Microcystin-leucine arginine blocks vasculogenesis and angiogenesis through impairing cytoskeleton and impeding endothelial cell migration by downregulating integrin-mediated Rho/ROCK signaling pathway

Wang, Qilong; Chen, Guoliang; Zhang, Qian; Wang, Mingxing; Wang, Guixue; Hu, Tingzhang

doi:10.1007/s11356-021-15337-9

Cited by 9 publications

(3 citation statements)

References 39 publications

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“…The studies of invertebrates were not listed in the tables, but some studies on crustacea ( Penaeus monodon , Daphnia magna , Daphnia similis ) (Bownik and Pawlik-Skowrońska 2019 ; Ferrão-Filho and da Silva 2019 ) and on mollusca ( Elliptio complanata , Helix pomatia ) (Vehovszky et al 2012 ) have been performed. Recently, mass mortalities of sea otters (Miller et al 2010 ), dolphins (Brown et al 2018 ) and African elephants (Wang et al 2021a ) have been attributed to cyanotoxin poisonings, although confirmatory investigations into the elephant deaths are required. If cyanotoxins can cause the deaths of megafauna, it is clear that humans can also be endangered, inter-species variability being taken into account.…”

Section: Discussionmentioning

confidence: 99%

A review and assessment of cyanobacterial toxins as cardiovascular health hazards

et al. 2022

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Eutrophicated waters frequently support bloom-forming cyanobacteria, many of which produce potent cyanobacterial toxins (cyanotoxins). Cyanotoxins can cause adverse health effects in a wide range of organisms where the toxins may target the liver, other internal organs, mucous surfaces and the skin and nervous system. This review surveyed more than 100 studies concerning the cardiovascular toxicity of cyanotoxins and related topics. Over 60 studies have described various negative effects on the cardiovascular system by seven major types of cyanotoxins, i.e. the microcystin (MC), nodularin (NOD), cylindrospermopsin (CYN), anatoxin (ATX), guanitoxin (GNTX), saxitoxin (STX) and lyngbyatoxin (LTX) groups. Much of the research was done on rodents and fish using high, acutely toxin concentrations and unnatural exposure routes (such as intraperitoneal injection), and it is thus concluded that the emphasis in future studies should be on oral, chronic exposure of mammalian species at environmentally relevant concentrations. It is also suggested that future in vivo studies are conducted in parallel with studies on cells and tissues. In the light of the presented evidence, it is likely that cyanotoxins do not constitute a major risk to cardiovascular health under ordinary conditions met in everyday life. The risk of illnesses in other organs, in particular the liver, is higher under the same exposure conditions. However, adverse cardiovascular effects can be expected due to indirect effects arising from damage in other organs. In addition to risks related to extraordinary concentrations of the cyanotoxins and atypical exposure routes, chronic exposure together with co-existing diseases could make some of the cyanotoxins more dangerous to cardiovascular health.

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Section: Discussionmentioning

confidence: 99%

A review and assessment of cyanobacterial toxins as cardiovascular health hazards

et al. 2022

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“…These seemingly contradictory results suggested that MET plays different roles under different metabolic environments. To investigate the role of MET in damaged TM cells and ocular hypertension (OHT) mouse models, we used tert-butyl hydroperoxide (tBHP) to induce oxidative damage in TM cells ( Tang et al, 2013 ; Wang et al, 2021 ) and topical glucocorticoids to create OHT mouse models ( Li et al, 2021 ). The results showed that MET protected against cytoskeletal destruction in TM by activating the integrin/ROCK pathway and alleviated elevated IOP in steroid-induced OHT mouse models.…”

