Nanosystems based on siRNA silencing HuR expression counteract diabetic retinopathy in rat

Amadio, Marialaura; Pascale, Alessia; Cupri, Sarha; Pignatello, Rosario; Osera, Cecilia; D’Agata, Velia; D’Amico, Agata Grazia; Leggio, Gian Marco; Ruozi, Barbara; Govoni, Stefano; Drago, Filippo; Bucolo, Claudio

doi:10.1016/j.phrs.2016.07.042

Cited by 93 publications

(40 citation statements)

References 26 publications

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“…For instance, a key role for Erk1/2, as well as AMPK, in AMD has been suggested [ 63 ]. Moreover, recent studies have confirmed the importance of HuR in various ocular pathologies [ 64 , 65 ] and laid the foundation for the druggability assessment of HuR protein [ 66 ]; compounds able to directly act on the HuR protein and p62 mRNA complex formation may thus represent new potential tools regulating p62 content.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Stimulus Promotes Early HuR Protein Activation and p62/SQSTM1 Protein Synthesis in ARPE‐19 Cells by Triggering Erk1/2, p38^MAPK, and JNK Kinase Pathways

Marchesi

Thongon

Pascale

et al. 2018

Oxidative Medicine and Cellular Longevity

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RNA-binding protein dysregulation and altered expression of proteins involved in the autophagy/proteasome pathway play a role in many neurodegenerative disease onset/progression, including age-related macular degeneration (AMD). HuR/ELAVL1 is a master regulator of gene expression in human physiopathology. In ARPE-19 cells exposed to the proteasomal inhibitor MG132, HuR positively affects at posttranscriptional level p62 expression, a stress response gene involved in protein aggregate clearance with a role in AMD. Here, we studied the early effects of the proautophagy AICAR + MG132 cotreatment on the HuR-p62 pathway. We treated ARPE-19 cells with Erk1/2, AMPK, p38MAPK, PKC, and JNK kinase inhibitors in the presence of AICAR + MG132 and evaluated HuR localization/phosphorylation and p62 expression. Two-hour AICAR + MG132 induces both HuR cytoplasmic translocation and threonine phosphorylation via the Erk1/2 pathway. In these conditions, p62 mRNA is loaded on polysomes and its translation in de novo protein is favored. Additionally, for the first time, we report that JNK can phosphorylate HuR, however, without modulating its localization. Our study supports HuR's role as an upstream regulator of p62 expression in ARPE-19 cells, helps to understand better the early events in response to a proautophagy stimulus, and suggests that modulation of the autophagy-regulating kinases as potential therapeutic targets for AMD may be relevant.

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Section: Discussionmentioning

confidence: 99%

Autophagy Stimulus Promotes Early HuR Protein Activation and p62/SQSTM1 Protein Synthesis in ARPE‐19 Cells by Triggering Erk1/2, p38^MAPK, and JNK Kinase Pathways

Marchesi

Thongon

Pascale

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…SiRNA-containing lipid nanocarriers have also been studied, proving to be an alternative to DR therapy. These nanocarriers inhibit HuR and phospholipase A2, not allowing increased retinal VEGF levels [85,86]. Excess of glucose interferes with plasma tumour necrosis alpha (TNFα) and interleukin 6 (IL6) and VEGF plasma levels, and reduced retinal oxygen levels stimulate the release of macrophages, chemokines and microglial growth factors, as well as the expression of angiogenic factors [87][88][89][90].…”

Section: Diabetic Retinopathy Angiogenesis and Anti-angiogenic Therapymentioning

confidence: 99%

Diabetic Retinopathy and Ocular Melanoma: How Far We Are?

et al. 2020

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Diabetic retinopathy causes vascular damage to retinal neurons, presenting characteristics of chronic inflammation. The development of new therapies capable of combating vision loss involves knowledge of inflammatory retinal changes. Studies in animal models and patients with diabetes have shown a high expression of the inflammatory molecules that are involved in the progression of diabetic retinopathy. Uveal melanoma is an eye tumour that remains highly deadly, because despite the correct treatment, it still causes metastasis in about 50% of patients. This type of tumour has the ability to produce and store melanin, which may result in resistance to therapy. Over time there has been development of new therapies for this disease, such as radiotherapy and surgical resection. In this review, we discuss diabetic retinopathy and ocular melanoma, their relationship with angiogenesis and the current anti-angiogenic therapies for their treatment.

