Autophagy: A Novel Pharmacological Target in Diabetic Retinopathy

Adornetto, Annagrazia; Gesualdo, Carlo; Laganà, Maria Luisa; Trotta, Maria Consiglia; Rossi, Silvia; Russo, Rossella

doi:10.3389/fphar.2021.695267

Cited by 20 publications

(14 citation statements)

References 152 publications

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“…Abnormal retinal autophagy has recently emerged as a frequent event in neurological disorders [ 40 ] and in preclinical and clinical DR settings [ 5 , 41 , 42 ] and has been indicated as a novel therapeutic target for DR. Particularly, in this in vivo DR model, the marker of autophagosome formation LC3 was found upregulated in diabetic retinas, as well as the marker of autophagosome–lysosome formation ATG14.…”

Section: Discussionmentioning

confidence: 99%

“…Worthy of note, BDNF deficiency in different DR cell culture models was shown to contribute to abnormally increased autophagy [ 5 ], evidenced by enhanced microtubule-associated protein light chain 3 B (LC3B) expression [ 6 ]. This is a marker of autophagosome formation [ 7 ] strictly involved in the degradation of connexin 43 (Cnx43) [ 8 ], a gap junction reduced in DR and associated to retinal vascular cell death [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Systemic Beta-Hydroxybutyrate Affects BDNF and Autophagy into the Retina of Diabetic Mice

Trotta

Gesualdo

Herman

et al. 2022

IJMS

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Background: Diabetic retinopathy (DR) is a neurovascular disease, characterized by a deficiency of brain-derived neurotrophic factor (BDNF), a regulator of autophagy. Beta-hydroxybutyrate (BHB), previously reported as a protective agent in DR, has been associated with BDNF promotion. Here, we investigated whether systemic BHB affects the retinal levels of BDNF and local autophagy in diabetic mice with retinopathy; Methods: C57BL/6J mice were administered with intraperitoneal (i.p.) streptozotocin (STZ) (75 mg/kg) injection to develop diabetes. After 2 weeks, they received i.p. injections of BHB (25–50–100 mg/kg) twice a week for 10 weeks. Retinal samples were collected in order to perform immunofluorescence, Western blotting, and ELISA analysis; Results: BHB 50 mg/kg and 100 mg/kg significantly improved retinal BDNF levels (p < 0.01) in diabetic mice. This improvement was negatively associated with autophagosome–lysosome formations (marked by LC3B and ATG14) and to higher levels of connexin 43 (p < 0.01), a marker of cell integrity. Moreover, BHB administration significantly reduced M1 microglial activation and autophagy (p < 0.01); Conclusions: The systemic administration of BHB in mice with DR improves the retinal levels of BDNF, with the consequent reduction of the abnormal microglial autophagy. This leads to retinal cell safety through connexin 43 restoration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systemic Beta-Hydroxybutyrate Affects BDNF and Autophagy into the Retina of Diabetic Mice

Trotta

Gesualdo

Herman

et al. 2022

IJMS

Self Cite

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“…Therefore, Sir3 may inhibit angiogenesis in HRECs through autophagy ( 38 ). Another study by 39 showed that Müller cells stimulated by HOG-LDL had activated AMPK and increases in the levels of the autophagy-related proteins ATG-5, Beclin-1, and LC3II/LC3I and the expression of the apoptosis-related protein caspase-3. This finding suggests that autophagy activation can lead to apoptosis.…”

Section: Autophagy Diabetes and Diabetic Complicationsmentioning

confidence: 99%

The relationship between HMGB1 and autophagy in the pathogenesis of diabetes and its complications

et al. 2023

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Diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose levels and has become the third leading threat to human health after cancer and cardiovascular disease. Recent studies have shown that autophagy is closely associated with diabetes. Under normal physiological conditions, autophagy promotes cellular homeostasis, reduces damage to healthy tissues and has bidirectional effects on regulating diabetes. However, under pathological conditions, unregulated autophagy activation leads to cell death and may contribute to the progression of diabetes. Therefore, restoring normal autophagy may be a key strategy to treat diabetes. High-mobility group box 1 protein (HMGB1) is a chromatin protein that is mainly present in the nucleus and can be actively secreted or passively released from necrotic, apoptotic, and inflammatory cells. HMGB1 can induce autophagy by activating various pathways. Studies have shown that HMGB1 plays an important role in insulin resistance and diabetes. In this review, we will introduce the biological and structural characteristics of HMGB1 and summarize the existing knowledge on the relationship between HMGB1, autophagy, diabetes, and diabetic complications. We will also summarize potential therapeutic strategies that may be useful for the prevention and treatment of diabetes and its complications.

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“…Cell death (through apoptosis, necrosis, and autophagy) can be induced by reactive oxygen species (ROS) and inflammatory cytokines (ILs) secreted in response to hyperglycemia (Volpe et al, 2018). As a result, retinal impairment is associated with autophagy activity in diabetic patients (Adornetto et al, 2021). In fact, the onset and development of ARMD has been attributed to the dysfunction of autophagy of RPE cells.…”

Section: Autophagy In Other Eye Diseasesmentioning

confidence: 99%

Autophagy in graves’ ophthalmopathy

Chen

Gao

Liu

et al. 2023

Front. Cell Dev. Biol.

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Graves’ ophthalmopathy (GO) is an inflammatory autoimmune disease that affects the eyes. It can significantly alter the quality of life in patients because of its distinctive pathological appearance and the effect on vision. To date, the exact pathological mechanism of GO has not been explicitly discovered. However, several studies have associated autophagy with this disease. Autophagy is a catabolic process that helps maintain homeostasis in all organisms by protecting the cells and tissues from various endogenous and exogenous stress factors. Based on our results, patients affected with GO have comparatively elevated levels of autophagy, which critically affects the pathological mechanism of the GO. In this review, we have summarized the autophagy mechanism in the pathogenesis of GO.

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Autophagy: A Novel Pharmacological Target in Diabetic Retinopathy

Cited by 20 publications

References 152 publications

Systemic Beta-Hydroxybutyrate Affects BDNF and Autophagy into the Retina of Diabetic Mice

Systemic Beta-Hydroxybutyrate Affects BDNF and Autophagy into the Retina of Diabetic Mice

The relationship between HMGB1 and autophagy in the pathogenesis of diabetes and its complications

Autophagy in graves’ ophthalmopathy

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