Sustained Inhibition of NF-κB Activity Mitigates Retinal Vasculopathy in Diabetes

Homme, Rubens P.; Sandhu, Harpal S.; George, Akash K.; Tyagi, Suresh C.; Singh, Mahavir

doi:10.1016/j.ajpath.2021.01.016

Cited by 18 publications

(17 citation statements)

References 103 publications

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“…109,110 Interestingly, the NF-κB pathway also had a similar effect. 58 Our findings demonstrated that the IL-17A/NF-κB signaling pathway was activated in the rat model induced by aldosterone, which is consistent with the previous results of RNA sequencing of rats RPE-choroid complexes 24 h after aldosterone intravitreal injection. 61 Based on the characteristics of the IL-17 and NF-κB, the effect of melatonin on the IL-17A/NF-κB signaling pathway activation is also a hotspot in recent research.…”

Section: Discussionsupporting

confidence: 92%

“…Melatonin reduced aldosteroneinduced the expression of inflammatory factors in rat eyesInflammatory response was intensively implicated in the barrier dysfunction,58 several inflammatory cytokines, chemokines, and adhesion molecules were examined in aldosterone-injected eyes with or without melatonin treatment. The results of Western blot (Figure7A) revealed that the levels of cyclooxygenase-2 (COX-2), chemokine C-X-C motif ligand 1 (CXCL-1), MMP-2, and MMP-9 were upregulated significantly compared with the control group, and intraperitoneal injection of melatonin in advance reduced the expression of these factors (Figure7B-E, *p < .05, **p < .01, ***p < .001, and ****p < .0001).…”

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confidence: 99%

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Melatonin prevents experimental central serous chorioretinopathy in rats

Cui

et al. 2022

Journal of Pineal Research

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Central serous chorioretinopathy (CSC) is a vision‐threatening disease with no validated treatment and unclear pathogenesis. It is characterized by dilation and leakage of choroidal vasculature, resulting in the accumulation of subretinal fluid, and serous detachment of the neurosensory retina. Numerous studies have demonstrated that melatonin had multiple protective effects against endothelial dysfunction, vascular inflammation, and blood–retinal barrier (BRB) breakdown. However, the effect of melatonin on CSC, and its exact pathogenesis, is not well understood thus far. In this study, an experimental model was established by intravitreal injection of aldosterone in rats, which mimicked the features of CSC. Our results found that melatonin administration in advance significantly inhibited aldosterone‐induced choroidal thickening and vasodilation by reducing the expression of calcium‐activated potassium channel KCa2.3, and attenuated tortuosity of choroid vessels. Moreover, melatonin protected the BRB integrity and prevented the decrease in tight junction protein (ZO‐1, occludin, and claudin‐1) levels in the rat model induced by aldosterone. Additionally, the data also showed that intraperitoneal injection of melatonin in advance inhibited aldosterone‐induced macrophage/microglia infiltration, and remarkably diminished the levels of inflammatory cytokines (interleukin‐6 [IL‐6], IL‐1β, and cyclooxygenase‐2), chemokines (chemokine C–C motif ligand 3, and C–X–C motif ligand 1), and matrix metalloproteinases (MMP‐2 and MMP‐9). Luzindole, as the nonselective MT1 and MT2 antagonist, and 4‐phenyl‐2‐propionamidotetraline, as the selective MT2 antagonist, neutralized the melatonin‐induced inhibition of choroidal thickening and choroidal vasodilation, indicating that melatonin might exert the effects via binding to its receptors. Furthermore, the IL‐17A/nuclear factor‐κB signaling pathway was activated by intravitreal administration of aldosterone, while it was suppressed in melatonin‐treated in advance rat eyes. This study indicates that melatonin could serve as a promising safe therapeutic strategy for CSC patients.

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

Melatonin prevents experimental central serous chorioretinopathy in rats

Cui

et al. 2022

Journal of Pineal Research

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“…Therefore, we investigated whether NF-κB has a role in MK production upon TLR triggering in macrophages and dendritic cells. This was done by assessing the effect of 5 μM JSH-23 (Sigma-Aldrich, Germany), a selective inhibitor of NF-κB [ 40 , 41 ] that inhibits its activity by blocking NF-κB p65 translocation [ 42 , 43 ], on the production of MK upon PBMCs, macrophages and MDDCs (n = 4 for each) triggering with 20 and 40 ng/ml LPS. The treatment of PBMCs with JSH-23 decreased the production of MK to 30% and 32.5%, induced with 20 and 40 ng/ml of LPS, respectively, compared to that induced by LPS ( p = 0.0028 and 0.018, respectively; Fig 3C ).…”

Section: Resultsmentioning

confidence: 99%

“…Our results showed that the selective inhibitor of NF-κB [ 40 , 41 ], JSH-23, which inhibits its activity by blocking NF-κB p65 translocation [ 42 , 43 ], inhibited MK production by macrophages and MDDCs upon stimulation with LPS. JSH-23, blocks inflammatory cytokine production induced by LPS [ 43 ] and it was used to study effects of NF-kB inhibition on biological activities [ 41 , 42 , 65 , 66 ]. NF-kB inhibitors are used to demonstrate its implication in the production of different molecules including MK [ 38 , 40 , 65 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