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“…Hyperglycemia-induced VEGF expression increase in rat retina is mediated by protein kinase Cβ/human antigen R [ 65 ] and phospholipase A2 [ 66 ] pathways. Lipid-based nanocarriers containing siRNA silencing HuR expression [ 67 ] and phospholipase A2 inhibitors [ 66 ] could represent additional pharmacological tools to manage DR as they block the increase in retinal VEGF levels found in diabetic rats.…”

Section: What Is the Role Of Inflammation In Brb Rupture Occurringmentioning

confidence: 99%

Potential Interplay between Hyperosmolarity and Inflammation on Retinal Pigmented Epithelium in Pathogenesis of Diabetic Retinopathy

Willermain

Scifo

Weber

et al. 2018

IJMS

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Diabetic retinopathy is a frequent eyesight threatening complication of type 1 and type 2 diabetes. Under physiological conditions, the inner and the outer blood-retinal barriers protect the retina by regulating ion, protein, and water flux into and out of the retina. During diabetic retinopathy, many factors, including inflammation, contribute to the rupture of the inner and/or the outer blood-retinal barrier. This rupture leads the development of macular edema, a foremost cause of sight loss among diabetic patients. Under these conditions, it has been speculated that retinal pigmented epithelial cells, that constitute the outer blood-retinal barrier, may be subjected to hyperosmolar stress resulting from different mechanisms. Herein, we review the possible origins and consequences of hyperosmolar stress on retinal pigmented epithelial cells during diabetic retinopathy, with a special focus on the intimate interplay between inflammation and hyperosmolar stress, as well as the current and forthcoming new pharmacotherapies for the treatment of such condition.

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Nanosystems based on siRNA silencing HuR expression counteract diabetic retinopathy in rat

Cited by 93 publications

References 26 publications

Autophagy Stimulus Promotes Early HuR Protein Activation and p62/SQSTM1 Protein Synthesis in ARPE‐19 Cells by Triggering Erk1/2, p38^MAPK, and JNK Kinase Pathways

Autophagy Stimulus Promotes Early HuR Protein Activation and p62/SQSTM1 Protein Synthesis in ARPE‐19 Cells by Triggering Erk1/2, p38^MAPK, and JNK Kinase Pathways

Diabetic Retinopathy and Ocular Melanoma: How Far We Are?

Potential Interplay between Hyperosmolarity and Inflammation on Retinal Pigmented Epithelium in Pathogenesis of Diabetic Retinopathy

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Nanosystems based on siRNA silencing HuR expression counteract diabetic retinopathy in rat

Cited by 93 publications

References 26 publications

Autophagy Stimulus Promotes Early HuR Protein Activation and p62/SQSTM1 Protein Synthesis in ARPE‐19 Cells by Triggering Erk1/2, p38MAPK, and JNK Kinase Pathways

Autophagy Stimulus Promotes Early HuR Protein Activation and p62/SQSTM1 Protein Synthesis in ARPE‐19 Cells by Triggering Erk1/2, p38MAPK, and JNK Kinase Pathways

Diabetic Retinopathy and Ocular Melanoma: How Far We Are?

Potential Interplay between Hyperosmolarity and Inflammation on Retinal Pigmented Epithelium in Pathogenesis of Diabetic Retinopathy

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Product

Resources

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Autophagy Stimulus Promotes Early HuR Protein Activation and p62/SQSTM1 Protein Synthesis in ARPE‐19 Cells by Triggering Erk1/2, p38^MAPK, and JNK Kinase Pathways

Autophagy Stimulus Promotes Early HuR Protein Activation and p62/SQSTM1 Protein Synthesis in ARPE‐19 Cells by Triggering Erk1/2, p38^MAPK, and JNK Kinase Pathways