online)	1759-4820
ISSN	1759-4812
DOI	10.1038/nrurol.2016.23
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Article: Endogenous mitochondrial double-stranded RNA is not an activator of the type I interferon response in human pancreatic beta cells.

Coomans de Brachène, Alexandra / Castela, Angela / Musuaya, Anyïshai E / Marselli, Lorella / Marchetti, Piero / Eizirik, Decio L

Auto- immunity highlights

2021 Volume 12, Issue 1, Page(s) 6

Abstract: Background: Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells. Interferon-α (IFNα), an antiviral cytokine, is expressed in the pancreatic islets in early T1D, which may be secondary to ... ...

Abstract	Background: Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells. Interferon-α (IFNα), an antiviral cytokine, is expressed in the pancreatic islets in early T1D, which may be secondary to viral infections. However, not all patients harboring a type I IFN signature present signals of viral infection, suggesting that this response might be initiated by other "danger signals". Accumulation of mitochondrial double-stranded RNA (mtdsRNA; a danger signal), secondary to silencing of members of the mitochondrial degradosome, PNPT1 and SUV3, has been described to activate the innate immune response. Methods: To evaluate whether mtdsRNA represents a "danger signal" for pancreatic beta cells in the context of T1D, we silenced PNPT1 and/or SUV3 in slowly proliferating human insulin-secreting EndoC-βH1 cells and in non-proliferating primary human beta cells and evaluated dsRNA accumulation by immunofluorescence and the type I IFN response by western blotting and RT-qPCR. Results: Only the simultaneous silencing of PNPT1/SUV3 induced dsRNA accumulation in EndoC-βH1 cells but not in dispersed human islets, and there was no induction of a type I IFN response. By contrast, silencing of these two genes individually was enough to induce dsRNA accumulation in fibroblasts present in the human islet preparations. Conclusions: These data suggest that accumulation of endogenous mtdsRNA following degradosome knockdown depends on the proliferative capacity of the cells and is not a mediator of the type I IFN response in human pancreatic beta cells.
Language	English
Publishing date	2021-03-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2563376-4
ISSN	2038-3274 ; 2038-0305
ISSN (online)	2038-3274
ISSN	2038-0305
DOI	10.1186/s13317-021-00148-2
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Article ; Online: Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β cells.

Szymczak, Florian / Alvelos, Maria Inês / Marín-Cañas, Sandra / Castela, Ângela / Demine, Stéphane / Colli, Maikel Luis / Op de Beeck, Anne / Thomaidou, Sofia / Marselli, Lorella / Zaldumbide, Arnaud / Marchetti, Piero / Eizirik, Décio L

Science advances

2022 Volume 8, Issue 37, Page(s) eabn5732

Abstract: IFNα is a key regulator of the dialogue between pancreatic β cells and the immune system in early type 1 diabetes (T1D). IFNα up-regulates HLA class I expression in human β cells, fostering autoantigen presentation to the immune system. We observed by ... ...

Abstract	IFNα is a key regulator of the dialogue between pancreatic β cells and the immune system in early type 1 diabetes (T1D). IFNα up-regulates HLA class I expression in human β cells, fostering autoantigen presentation to the immune system. We observed by bulk and single-cell RNA sequencing that exposure of human induced pluripotent-derived islet-like cells to IFNα induces expression of HLA class I and of other genes involved in antigen presentation, including the transcriptional activator NLRC5. We next evaluated the global role of NLRC5 in human insulin-producing EndoC-βH1 and human islet cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I, antigen presentation-related genes, and chemokines. NLRC5 also mediates the effects of IFNα on alternative splicing, a generator of β cell neoantigens, suggesting that it is a central player of the effects of IFNα on β cells that contribute to trigger and amplify autoimmunity in T1D.
MeSH term(s)	Alternative Splicing ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism ; Humans ; Insulin-Secreting Cells ; Interferon-alpha/pharmacology ; Intracellular Signaling Peptides and Proteins/metabolism ; Islets of Langerhans/metabolism ; Transcription, Genetic
Chemical Substances	Interferon-alpha ; Intracellular Signaling Peptides and Proteins ; NLRC5 protein, human
Language	English
Publishing date	2022-09-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abn5732
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Article: ADAR1-dependent editing regulates human β cell transcriptome diversity during inflammation.

