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Possible toxicity mechanisms of GFNs
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Possible toxicity mechanisms of GFNs
Although some physicochemical properties and the toxicity of GFNs have been well studied by many scholars, the exact mechanisms underlying the toxicity of GFNs remain obscure. A schematic of the main mechanisms of GFNs cytotoxicity is illustrated in Fig. 3.
Fig. 3
Schematic diagram showed the possible mechanisms of GFNs cytotoxicity. GFNs get into cells through different ways, which induce in ROS generation, LDH and MDA increase, and Ca2+ release. Subsequently, GFNs cause kinds of cell injury, for instance, cell membrane damage, inflammation, DNA damage, mitochondrial disorders, apoptosis or necrosis
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Physical destruction
Graphene is a unique nanomaterial compared with other spherical or one-dimensional nanoparticles due to its two-dimensional structure with sp2-carbons. The physical interaction of graphene nanoparticles with cell membranes is one of the major causes of graphene cytotoxicity [7, 170, 171]. Graphene has high capability to bind with the α -helical structures of peptides because of its favourable surface curvature [172]. At concentration above 75 μ g/mL, pristine graphene largely adhered to the surfaces of RAW 264. 7 cells and resulted in abnormal stretching of the cell membrane [104]. The strong hydrophobic interactions of GFNs with the cell membrane lead to the morphological extension of F-actin filopodial and cytoskeletal dysfunction. Furthermore, the sharpened edges of GNS may act as ‘blades’, inserting and cutting through bacterial cell membranes [173]. Moreover, GO also damaged the outer membrane of E. coli bacteria directly, resulting in the release of intracellular components [173]. However, TEM imaging revealed that pre-coating GO with FBS eliminated the destruction of cell membranes [166].
ROS production leading to oxidative stress
Oxidative stress arises when increasing levels of ROS overwhelm the activity of antioxidant enzymes, including catalase, SOD, or glutathione peroxidase (GSH-PX) [174]. ROS act as second messengers in many intracellular signalling cascades and lead to cellular macromolecular damage, such as membrane lipid breakdown, DNA fragmentation, protein denaturation and mitochondrial dysfunction, which greatly influence cell metabolism and signalling [175–177]. The interactions of GO with cells can lead to excessive ROS generation, which is the first step in the mechanisms of carcinogenesis, ageing, and mutagenesis [83, 122]. Oxidative stress had a significant role in GO-induced acute lung injury [30], and the inflammatory responses caused by oxidative stress often emerged upon exposure to GFNs [133, 177, 178]. The activity of SOD and GSH-PX decreased after exposed to GO in a time- and dosage-dependent manner [82, 106, 119]. Similarly, oxidative stress was the key cause of apoptosis and DNA damage after HLF cells were exposed to GO [148]. Both the mitogen-activated protein kinase (MAPK) (JNK, ERK and p38) and TGF-beta-related signalling pathways were triggered by ROS generation in pristine graphene-treated cells, accompanied by the activation of Bim and Bax, which are two pro-apoptotic members of the Bcl-2 protein family. As a result, caspase-3 and its downstream effector proteins such as PARP were activated, and apoptosis was initiated [83, 179]. Detailed information regarding the MAPK-, TGF-β - and TNF-α -related signalling pathways, which induce inflammation, apoptosis and necrosis, are summarized in Fig. 4.
Fig. 4
Schematic diagram of MAPKs, TGF-beta and TNF-α dependent pathways involved in GFNs toxicity. ROS was the main factors activating the MAPKs and TGF-beta signaling pathways to lead to the activation of Bim and Bax, triggering the cascade of caspases and JNK pathway. The activation of caspase 3 and RIP1 resulted in apoptosis and necrosis finally
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