PARP Inhibitor Protects Against Chronic Hypoxia/Reoxygenation-Induced Retinal Injury by Regulation of MAPKs, HIF1α, Nrf2, and NFκB

Kovács, Krisztina; Vaczy, Alexandra; Fekete, Katalin; Kovari, Petra; Atlasz, Tamás; Reglődi, Dóra; Gábriel, Róbert; Gallyas, Ferenc; Sümegi, Balázs

doi:10.1167/iovs.18-25936

Cited by 34 publications

(41 citation statements)

References 63 publications

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“…RACK1 may promote the expression of VEGF in endothelial cells and subsequently facilitate angiogenesis [26]. PARP1, activated by reactive oxygen species, was proven to be involved in in ammation, cell death, and retinal disease progression [27,28]. In summary, its stronger effects at a given dose and more numerous gene targets may be two major reasons that HXMMT is more strongly recommended than CXC by TCM doctors for treating fresh VH secondary to PDR.…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

Yao

Xin

Zhan

et al. 2020

Preprint

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Background Compound Xueshuantong capsule (CXC) and Hexuemingmu tablet (HXMMT) are two important Chinese patent medicines (CPMs) frequently used to treat proliferative diabetic retinopathy (PDR), especially when complicated with vitreous hemorrhage (VH). However, a network pharmacology approach to understand the therapeutic mechanisms of these two CPMs in PDR has not been applied. The aim of the study was to identify differences in active ingredients between CXC and HXMMT and to comparatively predict and further analyze the molecular targets shared by these CPMs and PDR. Materials and methods The differentially expressed messenger RNAs (mRNAs) between normal retinal tissues in healthy individuals and active fibrovascular membranes in PDR patients were retrieved from the Gene Expression Omnibus database. The active ingredients of CXC and HXMMT and the targets of these ingredients were retrieved from the Traditional Chinese Medicine Systems Pharmacology database. The intersections of the CPM (CXC and HXMMT) targets and PDR targets were determined. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed, and the ingredient-target networks, protein-protein interaction networks and KEGG-target (KEGG-T) networks were constructed. Results There CXC contains 4 herbal drugs in CXC, and HXMMT contains 19. Radix salviae is the only herbal drug common to both. CXC had 34 potential therapeutic targets in PDR, while HXMMT had these 34 and 10 additional targets. Both CPMs shared the following main processes: response to reactive oxygen species and oxidative stress, regulation of blood vessel diameter and size, vasoconstriction, smooth muscle contraction, hemostasis and blood coagulation. The shared pathways included the AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, relaxin signaling pathway, IL-17 signaling pathway, etc. Conclusions Both CXC and HXMMT include components effective in treating PDR. Radix salviae, the only herbal drug common to both CPMs, contains many useful active ingredients. HXMMT has more therapeutic targets shared by different active ingredients and more abundant gene functions than CXC. Moreover, the AGE-RAGE signaling pathway in diabetic complications was the most significantly enriched pathway in both networks. However, these findings should be verified through further research.

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Section: Discussionmentioning

confidence: 99%

Network Pharmacology-based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

Yao

Xin

Zhan

et al. 2020

Preprint

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“…Thus, hyperglycemia initiates in the retina of diabetic rats chronic upregulation of PARP1 expression. As a rule, PARP activation is studied by using the specific PARP inhibitors since the suppression of PARP overactivity may provide cell viability and functional capability in various cell types (Obrosova et al, 2004;Kovacs et al, 2019). Especially, in the retina the inhibition of PARP can reduce degenerative changes in retina exposed to oxidative stress as was demonstrated by Kovacs et al (2019) in a rat retinal hypoxia/reoxygenation model.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the suppression of astroglial reactivity in the retina was demonstrated in rats with STZ-induced diabetes via PARP inhibition (Guzik, 2016). On the other hand, PARP inhibitors can ameliorate retinal inflammation (Kovacs et al, 2019). Further evidence of the beneficial effect of the limiting glial cells in the retina was obtained with curcumin exposure of diabetic rats (Zuo et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Water-soluble C60 fullerene ameliorates astroglial reactivity and TNFa production in retina of diabetic rats

Nedzvetsky¹,

Sukharenko²,

Baydaş³

et al. 2019

Regul. Mech. Biosyst.