Szymczak, Florian / Cohen-Fultheim, Roni / Thomaidou, Sofia / de Brachène, Alexandra Coomans / Castela, Angela / Colli, Maikel / Marchetti, Piero / Levanon, Erez / Eizirik, Decio / Zaldumbide, Arnaud

Frontiers in endocrinology

2022 Volume 13, Page(s) 1058345

Abstract: Introduction: Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic sensors that orchestrate type I interferon signaling and the ...

Abstract	Introduction: Enterovirus infection has long been suspected as a possible trigger for type 1 diabetes. Upon infection, viral double-stranded RNA (dsRNA) is recognized by membrane and cytosolic sensors that orchestrate type I interferon signaling and the recruitment of innate immune cells to the pancreatic islets. In this context, adenosine deaminase acting on RNA 1 (ADAR1) editing plays an important role in dampening the immune response by inducing adenosine mispairing, destabilizing the RNA duplexes and thus preventing excessive immune activation. Methods: Using high-throughput RNA sequencing data from human islets and EndoC-βH1 cells exposed to IFNα or IFNγ/IL1β, we evaluated the role of ADAR1 in human pancreatic β cells and determined the impact of the type 1 diabetes pathophysiological environment on ADAR1-dependent RNA editing. Results: We show that both IFNα and IFNγ/IL1β stimulation promote ADAR1 expression and increase the A-to-I RNA editing of Alu-Containing mRNAs in EndoC-βH1 cells as well as in primary human islets. Discussion: We demonstrate that ADAR1 overexpression inhibits type I interferon response signaling, while ADAR1 silencing potentiates IFNα effects. In addition, ADAR1 overexpression triggers the generation of alternatively spliced mRNAs, highlighting a novel role for ADAR1 as a regulator of the β cell transcriptome under inflammatory conditions.
MeSH term(s)	Humans ; Adenosine Deaminase/genetics ; Adenosine Deaminase/metabolism ; Diabetes Mellitus, Type 1 ; Inflammation/genetics ; Insulin-Secreting Cells/metabolism ; Interferon Type I/genetics ; Interferon Type I/metabolism ; RNA, Double-Stranded ; RNA, Messenger ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Transcriptome
Chemical Substances	Adenosine Deaminase (EC 3.5.4.4) ; Interferon Type I ; RNA, Double-Stranded ; RNA, Messenger ; RNA-Binding Proteins ; ADAR protein, human (EC 3.5.4.37)
Language	English
Publishing date	2022-11-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2022.1058345
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Article ; Online: Exercise as a non-pharmacological intervention to protect pancreatic beta cells in individuals with type 1 and type 2 diabetes.

Coomans de Brachène, Alexandra / Scoubeau, Corentin / Musuaya, Anyïshai E / Costa-Junior, Jose Maria / Castela, Angela / Carpentier, Julie / Faoro, Vitalie / Klass, Malgorzata / Cnop, Miriam / Eizirik, Decio L

Diabetologia

2022 Volume 66, Issue 3, Page(s) 450–460

Abstract: Aims/hypothesis: Diabetes is characterised by progressive loss of functional pancreatic beta cells. None of the therapeutic agents used to treat diabetes arrest this process; preventing beta cell loss remains a major unmet need. We have previously shown ...

