Copper oxide nanoparticles (CuO NPs) are used extensively in a variety of applications such as antimicrobial agent, photo-catalyst and gas sensors. The expanding production and widespread utilization ...of CuO NPs may pose risks to individual organisms and ecosystem. Comprehensive understanding the CuO NPs-induced adverse effects and their underlying mechanism are of great importance to assess the environmental risk of CuO NPs and to expand their use safely. However, toxic effects of CuO NPs to individual organisms and the mechanism of their action are still deficient and ambiguities. To ensure the safely use of CuO NPs, more attention should be paid on the long-term and chronic effects of CuO NPs at low concentration. Efforts should be devoted to develop techniques to differentiate toxicities induced by CuO NPs or dissolved Cu2+, and to reduce the toxicity of CuO NPs by controlling the particle diameter, modifying surface characteristic, selecting proper exposure route and regulating the release of Cu2+ from CuO NPs. This review provides a brief overview of toxicity of CuO NPs to individual organisms with a broad range of taxa (microorganisms, algae, plants, invertebrates and vertebrates) and to discuss the underlying toxicity mechanisms including oxidative stress, dynamic unbalance and coordination effects.
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A brief overview of toxicity of CuO NPs to individual organisms with a broad range of taxa is summarized and the mechanisms of their action are discussed.
The Keap1–Nrf2–ARE ((Kelch‐like ECH‐Associating protein 1) nuclear factor erythroid 2 related factor 2‐antioxidant response element) pathway is one of the most important defense mechanisms against ...oxidative and/or electrophilic stresses, and it is closely associated with inflammatory diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and aging. In recent years, progress has been made in strategies aimed at modulating the Keap1–Nrf2–ARE pathway. The Nrf2 activator DMF (Dimethylfumarates) has been approved by the FDA as a new first‐line oral drug to treat patients with relapsing forms of multiple sclerosis, while a phase 3 study of another promising candidate, CDDO‐Me, was terminated for safety reasons. Directly inhibiting Keap1–Nrf2 protein–protein interactions as a novel Nrf2‐modulating strategy has many advantages over using electrophilic Nrf2 activators. The development of Keap1–Nrf2 protein–protein interaction inhibitors has become a topic of intense research, and potent inhibitors of this target have been identified. In addition, inhibiting Nrf2 activity has attracted an increasing amount of attention because it may provide an alternative cancer therapy. This review summarizes the molecular mechanisms and biological functions of the Keap1–Nrf2–ARE system. The main focus of this review is on recent progress in studies of agents that target the Keap1–Nrf2–ARE pathway and the therapeutic applications of such agents.
Oxidative stress was predominantly involved in the pathogenesis of acute kidney injury (AKI). Recent studies had reported the protective role of specific microRNAs (miRNAs) against oxidative stress. ...Hence, we investigated the levels of miR140-5p and its functional role in the pathogenesis of Cisplatin induced AKI. A mice Cisplatin induced-AKI model was established. We found that miR-140-5p expression was markedly increased in mice kidney. Bioinformatics analysis revealed nuclear factor erythroid 2-related factor (Nrf2) was a potential target of miR-140-5p, We demonstrated that miR-140-5p did not affect Kelch-like ECH-associated protein 1 (Keap1) level but directly targeted the 3′-UTR of Nrf2 mRNA and played a positive role in the regulation of Nrf2 expression which was confirmed by luciferase activity assay and western blot. What was more, consistent with miR140-5p expression, the mRNA and protein levels of Nrf2, as well as antioxidant response element (ARE)-driven genes Heme Oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase l (NQO1) were significantly increased in mice kidney tissues. In vitro study, Enforced expression of miR-140-5p in HK2 cells significantly attenuated oxidative stress by decreasing ROS level and increasing the expression of manganese superoxide dismutase (MnSOD). Simultaneously, miR-140-5p decreased lactate dehydrogenase (LDH) leakage and improved cell vitality in HK2 cells under Cisplatin-induced oxidative stress. However, HK2 cells transfected with a siRNA targeting Nrf2 abrogated the protective effects of miR-140-5p against oxidative stress. These results indicated that miR-140-5p might exert its anti-oxidative stress function via targeting Nrf2. Our findings showed the novel transcriptional role of miR140-5p in the expression of Nrf2 and miR-140-5p protected against Cisplatin induced oxidative stress by activating Nrf2-dependent antioxidant pathway, providing a potentially therapeutic target in acute kidney injury.
•miR-140-5p expression was up-regulated in Cisplatin induced AKI.•miR-140-5p directly targeted the 3′-UTR of Nrf2 mRNA.•miR-140-5p activated the Nrf2/ARE signaling pathway and served as an early protective response against oxidative stress.