Human macrophages and monocyte-derived dendritic cells stimulate the proliferation of endothelial cells through midkine production

et al. 2022

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The cytokine midkine (MK) is a growth factor that is involved in different physiological processes including tissue repair, inflammation, the development of different types of cancer and the proliferation of endothelial cells. The production of MK by primary human macrophages and monocyte-derived dendritic cells (MDDCs) was never described. We investigated whether MK is produced by primary human monocytes, macrophages and MDDCs and the capacity of macrophages and MDDCs to modulate the proliferation of endothelial cells through MK production. The TLR stimulation of human monocytes, macrophages and MDDCs induced an average of ≈200-fold increase in MK mRNA and the production of an average of 78.2, 62, 179 pg/ml MK by monocytes, macrophages and MDDCs respectively (p < 0.05). MK production was supported by its detection in CD11c+ cells, CLEC4C+ cells and CD68+ cells in biopsies of human tonsils showing reactive lymphoid follicular hyperplasia. JSH-23, which selectively inhibits NF-κB activity, decreased the TLR-induced production of MK in PMBCs, macrophages and MDDCs compared to the control (p < 0.05). The inhibition of MK production by macrophages and MDDCs using anti-MK siRNA decreased the capacity of their supernatants to stimulate the proliferation of endothelial cells (p = 0.01 and 0.04 respectively). This is the first study demonstrating that the cytokine MK is produced by primary human macrophages and MDDCs upon TLR triggering, and that these cells can stimulate endothelial cell proliferation through MK production. Our results also suggest that NF-κB plays a potential role in the production of MK in macrophages and MDDCs upon TLR stimulation. The production of MK by macrophages and MDDCs and the fact that these cells can enhance the proliferation of endothelial cells by producing MK are novel immunological phenomena that have potentially important therapeutic implications.

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“…In the past, special attention has been paid to the role of AR in its pathogenesis. Several associations between AR and early diabetic retinopathy have been described in detail, including the localization of AR in the retina; the role for increased AR activity in retinal capillary cell loss and formation of acellular capillaries, capillary basement membrane thickening, increased vascular permeability, and disruption of the blood-retinal barrier; increased leukocyte adhesion to endothelial cells; neovascularization with advanced proliferative DR (as learnt from animal models of diabetes); and galactose feeding [ 189 , 190 , 191 , 192 ]. Further, potential mechanisms underlying the interactions between AR and other pathogenetic factors such as formation of AGEs; oxidative-nitrosative stress; PKC, MAPK, and poly (ADP-ribose) polymerase activation; inflammation; and growth factor imbalance have been studied [ 193 ].…”

Section: Introductionmentioning

confidence: 99%

Physiological and Pathological Roles of Aldose Reductase

2021

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Aldose reductase (AR) is an aldo-keto reductase that catalyzes the first step in the polyol pathway which converts glucose to sorbitol. Under normal glucose homeostasis the pathway represents a minor route of glucose metabolism that operates in parallel with glycolysis. However, during hyperglycemia the flux of glucose via the polyol pathway increases significantly, leading to excessive formation of sorbitol. The polyol pathway-driven accumulation of osmotically active sorbitol has been implicated in the development of secondary diabetic complications such as retinopathy, nephropathy, and neuropathy. Based on the notion that inhibition of AR could prevent these complications a range of AR inhibitors have been developed and tested; however, their clinical efficacy has been found to be marginal at best. Moreover, recent work has shown that AR participates in the detoxification of aldehydes that are derived from lipid peroxidation and their glutathione conjugates. Although in some contexts this antioxidant function of AR helps protect against tissue injury and dysfunction, the metabolic transformation of the glutathione conjugates of lipid peroxidation-derived aldehydes could also lead to the generation of reactive metabolites that can stimulate mitogenic or inflammatory signaling events. Thus, inhibition of AR could have both salutary and injurious outcomes. Nevertheless, accumulating evidence suggests that inhibition of AR could modify the effects of cardiovascular disease, asthma, neuropathy, sepsis, and cancer; therefore, additional work is required to selectively target AR inhibitors to specific disease states. Despite past challenges, we opine that a more gainful consideration of therapeutic modulation of AR activity awaits clearer identification of the specific role(s) of the AR enzyme in health and disease.

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Sustained Inhibition of NF-κB Activity Mitigates Retinal Vasculopathy in Diabetes

Cited by 18 publications

References 103 publications

Melatonin prevents experimental central serous chorioretinopathy in rats

Melatonin prevents experimental central serous chorioretinopathy in rats

Human macrophages and monocyte-derived dendritic cells stimulate the proliferation of endothelial cells through midkine production

Physiological and Pathological Roles of Aldose Reductase

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