Abstract	Aims/hypothesis: Diabetes is characterised by progressive loss of functional pancreatic beta cells. None of the therapeutic agents used to treat diabetes arrest this process; preventing beta cell loss remains a major unmet need. We have previously shown that serum from eight young healthy male participants who exercised for 8 weeks protected human islets and insulin-producing EndoC-βH1 cells from apoptosis induced by proinflammatory cytokines or the endoplasmic reticulum (ER) stressor thapsigargin. Whether this protective effect is influenced by sex, age, training modality, ancestry or diabetes is unknown. Methods: We enrolled 82 individuals, male or female, non-diabetic or diabetic, from different origins, in different supervised training protocols for 8-12 weeks (including training at home during the COVID-19 pandemic). EndoC-βH1 cells were treated with 'exercised' serum or with the exerkine clusterin to ascertain cytoprotection from ER stress. Results: The exercise interventions were effective and improved [Formula: see text] values in both younger and older, non-obese and obese, non-diabetic and diabetic participants. Serum obtained after training conferred significant beta cell protection (28% to 35% protection after 4 and 8 weeks of training, respectively) from severe ER stress-induced apoptosis. Cytoprotection was not affected by the type of exercise training or participant age, sex, BMI or ancestry, and persisted for up to 2 months after the end of the training programme. Serum from exercised participants with type 1 or type 2 diabetes was similarly protective. Clusterin reproduced the beneficial effects of exercised sera. Conclusions/interpretation: These data uncover the unexpected potential to preserve beta cell health by exercise training, opening a new avenue to prevent or slow diabetes progression through humoral muscle-beta cell crosstalk.
MeSH term(s)	Humans ; Male ; Female ; Infant ; Insulin-Secreting Cells/metabolism ; Diabetes Mellitus, Type 2/therapy ; Diabetes Mellitus, Type 2/metabolism ; Clusterin/metabolism ; Clusterin/pharmacology ; Pandemics ; COVID-19 ; Apoptosis/physiology ; Endoplasmic Reticulum Stress
Chemical Substances	Clusterin
Language	English
Publishing date	2022-11-19
Publishing country	Germany
Document type	Journal Article ; 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/s00125-022-05837-9
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Article ; Online: Interferons are key cytokines acting on pancreatic islets in type 1 diabetes.

Coomans de Brachène, Alexandra / Alvelos, Maria Ines / Szymczak, Florian / Zimath, Priscila L / Castela, Angela / Marmontel de Souza, Bianca / Roca Rivada, Arturo / Marín-Cañas, Sandra / Yi, Xiaoyan / Op de Beeck, Anne / Morgan, Noel G / Sonntag, Sebastian / Jawurek, Sayro / Title, Alexandra C / Yesildag, Burcak / Pattou, François / Kerr-Conte, Julie / Montanya, Eduard / Nacher, Montserrat /

Marselli, Lorella / Marchetti, Piero / Richardson, Sarah J / Eizirik, Decio L

Diabetologia

2024 Volume 67, Issue 5, Page(s) 908–927

Abstract: Aims/hypothesis: The proinflammatory cytokines IFN-α, IFN-γ, IL-1β and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, ...

Abstract	Aims/hypothesis: The proinflammatory cytokines IFN-α, IFN-γ, IL-1β and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown. Methods: We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes. Results: IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1β and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to 'danger signals' such as viral infections. Zinc finger NFX1-type containing 1 (ZNFX1), a double-stranded RNA sensor, was identified as highly induced by IFNs and shown to play a key role in the antiviral response in beta cells. Conclusions/interpretation: These data suggest that IFN-α and IFN-γ are key cytokines at the islet level in human type 1 diabetes, contributing to the triggering and amplification of autoimmunity.
MeSH term(s)	Humans ; Cytokines/metabolism ; Diabetes Mellitus, Type 1/metabolism ; Interferons/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Interferon-gamma/metabolism ; Islets of Langerhans/metabolism
Chemical Substances	Cytokines ; Interferons (9008-11-1) ; Tumor Necrosis Factor-alpha ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2024-02-26
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-024-06106-7
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Article ; Online: Xanthohumol and 8-prenylnaringenin reduce type 2 diabetes-associated oxidative stress by downregulating galectin-3.

Luís, Carla / Costa, Raquel / Rodrigues, Ilda / Castela, Ângela / Coelho, Pedro / Guerreiro, Susana / Gomes, Joana / Reis, Celso / Soares, Raquel

Porto biomedical journal

2018 Volume 4, Issue 1, Page(s) e23

Abstract: Background: Galectin-3 (Gal3) expression is associated with accumulation of Advanced Glycation End products (AGE), a common feature in diabetes mellitus (DM). The role of Gal3 in oxidative stress is, however, controversial, being considered in the ... ...

