Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities

Sorenson, Christine M.; Song, Yong; Zaitoun, Ismail; Wang, Shoujian; Hanna, Barbara; Darjatmoko, Soesiawati R.; Gurel, Zafer; Fisk, Debra L.; McDowell, Colleen M; McAdams, Ryan M.

doi:10.3389/fcell.2021.737426

Cited by 8 publications

(11 citation statements)

References 75 publications

(111 reference statements)

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“…We also demonstrated that caffeine inhibits the migration of retinal and choroidal endothelial cells. [19] Thus, the results of the current study suggesting that the A2A receptor may have altered expression in human eyes with AMD fits well with prior findings. Together these results suggest a potential role for adenosine receptor antagonism in preventing changes associated with AMD.…”

Section: Discussionsupporting

confidence: 90%

“…We previously showed predominant expression of A1 receptor in mouse microglia and retinal vascular cells. [19] Receptors A2A, A2B, and A3 displayed gene expression within both the retina and choroid. Although A1 receptor expression was significantly lower, the expression of A2A and A3 were significantly higher in the choroid/RPE compared with the retina, as we previously reported in human and mouse tissue samples.…”

Section: Adenosine Receptors Mrna Expression In Retina and Rpe/choroi...mentioning

confidence: 99%

“…Although A1 receptor expression was significantly lower, the expression of A2A and A3 were significantly higher in the choroid/RPE compared with the retina, as we previously reported in human and mouse tissue samples. [19] The average relative expression of each adenosine receptor in both the retina and choroid/RPE is shown in Figure 5.…”

Section: Adenosine Receptors Mrna Expression In Retina and Rpe/choroi...mentioning

confidence: 99%

“…[18] We recently showed that caffeine is efficacious in mitigating choroidal neovascularization in a preclinical model of wet AMD. [19] However, the identity of adenosine receptor(s) involved in these activities remains unknown, and results have yet to be verified in humans. Here we assessed the presence of specific adenosine receptors in the retina and choroid of human donor eye samples from control and patients with wet and dry AMD.…”

Section: Introductionmentioning

confidence: 99%

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Adenosine Receptors Expression in Human Retina and Choroid with Age-related Macular Degeneration

Song

Zaitoun

Wang

et al. 2023

JOVR

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Purpose: Adenosine signaling modulates ocular inflammatory processes, and its antagonism mitigates neovascularization in both newborns and preclinical models of ocular neovascularization including age-related macular degeneration (AMD). The adenosine receptor expression patterns have not been well characterized in the human retina and choroid. Methods: Here we examined the expression of adenosine receptor subtypes within the retina and choroid of human donor eyes with and without AMD. Antibodies specifically targeting adenosine receptor subtypes A1, A2A, A2B, and A3 were used to assess their expression patterns. Quantitative real-time PCR analysis was used to confirm gene expression of these receptors within the normal human retina and choroid. Results: We found that all four receptor subtypes were expressed in several layers of the retina, and within the retinal pigment epithelium and choroid. The expression of A1 receptors was more prominent in the inner and outer plexiform layers, where microglia normally reside, and supported by RNA expression in the retina. A2A and A2B showed similar expression patterns with prominent expression in the vasculature and retinal pigment epithelium. No dramatic differences in expression of these receptors were observed in eyes from patients with dry or wet AMD compared to control, with the exception A3 receptors. Eyes with dry AMD lost expression of A3 in the photoreceptor outer segments compared with eyes from control or wet AMD. Conclusion: The ocular presence of adenosine receptors is consistent with their proposed role in modulation of inflammation in both the retina and choroid, and their potential targeting for AMD treatment.

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Section: Discussionsupporting

confidence: 90%

Section: Adenosine Receptors Mrna Expression In Retina and Rpe/choroi...mentioning

confidence: 99%

Section: Adenosine Receptors Mrna Expression In Retina and Rpe/choroi...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adenosine Receptors Expression in Human Retina and Choroid with Age-related Macular Degeneration

Song

Zaitoun

Wang

et al. 2023

JOVR

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“…IM-HCF cells were cultured in six-well plates at a density of 1.5 × 10 6 cells/well; the day after, cells were stimulated with TGF-β at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. Cells were treated with two different A 2A receptor antagonists, Istradefylline (Tocris Bioscience Bristol, Bristol, UK) and ZM241385 (Tocris Bioscience Bristol, Bristol, UK), for 24 h, at concentrations of 10 µM and 1 µM, respectively, alone or following TGF-β challenge, as previously described [ 53 , 54 ].…”

Section: Methodsmentioning

confidence: 99%

Biglycan Involvement in Heart Fibrosis: Modulation of Adenosine 2A Receptor Improves Damage in Immortalized Cardiac Fibroblasts

Scuruchi

Mannino

Imbesi

et al. 2023

IJMS

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Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-β activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-β binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A2AR, may play a key role in stimulating fibrotic damage through collagen production/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A2AR and BGN modulation in an in vitro model of TGF-β-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-β at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-β stimulus, cells were treated with two different A2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 µM and 1 µM, respectively. Both A2AR antagonists were able to regulate the oxidative stress induced by TGF-β through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3/9, BGN, caspase-1 and IL-1β gene expression was markedly decreased following A2AR antagonist treatment in TGF-β-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, α-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A2AR. These results suggest that A2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling.

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Targeting purinergic receptors to attenuate inflammation of dry eye

Wang

Fan

Song

2022

Purinergic Signalling

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Inflammation is one of the potential factors to cause the damage of ocular surface in dry eye disease (DED). Increasing evidence indicated that purinergic A1, A2A, A3, P2X4, P2X7, P2Y1, P2Y2, and P2Y4 receptors play an important role in the regulation of inflammation in DED: A1 adenosine receptor (A1R) is a systemic pro-inflammatory factor; A2AR is involved in the activation of the MAPK/NF-kB pathway; A3R combined with inhibition of adenylate cyclase and regulation of the mitogen-activated protein kinase (MAPK) pathway leads to regulation of transcription; P2X4 promotes receptor-associated activation of pro-inflammatory cytokines and inflammatory vesicles; P2X7 promotes inflammasome activation and release of pro-inflammatory cytokines IL-1β and IL-18; P2Y receptors affect the phospholipase C(PLC)/IP3/Ca2+ signaling pathway and mucin secretion. These suggested that purinergic receptors would be promising targets to control the inflammation of DED in the future.

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Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities

Cited by 8 publications

References 75 publications

Adenosine Receptors Expression in Human Retina and Choroid with Age-related Macular Degeneration

Adenosine Receptors Expression in Human Retina and Choroid with Age-related Macular Degeneration

Biglycan Involvement in Heart Fibrosis: Modulation of Adenosine 2A Receptor Improves Damage in Immortalized Cardiac Fibroblasts

Targeting purinergic receptors to attenuate inflammation of dry eye

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