Scutellarein alleviates the dysfunction of inner blood-retinal-barrier initiated by hyperglycemia-stimulated microglia cells

Han, Li; Mei, Xiyu; Wang, Meng-Na; Zhang, Tianyu; Zhang, Yue; Lü, Bin; Sheng, Yuchen

doi:10.18240/ijo.2020.10.05

Cited by 10 publications

(24 citation statements)

References 27 publications

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“…Retinal capillary leakage assay was analyzed by previously reported methods with modifications [ 15 , 16 , 17 , 18 ]. Briefly, the mixture of tetramethylrhodamine isothiocyanate conjugate Concanavalin A (TRITC-ConcanavalinA) (indicating vascularity, 25 μg/g, Cat#C860, Thermo Fisher Scientific, MA, USA) and FITC-dextran (indicating vascular leakage, 50 μg/g, Cat#46945, Sigma-Aldrich, St. Louis, MO, USA) were injected into the superior vena cava.…”

Section: Methodsmentioning

confidence: 99%

C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood–Retinal Barrier Tight Junctions

Yan

Wang

Meng

et al. 2022

Cells

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Background The impairment of the inner blood–retinal barrier (iBRB) increases the pathological development of diabetic retinopathy (DR), a severe complication in diabetic patients. Identifying approaches to preserving iBRB integrity and function is a significant challenge in DR. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly discovered adipokine and a vital biomarker, predicting DR severity. We sought to determine whether and how CTRP3 affects the pathological development of non-proliferative diabetic retinopathy (NPDR). Methods To clarify the pathophysiologic progress of the blood–retinal barrier in NPDR and explore its potential mechanism, a mouse Type 2 diabetic model of diabetic retinopathy was used. The capillary leakage was assessed by confocal microscope with fluorescent-labeled protein in vivo. Furthermore, the effect of CTRP3 on the inner blood–retinal barrier (iBRB) and its molecular mechanism was clarified. Results The results demonstrated that CTRP3 protects iBRB integrity and resists the vascular permeability induced by DR. Mechanistically, the administration of CTRP3 activates the AMPK signaling pathway and enhances the expression of Occludin and Claudin-5 (tight junction protein) in vivo and in vitro. Meanwhile, CTRP3 improves the injury of human retinal endothelial cells (HRMECs) induced by high glucose/high lipids (HG/HL), and its protective effects are AMPK-dependent. Conclusions In summary, we report, for the first time, that CTRP3 prevents diabetes-induced retinal vascular permeability via stabilizing the tight junctions of the iBRB and through the AMPK-dependent Occludin/Claudin-5 signaling pathway, thus critically affecting the development of NPDR.

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Section: Methodsmentioning

confidence: 99%

C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood–Retinal Barrier Tight Junctions

Yan

Wang

Meng

et al. 2022

Cells

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“…Despite the great variability among studies, including differences in glucose concentration, exposure time and cell type, many approaches concur that HG treatment triggers the overexpression of classically considered "pro-inflammatory" markers, including ionized calcium-binding adapter molecule 1 (Iba1) [12,[20][21][22][23][24], cluster of differentiation (CD)68 [8,13]; high mobility group box-1 protein (HMGB1) [17,25] and CD11b [15,26], and concomitantly downregulates the expression of "anti-inflammatory" microglial markers, such as CD206 [8,17] and arginase-1 [26]. Interestingly, ASK1 increases CD68, tumor necrosis factor alpha (TNF-α) and IL-6 expression while concomitantly decreases CD206 and IL-10 expression [8].…”

Section: High Glucosementioning

confidence: 99%

“…Moreover, HG-triggered ASK1 activation promotes miR-Let7A expression and, conversely, Let7A reduces ASK1 activation, exerting an "anti-inflammatory like" effect on microglia by reverting ASK1-mediated N-Myc and c-Myc activation [8]. Accordingly, HG exposure on microglia upregulates pro-inflammatory mediators, such as TNF-α [8, 11, 15, 17, 18, 21-24, 26, 26-28]; IL-6 [8,11,15,22,23,26,29,30], IL-1β [11, 12, 17, 18, 21-23, 28, 31, 32]; interferon-gamma (IFN-γ) [30]; GRO, which is a rat ortholog of human IL-8 [11,14]; inducible nitric oxide synthase (iNOS) [18,26]; nitric oxide (NO) and prostaglandin E2 [18] and monocyte chemoattractant protein 1 (MCP-1, also referred to as CCL2) [27]. Remarkably, exposure of human microglia to chronic long-term hyperglycemia (up to 12 days in culture) revealed that dynamic changes of microglial phenotypes are mediated by extracellular signal-regulated kinase (ERK)5 signaling [33].…”

Section: High Glucosementioning

confidence: 99%

“…Regarding the pathways activated by d-glucose, HG induces reactive oxygen species (ROS) formation [14,16,23,27] and subsequent activation of oxidative-stress induced pathways, including protein kinase C [14] and nuclear factor kappa B (NF-κB) [27], whose activation result in inflammatory responses. In fact, HG activates the NF-κB pathway at different levels: toll-like receptor 4 (TLR4) upregulation [18], increased phosphorylation of NF-κB p65 subunit [15,23], IKK and IκB (inhibitors of NF-κB kinase) [22], and nuclear translocation from cytosol to nucleus of p65 [18,21,22,25] and early growth response protein 1 [23]. Accordingly, HG induces matrix metalloproteinase-9 overexpression via HMGB1/TLR4/ p38/NF-κB signaling pathway [25].…”