Abstract	Background: Galectin-3 (Gal3) expression is associated with accumulation of Advanced Glycation End products (AGE), a common feature in diabetes mellitus (DM). The role of Gal3 in oxidative stress is, however, controversial, being considered in the literature to play either a protective role or exacerbating disease. Methods: Herein, we examined the interplay between Gal3 and oxidative stress in a high-fat diet -induced type 2 DMC57Bl/6 mice model. Because natural polyphenols are known to play antioxidant and anti-inflammatory roles and to modulate metabolic activity, we further evaluated the effect of xanthohumol and 8-prenylnaringenin polyphenols in this crosstalk. Results: Gal3 expression was accompanied by 3-nitrotyrosine and AGE production in liver and kidney of diabetic mice compared to healthy animals (fed with standard diet). Oral supplementation with polyphenols decreased the levels of these oxidative biomarkers as evaluated by immunohistochemistry and western blotting. Interestingly, blocking Gal3 by incubating human microvascular endothelial cells with modified citrus pectin increased 3-nitrotyrosine protein expression. Conclusions: These findings imply that Gal3 overexpression is probably controlling oxidative stress in endothelial cells. In conclusion, our results indicate that supplementation with 8-prenylnaringenin or xanthohumol reverses diabetes-associated oxidation in liver and kidney, and consequently decreases this diabetic biomarker that predispose to cardiovascular complications.
Language	English
Publishing date	2018-08-08
Publishing country	United States
Document type	Journal Article
ISSN	2444-8672
ISSN (online)	2444-8672
DOI	10.1016/j.pbj.0000000000000023
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Article ; Online: Testosterone, endothelial health, and erectile function.

Castela, Angela / Vendeira, Pedro / Costa, Carla

ISRN endocrinology

2011 Volume 2011, Page(s) 839149

Abstract: Experimental and clinical studies have reported that testosterone has a critical role in the maintenance of homeostatic and morphologic corpus cavernosum components, essential for normal erectile physiology. Although the exact mechanisms mediated by ... ...

Abstract	Experimental and clinical studies have reported that testosterone has a critical role in the maintenance of homeostatic and morphologic corpus cavernosum components, essential for normal erectile physiology. Although the exact mechanisms mediated by testosterone in erectile function are still under investigation, recent research has suggested an important role in the regulation of endothelial cell (EC) biological functions. Besides stimulating the production of EC mediators, testosterone is also thought to promote the vasculogenic reendothelialization process, mediated by bone marrow-derived endothelial progenitor cells. Additionally, testosterone seems to modulate other erectile tissue components, including trabecular smooth muscle cells, nerve fibers, and tunica albuginea structure, all essential for the erectile process. This paper summarizes current data regarding testosterone-induced cellular and molecular mechanisms that regulate penile tissue components, focusing particularly on the role of testosterone in endothelial health and erectile function.
Language	English
Publishing date	2011-09-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2623566-3
ISSN	2090-4649 ; 2090-4630
ISSN (online)	2090-4649
ISSN	2090-4630
DOI	10.5402/2011/839149
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Article ; Online: The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells.

Alvelos, Maria Inês / Brüggemann, Mirko / Sutandy, Fx Reymond / Juan-Mateu, Jonàs / Colli, Maikel Luis / Busch, Anke / Lopes, Miguel / Castela, Ângela / Aartsma-Rus, Annemieke / König, Julian / Zarnack, Kathi / Eizirik, Décio L

Life science alliance

2020 Volume 4, Issue 3

Abstract: In pancreatic β-cells, the expression of the splicing factor SRSF6 is regulated by GLIS3, a transcription factor encoded by a diabetes susceptibility gene. ...

