Divergent Effects of HSP70 Overexpression in Photoreceptors During Inherited Retinal Degeneration

Jiang, Ke; Fairless, Elizabeth; Kanda, Atsuhiro; Gotoh, Noriko; Cogliati, Tiziana; Li, Tiansen; Swaroop, Anand

doi:10.1167/iovs.61.12.25

Cited by 4 publications

(2 citation statements)

References 74 publications

(79 reference statements)

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“…The most significantly upregulated gene was the heat-shock response gene HSPA6, while HSPA12A was also upregulated, suggesting that eupatilin might activate the heat shock response. In certain models of retinal degeneration, HSPA1A overexpression is thought to play a protective role in stressed photoreceptors (64,65). For instance, HSPA6 and HSPA1A contribute to protection of differentiated human neuronal cells from cellular stress (66,67).…”

Section: Discussionmentioning

confidence: 99%

Eupatilin improves cilia defects in human CEP290 ciliopathy models

Corral-Serrano¹,

Sladen²,

Ottaviani

et al. 2023

Preprint

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The photoreceptor outer segment is a highly specialized primary cilium essential for phototransduction and vision. Biallelic pathogenic variants in the cilia-associated gene CEP290 cause non-syndromic Leber congenital amaurosis 10 (LCA10) and syndromic diseases, where the retina is also affected. While RNA antisense oligonucleotides and gene editing are potential treatment options for the common deep intronic variant c.2991+1655A>G in CEP290, there is a need for variant-independent approaches that could be applied to a broader spectrum of ciliopathies. Here, we generated several distinct human models of CEP290-related retinal disease and investigated the effects of the flavonoid eupatilin as a potential treatment. Eupatilin improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, in gene-edited CEP290 knockout (CEP290 KO) RPE1 cells, and in both CEP290 LCA10 and CEP290 KO iPSCs-derived retinal organoids. Furthermore, eupatilin reduced rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids. Eupatilin altered gene transcription in retinal organoids, by modulating the expression of rhodopsin, and by targeting cilia and synaptic plasticity pathways. This work sheds light into the mechanism of action of eupatilin, and supports its potential as a variant-independent approach for CEP290-associated ciliopathies.

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Section: Discussionmentioning

confidence: 99%

Eupatilin improves cilia defects in human CEP290 ciliopathy models

Corral-Serrano¹,

Sladen²,

Ottaviani

et al. 2023

Preprint

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show abstract

“…For example, during heat stress, coenzyme Q10 protects primary myocardial cells by upregulating HSP70 expression [20]. In the mouse model of retinal degeneration, the expression of endogenous HSP70 is briefly elevated at the early stage and then sharply decreased with cell death, suggesting that this is the initial adaptive response of HSP70 to cellular stress [21]. In addition, the continuously increased expression of HSP70 is a feature of many tumor cells, and the increased reactivity of HSP70 can promote the folding of cancer-related proteins, promote the activity of tumor cells, inhibit the apoptosis of tumor cells, and have a significant protective effect on tumor cells [22].…”

Section: Discussionmentioning

confidence: 99%

The regulatory mechanism of HSP70 in endoplasmic reticulum stress in pepsin-treated laryngeal epithelium cells and laryngeal cancer cells

Chen

Wang

et al. 2022

Aging

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Backgrounds: Excessive pepsin can damage both normal laryngeal epithelial cells and laryngeal cancer (LC) cells. Heat shock protein 70 (HSP70) is closely related to pepsin. In this paper, we will explore the different significance of the regulatory role of HSP70 in endoplasmic reticulum stress (ERS) level in pepsin-treated laryngeal epithelial cells and LC cells. Methods: In cell experiments, laryngeal epithelial cells and LC cells were selected and induced by different concentrations of pepsin. Cell activity was detected by CCK8, cell apoptosis was detected by flow cytometry, and autophagy was detected by autophagy detection kit. The expression of ER)-related proteins was detected by immunofluorescence (IF) and Western blot. Cell transfection was used to inhibit HSP70 expression in both cells, and ERS, apoptosis, and autophagy were measured using related techniques. In animal experiments, a mouse model bearing LC was established. TUNEL assay detected apoptosis, autophagy kit detected autophagy, and ER-related protein expression was detected by Western blot. Results: HSP70 was increased in pepsin-stimulated laryngeal epithelial cells and LC cells, thereby inhibiting ER and ER-induced apoptosis and autophagy. Inhibition of HSP70 reduced the expression of glucose regulated protein 78 (GRP78) in pepsin-stimulated laryngeal epithelial cells and LC cells, and only inhibited downstream apoptosis-related pathways in laryngeal epithelial cells rather than in LC cells. Inhibition of HSP70 and ER could significantly promote apoptosis and inhibit tumor growth in the absence of pepsin stimulation in vivo. Conclusion: ER level regulated by HSP70 had different significance in laryngeal epithelial cells and LC cells treated with pepsin.

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The contribution of pattern recognition receptor signalling in the development of age related macular degeneration: the role of toll-like-receptors and the NLRP3-inflammasome

Brandli,

Vessey,

Fletcher

2024

J Neuroinflammation

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Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss, characterised by the dysfunction and death of the photoreceptors and retinal pigment epithelium (RPE). Innate immune cell activation and accompanying para-inflammation have been suggested to contribute to the pathogenesis of AMD, although the exact mechanism(s) and signalling pathways remain elusive. Pattern recognition receptors (PRRs) are essential activators of the innate immune system and drivers of para-inflammation. Of these PRRs, the two most prominent are (1) Toll-like receptors (TLR) and (2) NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-inflammasome have been found to modulate the progression of AMD. Mutations in TLR2 have been found to be associated with an increased risk of developing AMD. In animal models of AMD, inhibition of TLR and NLRP3 has been shown to reduce RPE cell death, inflammation and angiogenesis signalling, offering potential novel treatments for advanced AMD. Here, we examine the evidence for PRRs, TLRs2/3/4, and NLRP3-inflammasome pathways in macular degeneration pathogenesis.

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Divergent Effects of HSP70 Overexpression in Photoreceptors During Inherited Retinal Degeneration

Cited by 4 publications

References 74 publications

Eupatilin improves cilia defects in human CEP290 ciliopathy models

Eupatilin improves cilia defects in human CEP290 ciliopathy models

The regulatory mechanism of HSP70 in endoplasmic reticulum stress in pepsin-treated laryngeal epithelium cells and laryngeal cancer cells

The contribution of pattern recognition receptor signalling in the development of age related macular degeneration: the role of toll-like-receptors and the NLRP3-inflammasome

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