Dispersible MoS₂ Nanosheets Activated TGF-β/Smad Pathway and Perturbed the Metabolome of Human Dermal Fibroblasts

Abstract

In postgraphene two-dimensional materials (2DMs), MoS2 has attracted increasing attention in the biomedical field due to its excellent physicochemical properties. However, the toxicity and biocompatibility evaluation of MoS2 is not fully addressed. Herein, chitosan functionalized MoS2 (CS-MoS2) nanosheets, which showed perfect dispersibility and stability performances, were synthesized and characterized. We found that CS-MoS2 nanosheets inhibited the viability of human dermal fibroblasts (HDFs) moderately while causing cell membrane instability, ROS generation, and DNA damage in a dosage-dependent manner. CS-MoS2 nanosheets did not induce significant changes in the cell morphologies, but they seemed to impair the cell division of HDFs. CS-MoS2 nanosheets (100 μg/mL) activated EGFR and induced reactive oxygen species, Smad, and IL-1, which in turn led to cell inflammation and apoptosis. Furthermore, HDFs showed cellular stress responses when they were exposed to low concentrations of CS-MoS2 nanosheets (25 and 100 μg/mL) because most of the intracellular metabolites such as amino acids were induced at 25 μg/mL but were inhibited at 100 μg/mL. Pyroglutamic acid, phosphoric acid, and inositol might be used as biomarkers for evaluating the toxicity of CS-MoS2 nanosheets. Additionally, 100 μg/mL CS-MoS2 nanosheets inhibited glutathione metabolism and induced the imbalance of cellular redox homeostasis. It further suppressed the tricarboxylic acid cycle and other metabolic pathways, causing insufficient supply of substrates and energy for HDFs. These findings will fuel the risk assessment of MoS2 and other 2DMs and guide the safe material design and 2DM applications.

<p>Immunostimulatory Potential of MoS₂ Nanosheets: Enhancing Dendritic Cell Maturation, Migration and T Cell Elicitation</p>

“…Actually, whether MSN exposure induces ROS production is still a controversial topic. Yu et al demonstrated that chitosan functionalized MSNs induced ROS accumulation in human dermal cells 37 and in the gills and liver of adult zebrafish. 38 Consistently, Pardo et al 39 found that fullerene-like MSNs could induce robust protective antioxidant/detoxification defenses in human bronchial cells, indicating ROS generation in this cell line.…”

Two-Dimensional Transition Metal Dichalcogenides: Synthesis, Biomedical Applications and Biosafety Evaluation

“…However, the interaction between 2D TMDCs and cells certainly will disturb cell homeostasis. Further biosafety evaluation indicated that 2D TMDCs affected cell behaviors, such as cell proliferation, differentiation (Zou et al, 2017), cell adhesion, spreading (Suhito et al, 2017), oxidative stress (Yang et al, 2014), cell metabolism (Yu Y. et al, 2017), and cell autophagy . Singlelayer MoS 2 nanosheets promoted proliferation and accelerated myogenic differentiation in human embryonic lung fibroblasts (HELFs).…”

“…High levels of oxidative stress induced by single-layer MoS 2 nanosheets caused disturbance to Akt related signaling pathway (Zou et al, 2017) and enhanced antibacterial activity (Yang et al, 2014). In addition, chitosan functionalized MoS 2 nanosheets activated TGF-β/Smad pathway and disturbed cellular metabolic process through interacting with EGFR on human dermal fibroblasts cells surface (Yu Y. et al, 2017). WS 2 nanosheets induced obvious alterations in metabolic pathways and metabolites and the phase composition made a difference on metabolomics in algae (Yuan et al, 2018).…”

“…The existing limited studies have shown that cell viability and some other cell behaviors, such as cell proliferation (Zou et al, 2017), oxidative stress (Yang et al, 2014), cell autophagy , and metabolism (Yu Y. et al, 2017) were affected by 2D TMDCs. In this review, I will give a brief summary based on present progress on the synthesis and surface modification methods, biomedical applications, and biosafety evaluation of 2D TMDCs.…”

Interactions of Transition Metal Dichalcogenide Nanosheets With Mucin: Quartz Crystal Microbalance With Dissipation, Surface Plasmon Resonance, and Spectroscopic Probing

“…However, TMDs could potentially be risky to human health and the environment (Guiney et al, 2015, 2018; Kumar et al, 2017). For example, MoS 2 has been shown to be toxic toward planktonic cells, biofilms, and mammalian cells in the presence of electron donors (Fan et al, 2015), to bind to the K + channels and disturb their functions (Gu et al, 2018), to activate TGF-beta/Smad pathways and perturb the metabolome of human dermal fibroblasts (Yu et al, 2017), and to exhibit cytotoxicity and impact inflammation (Moore et al, 2017).…”