Abstract	In pancreatic β-cells, the expression of the splicing factor SRSF6 is regulated by GLIS3, a transcription factor encoded by a diabetes susceptibility gene.
MeSH term(s)	Alternative Splicing/genetics ; Binding Sites ; Cell Line ; Cell Survival/genetics ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 2/genetics ; Exons ; Gene Expression Regulation ; Gene Knockdown Techniques ; Humans ; Insulin-Secreting Cells/metabolism ; LIM Domain Proteins/genetics ; Phosphoproteins/chemistry ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Interaction Maps ; RNA/metabolism ; Serine-Arginine Splicing Factors/chemistry ; Serine-Arginine Splicing Factors/genetics ; Serine-Arginine Splicing Factors/metabolism ; Transcription Factors/genetics ; Transcriptome ; Transfection
Chemical Substances	LIM Domain Proteins ; LMO7 protein, human ; Phosphoproteins ; SRSF6 protein, human ; Transcription Factors ; Serine-Arginine Splicing Factors (170974-22-8) ; RNA (63231-63-0)
Language	English
Publishing date	2020-12-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202000825
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Article ; Online: Preclinical evaluation of tyrosine kinase 2 inhibitors for human beta-cell protection in type 1 diabetes.

Coomans de Brachène, Alexandra / Castela, Angela / Op de Beeck, Anne / Mirmira, Raghavendra G / Marselli, Lorella / Marchetti, Piero / Masse, Craig / Miao, Wenyan / Leit, Silvana / Evans-Molina, Carmella / Eizirik, Decio L

Diabetes, obesity & metabolism

2020 Volume 22, Issue 10, Page(s) 1827–1836

Abstract: Aim: Type 1 diabetes (T1D) is a chronic autoimmune disease leading to progressive loss of pancreatic beta cells. Interferon (IFN)-α plays a critical role in the crosstalk between pancreatic beta cells and the immune system in early insulitis. In human ... ...

Abstract	Aim: Type 1 diabetes (T1D) is a chronic autoimmune disease leading to progressive loss of pancreatic beta cells. Interferon (IFN)-α plays a critical role in the crosstalk between pancreatic beta cells and the immune system in early insulitis. In human beta cells IFNα signals through JAK1 and TYK2, leading to endoplasmic reticulum stress, inflammation and HLA class I overexpression. IFNα, acting synergistically with IL-1β, induces apoptosis. Polymorphisms in TYK2 that decrease its activity are associated with protection against T1D, and we hypothesized that pharmacological inhibitors that specifically target TYK2 could protect human beta cells against the deleterious effects of IFNα. Materials and methods: Two TYK2 inhibitors provided by Nimbus Lakshmi were tested in human insulin-producing EndoC-βH1 cells and human islets to evaluate their effect on IFNα signalling, beta-cell function and susceptibility to viral infection using RT-qPCR, western blot, immunofluorescence, ELISA and nuclear dyes. Results: The two TYK2 inhibitors tested prevented IFNα-induced human beta-cell gene expression in a dose-dependent manner. They also protected human islets against IFNα + IL-1β-induced apoptosis. Importantly, these inhibitors did not modify beta-cell function or their survival following infection with the potential diabetogenic coxsackieviruses CVB1 and CVB5. Conclusions: The two TYK2 inhibitors tested inhibit the IFNα signalling pathway in human beta cells, decreasing its pro-inflammatory and pro-apoptotic effects without sensitizing the cells to viral infection. The preclinical findings could pave the way for future clinical trials with TYK2 inhibitors for the prevention and treatment of type 1 diabetes.
MeSH term(s)	Apoptosis ; Cytoprotection ; Diabetes Mellitus, Type 1/drug therapy ; Endoplasmic Reticulum Stress ; Humans ; Insulin-Secreting Cells ; TYK2 Kinase/genetics
Chemical Substances	TYK2 Kinase (EC 2.7.10.2)
Language	English
Publishing date	2020-07-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1454944-x
ISSN	1463-1326 ; 1462-8902
ISSN (online)	1463-1326
ISSN	1462-8902
DOI	10.1111/dom.14104
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