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The complications of both first and second types of diabetes mellitus patients are important cause of decline in quality of life and mortality worldwide. Diabetic retinopathy (DR) is a widespread complication that affects almost 60% of patients with prolonged (at least 10–15 years) diabetes. The critical role of glial cells has been shown in retinopathy initiation in the last decades. Furthermore, glial reactivity and inflammation could be key players in early pathogenesis of DR. Despite the large amount of research data, the approaches of effective DR therapy remain unclear. The progress of DR is accompanied by pro-inflammatory and pro-oxidative changes in retinal cells including astrocytes and Muller cells. Glial reactivity is a key pathogenetic factor of various disorders in neural tissue. Fullerene C60 nanoparticles were confirmed for both antioxidant and anti-inflammatory capability. In the presented study glioprotective efficacy of water-soluble hydrated fullerene C60 (C60HyFn) was tested in a STZ-diabetes model during 12 weeks. Exposure of the STZ-diabetic rat group to C60HyFn ameliorated the astrocyte reactivity which was determined via S100β and PARP1 overexpression. Moreover, C60HyFn induced the decrease of TNFα production in the retina of STZ-diabetic rats. By contrast, the treatment with C60HyFn of the normal control rat group didn’t change the content of all abovementioned markers of astrogliosis and inflammation. Thus, diabetes-induced abnormalities in the retina were suppressed via the anti-oxidant, anti-inflammatory and glioprotective effects of C60HyFn at low doses. The presented results demonstrate that C60HyFn can ensure viability of retinal cells viability through glioprotective effect and could be a new therapeutic nano-strategy of DR treatment.

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“…The cytoprotective effect of PARP inhibition (using 4-hydroxy-quinazoline) was also associated with Akt activation in an acute rat kidney rejection model [101]. Moreover, the cytoprotective effect of a clinically approved (for oncological indications) PARP inhibitor (olaparib) was also associated with Akt activation in hypoxia-reoxygenation induced acute retinal injury model [102]. However, similarly to the acute urinary retention experiments discussed above, the functional importance of Akt activation was not directly tested in these studies.…”

Section: Role Of the Parp-akt Interplay In Reperfusion Injurymentioning

confidence: 96%

“…However, similarly to the acute urinary retention experiments discussed above, the functional importance of Akt activation was not directly tested in these studies. In the latter model, olaparib treatment induced alterations in a host of additional pathways (MAPKs, HIF1α, Nrf2, and NFκB) [102]; thus, it is conceivable that these effects may have also contributed to its beneficial effects.…”

Section: Role Of the Parp-akt Interplay In Reperfusion Injurymentioning

confidence: 99%

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

Gallyas

Sümegi

Szabó

2020

Cancers

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Poly(ADP-ribose) polymerase (PARP) inhibitors have recently been introduced in the therapy of several types of cancers not responding to conventional treatments. However, de novo and acquired PARP inhibitor resistance is a significant limiting factor in the clinical therapy, and the underlying mechanisms are not fully understood. Activity of the cytoprotective phosphatidylinositol-3 kinase (PI3K)-Akt pathway is often increased in human cancer that could result from mutation, expressional change, or amplification of upstream growth-related factor signaling elements or elements of the Akt pathway itself. However, PARP-inhibitor-induced activation of the cytoprotective PI3K-Akt pathway is overlooked, although it likely contributes to the development of PARP inhibitor resistance. Here, we briefly summarize the biological role of the PI3K-Akt pathway. Next, we overview the significance of the PARP-Akt interplay in shock, inflammation, cardiac and cerebral reperfusion, and cancer. We also discuss a recently discovered molecular mechanism that explains how PARP inhibition induces Akt activation and may account for apoptosis resistance and mitochondrial protection in oxidative stress and in cancer.

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PARP Inhibitor Protects Against Chronic Hypoxia/Reoxygenation-Induced Retinal Injury by Regulation of MAPKs, HIF1α, Nrf2, and NFκB

Cited by 34 publications

References 63 publications

Network Pharmacology-based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

Network Pharmacology-based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

Water-soluble C60 fullerene ameliorates astroglial reactivity and TNFa production in retina of diabetic rats

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

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