Section: High Glucosementioning

confidence: 99%

“…Accordingly, HG induces matrix metalloproteinase-9 overexpression via HMGB1/TLR4/ p38/NF-κB signaling pathway [25]. In addition, HG treatment activates mitogen-activated protein kinase (MAPK) cascades, including p38 MAPK pathway [25], ERK1/2 phosphorylation [21][22][23][24], as well as its upstream kinases cRaf and mitogen-activated protein kinase kinase (MEK)1/2 [21,23,24]. HG induces hypoxia-inducible factor 1-alpha (HIF-1α) translocation into the nucleus, where it acts as a master transcription factor for regulating the expression of vascular endothelial growth factor (VEGF) [20,34], and such activation is mediated by ERK1/2 pathway [34].…”

Section: High Glucosementioning

confidence: 99%

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Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

Vargas-Soria

García-Alloza

Corraliza-Gomez

2023

J Neuroinflammation

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Diabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of blood glucose can damage multiple organs, including the brain. In fact, cognitive decline and dementia are increasingly being recognized as important comorbidities of diabetes. Despite the largely consistent link between diabetes and dementia, the underlying causes of neurodegeneration in diabetic patients remain to be elucidated. A common factor for almost all neurological disorders is neuroinflammation, a complex inflammatory process in the central nervous system for the most part orchestrated by microglial cells, the main representatives of the immune system in the brain. In this context, our research question aimed to understand how diabetes affects brain and/or retinal microglia physiology. We conducted a systematic search in PubMed and Web of Science to identify research items addressing the effects of diabetes on microglial phenotypic modulation, including critical neuroinflammatory mediators and their pathways. The literature search yielded 1327 records, including 18 patents. Based on the title and abstracts, 830 papers were screened from which 250 primary research papers met the eligibility criteria (original research articles with patients or with a strict diabetes model without comorbidities, that included direct data about microglia in the brain or retina), and 17 additional research papers were included through forward and backward citations, resulting in a total of 267 primary research articles included in the scoping systematic review. We reviewed all primary publications investigating the effects of diabetes and/or its main pathophysiological traits on microglia, including in vitro studies, preclinical models of diabetes and clinical studies on diabetic patients. Although a strict classification of microglia remains elusive given their capacity to adapt to the environment and their morphological, ultrastructural and molecular dynamism, diabetes modulates microglial phenotypic states, triggering specific responses that include upregulation of activity markers (such as Iba1, CD11b, CD68, MHC-II and F4/80), morphological shift to amoeboid shape, secretion of a wide variety of cytokines and chemokines, metabolic reprogramming and generalized increase of oxidative stress. Pathways commonly activated by diabetes-related conditions include NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, AGEs/RAGE and Akt/mTOR. Altogether, the detailed portrait of complex interactions between diabetes and microglia physiology presented here can be regarded as an important starting point for future research focused on the microglia–metabolism interface.

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Review on the pharmacological effects and pharmacokinetics of scutellarein

Lai,

2024

Archiv der Pharmazie

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Scutellarein is a flavonoid from Scutellaria baicalensis Georgi that has been shown to have a variety of pharmacological activities. This review aims to summarize the pharmacological and pharmacokinetic studies on scutellarein and provide useful information for relevant scholars. Pharmacological studies indicate that scutellarein possesses a diverse range of pharmacological properties, including but not limited to anti‐inflammatory, antioxidant, antiviral, neuroprotective, hypoglycemic, hypolipidemic, anticancer, and cardiovascular protective effects. Further investigation reveals that the pharmacological effects of scutellarein are driven by multiple mechanisms. These mechanisms encompass the scavenging of free radicals, inhibition of the activation of inflammatory signaling pathways and expression of inflammatory mediators, inhibition of the activity of crucial viral proteins, suppression of gluconeogenesis, amelioration of insulin resistance, improvement of cerebral ischemia‐reperfusion injury, induction of apoptosis in cancer cells, and prevention of myocardial hypertrophy, among others. In summary, these pharmacological studies suggest that scutellarein holds promise for the treatment of various diseases. It is imperative to conduct clinical studies to further elucidate the therapeutic effects of scutellarein. However, it is worth noting that studies on the pharmacokinetics reveal an inhibitory effect of scutellarein on uridine 5′‐diphosphate glucuronide transferases and cytochrome P450 enzymes, potentially posing safety risks.

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Scutellarein alleviates the dysfunction of inner blood-retinal-barrier initiated by hyperglycemia-stimulated microglia cells

Cited by 10 publications

References 27 publications

C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood–Retinal Barrier Tight Junctions

C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood–Retinal Barrier Tight Junctions

Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

Review on the pharmacological effects and pharmacokinetics of scutellarein

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