The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved

Giusti, Laura; Tesi, Matteo; Ciregia, Federica; Marselli, Lorella; Zallocco, Lorenzo; Suleiman, Mara; Luca, Carmela De; Guerra, S Del; Zuccarini, Mariachiara; Trerotola, Marco; Eizirik, Décio L.; Cnop, Miriam; Mazzoni, Maria Rosa; Marchetti, Piero; Lucacchini, Antonio; Ronci, Maurizio

doi:10.3390/cells11152465

Cited by 13 publications

(5 citation statements)

References 106 publications

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“…Also in our case, preferential HLA-B upregulation translated into an increased peptide presentation drastically skewed toward HLA-B ligands. Although remaining unnoticed, a preferential upregulation of HLA-B and, to a lesser degree, HLA-C, was also observed in RNA-seq studies of induced pluripotent stem cell-derived islet-like cells exposed to IFN-α 23 ; of sorted β-cells from T1D vs. non-diabetic donors 53,59 , despite a long disease duration; and in proteomics studies of islets from non-diabetic donors exposed to IFN-γ/IL-1β 60 . Mechanistically, this may reflect the structure of the HLA-B gene locus, which harbors two IFN response elements, while HLA-A and -C loci have only one 21,61 .…”

Section: Discussionmentioning

confidence: 78%

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells

Carré,

Zhou,

Perez-Hernandez

et al. 2023

Preprint

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Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but its effect on the repertoire of HLA Class I (HLA-I)-bound peptides presented by pancreatic β-cells is unknown. Using immunopeptidomics, we characterized the peptide/HLA-I presentation in in-vitro resting and IFN-α-exposed β-cells. IFN-α increased HLA-I expression and peptide presentation, including neo-sequences derived from alternative mRNA splicing, post-translational modifications - notably glutathionylation - and protein cissplicing. This antigenic landscape relied on processing by both the constitutive and immune proteasome. The resting β-cell immunopeptidome was dominated by HLA-A-restricted ligands. However, IFN-α only marginally upregulated HLA-A and largely favored HLA-B, translating into a major increase in HLA-B-restricted peptides and into an increased activation of HLA-Brestricted vs. HLA-A-restricted CD8+ T-cells. A preferential HLA-B hyper-expression was also observed in the islets of T1D vs. non-diabetic donors, and we identified islet-infiltrating CD8+ T-cells from T1D donors reactive to HLA-B-restricted granule peptides. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward epitopes presented by HLA-B, hence recruiting a distinct T-cell repertoire that may be relevant to T1D pathogenesis.

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Section: Discussionmentioning

confidence: 78%

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells

Carré,

Zhou,

Perez-Hernandez

et al. 2023

Preprint

Self Cite

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“…Metformin is an effective treatment for type 2 diabetes that lowers blood glucose levels and reduces insulin resistance. It has anti-inflammatory and antioxidant effects [ 148 , 149 ]. Metformin has been shown to increase the expression of mitochondrial sirtuin 3, an NAD + dependent deacetylase, that regulates oxidative phosphorylation and activates mitochondrial antioxidant MnSOD [ 149 , 150 ].…”

Section: Potential For Mitochondrial Targeting Therapies In Preeclampsiamentioning

confidence: 99%

Placental Mitochondrial Function and Dysfunction in Preeclampsia

Jahan

Vasam

Green

et al. 2023

IJMS

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The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational parent/fetal exchange, and ultimately, fetal development and growth. Not surprisingly, in cases of placental dysfunction—where aspects of placental development or function become compromised—adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero–placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunction in the pathogenesis and progression of the disease. In the current review, the evidence of placental mitochondrial dysfunction in the context of PE will be summarized, highlighting how altered mitochondrial function may be a common feature across distinct PE subtypes. Further, advances in this field of study and therapeutic targeting of mitochondria as a promising intervention for PE will be discussed.

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“…Metformin is an effective treatment for type 2 diabetes that lowers blood glucose levels and reduces insulin resistance. It has anti-inflammatory and antioxidant effects [143,144]. Metformin has been shown to increase the expression of mitochondrial Sirtuin 3, a known activator of antioxidant mnSOD2 [144].…”

Section: Metforminmentioning

confidence: 99%

Placental Mitochondrial Function and Dysfunction in Preeclampsia

Jahan¹,

Vasam²,

Green³

et al. 2023

Preprint

View full text Add to dashboard Cite

The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational-parent/fetal exchange and ultimately fetal development and growth. Not surprisingly, in cases of placental dysfunction - where aspects of placental development or function become compromised - adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero-placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunction in the pathogenesis and progression of the disease. In the current review, the evidence of placental mitochondrial dysfunction in the context of PE will be summarized, highlighting how altered mitochondrial function may be a common feature across distinct PE subtypes. Further, advances in this field of study and therapeutic targeting of mitochondria as a promising intervention for PE will be discussed.

show abstract

The Protective Action of Metformin against Pro-Inflammatory Cytokine-Induced Human Islet Cell Damage and the Mechanisms Involved

Cited by 13 publications

References 106 publications

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells

Placental Mitochondrial Function and Dysfunction in Preeclampsia

Placental Mitochondrial Function and Dysfunction in Preeclampsia

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