Section: Introductionmentioning

confidence: 99%

Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals

Zhang

Zhao

et al. 2023

eLife

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This study aimed to investigate the protective effect of metformin on trabecular meshwork (TM) and explore its molecular mechanisms in vivo and in vitro. Ocular hypertension (OHT) mouse models were induced with dexamethasone and further treated with metformin to determine the intraocular pressure (IOP)-lowering effect. Cultured human TM cells (HTMCs) were pre-stimulated with tert-butyl hydroperoxide (tBHP) to induce oxidative damage and then supplemented with metformin for another 24 hr. The expression of fibrotic markers and integrin/Rho-associated kinase (ROCK) signals, including α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), fibronectin, integrin beta 1, ROCK 1/2, AMP-activated protein kinase, myosin light chain 1, and F-actin were determined by western blotting and immunofluorescence. Reactive oxygen species (ROS) content was analysed using flow cytometry. Transmission electron microscopy was performed to observe microfilaments in HTMCs. It showed that metformin administration reduced the elevated IOP and alleviated the fibrotic activity of aqueous humour outflow in OHT models. Additionally, metformin rearranged the disordered cytoskeleton in the TM both in vivo and in vitro and significantly inhibited ROS production and activated integrin/ROCK signalling induced by tBHP in HTMCs. These results indicated that metformin reduced the elevated IOP in steroid-induced OHT mouse models and exerted its protective effects against oxidative injury by regulating cytoskeleton remodelling through the integrin/ROCK pathway. This study provides new insights into metformin use and preclinical evidence for the potential treatment of primary open-angle glaucoma.

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“…Excessive reactive oxygen species (ROS) in TM play an important role in the disruption of cytoskeletal integrity and apoptosis ( Hu, et al,2017 ), leading to pathological alterations in AHO and subsequent IOP rise ( Babizhayev and Bunin,1989 ; Sacca, et al,2016 ). To investigate the role of metformin in damaged TM cells and ocular hypertension (OHT) mouse models, we used tert-butyl hydroperoxide (tBHP) to induce oxidative damage in TM cells ( Tang, et al,2013 ; Wang, et al,2021 ) and topical glucocorticoids to create OHT mouse models ( Li, et al,2021 ). The results showed that metformin protected against cytoskeletal destruction in TM by enhancing the integrin/ROCK pathway and alleviated elevated IOP in steroid-induced OHT mouse models.…”

Section: Introductionmentioning

confidence: 99%

Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals

Zhang

Yin

et al. 2022

Preprint

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Background: This study aimed to investigate the protective effect of metformin on the trabecular meshwork (TM) and explore its molecular mechanisms in vivo and in vitro. Methods: Ocular hypertension (OHT) mouse models were induced with dexamethasone (DEX) and further treated with metformin to determine its IOP lowering effect. Cultured human TM cells (HTMC) were pre-stimulated with tert-butyl hydroperoxide (tBHP) to induce oxidative damage and then supplemented with metformin for another 24 h. The expression of fibrotic markers and integrin/ROCK signals, including α-SMA, TGF-β, fibronectin, F-actin, integrin beta 1, Rho-associated kinase (ROCK)1/2, AMP-activated protein kinase (AMPK), myosin light chain 1 (MLC 1), and F-actin were determined by western blotting (WB) and immunofluorescence (IF). Reactive oxygen species (ROS) content was analysed using flow cytometry (FCM). Results: Administration of metformin reduced the elevated IOP and alleviated the fibrotic activity of aqueous humour outflow in OHT models. Additionally, metformin rearranged the disordered cytoskeleton in the TM both in vivo and in vitro. Furthermore, metformin significantly inhibited ROS production and activated integrin/ROCK signalling induced by tBHP in HTMC. Conclusion: Metformin reduced the elevated IOP in steroid-induced OHT mouse models and exerted its protective effects against oxidative injury by regulating cytoskeleton remodelling through the integrin/ROCK pathway. This study provides new insights into metformin use and preclinical evidence for the potential treatment of primary open-angle glaucoma. Funding: This work was supported by the Key R&D Program of Zhejiang (2022C03112), Leading Scientific and Technological Innovation Talents in Zhejiang Province (2021R52012), National Key R&D Program of China (2020YFC2008200), Zhejiang Provincial National Science Foundation of China (LQ18H120010), Key Innovation and Guidance Program of the Eye Hospital, School of Ophthalmology & Optometry,Wenzhou Medical University (YNZD 2201903), and the Wenzhou Municipal Technological Innovation Program of High-level Talents (No. 604090352/577).

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Microcystin-leucine arginine blocks vasculogenesis and angiogenesis through impairing cytoskeleton and impeding endothelial cell migration by downregulating integrin-mediated Rho/ROCK signaling pathway

Cited by 9 publications

References 39 publications

A review and assessment of cyanobacterial toxins as cardiovascular health hazards

A review and assessment of cyanobacterial toxins as cardiovascular health hazards

Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals

Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals

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