CCR2 has been proven to play an important role in diabetes. However, the role of CCR2 in diabetic cardiomyopathy has not been examined. In this study, we investigated the effects of cardiac CCR2 on ...diabetic cardiomyopathy. We created a model of streptozotocin (STZ)-induced diabetic cardiomyopathy. Expression of CCR2 was upregulated in the hearts of STZ-induced diabetic mice. CCR2 knockout significantly improved STZ-induced cardiac dysfunction and fibrosis. Moreover, deletion of CCR2 inhibited STZ-induced apoptosis and the production of STZ-induced reactive oxygen species in the heart. CCR2 knockout resulted in M2 polarization in hearts of STZ-treated mice. Treatment with a CCR2 inhibitor reversed hyperglycemia-induced cardiac dysfunction in
mice. These results suggest that CCR2-induced inflammation and oxidative stress in the heart are involved in the development of diabetic cardiomyopathy and that CCR2 could be a novel target for therapy.
Cellular homeostasis requires the sensing of and adaptation to intracellular oxygen (O
) and reactive oxygen species (ROS). The Arg/N-degron pathway targets proteins that bear destabilizing ...N-terminal residues for degradation by the proteasome or via autophagy. Under normoxic conditions, the N-terminal Cys (Nt-Cys) residues of specific substrates can be oxidized by dioxygenases such as plant cysteine oxidases and cysteamine (2-aminoethanethiol) dioxygenases and arginylated by ATE1 R-transferases to generate Arg-CysO
(H) (R-C
). Proteins bearing the R-C
N-degron are targeted via Lys48 (K48)-linked ubiquitylation by UBR1/UBR2 N-recognins for proteasomal degradation. During acute hypoxia, such proteins are partially stabilized, owing to decreased Nt-Cys oxidation. Here, we show that if hypoxia is prolonged, the Nt-Cys of regulatory proteins can be chemically oxidized by ROS to generate Arg-CysO
(H) (R-C
), a lysosomal N-degron. The resulting R-C
is bound by KCMF1, a N-recognin that induces K63-linked ubiquitylation, followed by K27-linked ubiquitylation by the noncanonical N-recognin UBR4. Autophagic targeting of Cys/N-degron substrates is mediated by the autophagic N-recognin p62/SQTSM-1/Sequestosome-1 through recognition of K27/K63-linked ubiquitin (Ub) chains. This Cys/N-degron-dependent reprogramming in the proteolytic flux is important for cellular homeostasis under both chronic hypoxia and oxidative stress. A small-compound ligand of p62 is cytoprotective under oxidative stress through its ability to accelerate proteolytic flux of K27/K63-ubiquitylated Cys/N-degron substrates. Our results suggest that the Nt-Cys of conditional Cys/N-degron substrates acts as an acceptor of O
to maintain both O
and ROS homeostasis and modulates half-lives of substrates through either the proteasome or lysosome by reprogramming of their Ub codes.
Graphical abstract Possible molecular pathways of cytosolic glutathione (GSH) depletion and homocysteine (Hcy) elevation on oxidative stress, apoptosis and Ca2+ entry through TRPM2 and TRPV1 channels ...in hippocampal neurons of aged mice. Vitamin B6 functions as a coenzyme, pyridoxal 5′-phosphate (PLP). In the transsulfuration pathway homocysteine condenses with serine to form cystathionine in a reaction that is catalyzed by cystathionine β-synthase (CBS) and requires PLP. Cystathionine is hydrolyzed by a second PLP-containing enzyme, gamma-cystathionase, to form cysteine. Excess cysteine is oxidized to taurine and inorganic sulfates. It is likely that TRPM2 and TRPV1-mediated cytosolic Ca2+ accumulation in the hippocampus via cytosolic GSH depletion and Hcy elevation involves accumulation of extracellular and intracellular ROS and opening of the mitochondrial permeability transition (MPT) pore that consequently leads to mitochondrial dysfunction. As the oxidative damage and Ca2+ entry increase, molecules such as cytochrome c may be released from mitochondria and trigger apoptosis. At the extreme, oxidative stress and Ca2+ entry cause severe MPT or even the rupture of the mitochondrial membrane, substantial swelling of the mitochondria with rupture of the outer membrane and release of apoptosis-inducing factors such as caspase 3 and 9.
The switch from dark- to light-mediated development is critical for the survival and growth of seedlings, but the underlying regulatory mechanisms are incomplete. Here, we show that the steroids ...phytohormone brassinosteroids play crucial roles during this developmental transition by regulating chlorophyll biosynthesis to promote greening of etiolated seedlings upon light exposure. Etiolated seedlings of the brassinosteroids-deficient
(
) mutant accumulated excess protochlorophyllide, resulting in photo-oxidative damage upon exposure to light. Conversely, the gain-of-function mutant
(
) suppressed the protochlorophyllide accumulation of
, thereby promoting greening of etiolated seedlings. Genetic analysis indicated that phytochrome-interacting factors (PIFs) were required for BZR1-mediated seedling greening. Furthermore, we reveal that GROWTH REGULATING FACTOR 7 (
) and
are induced by BZR1 and PIF4 to repress chlorophyll biosynthesis and promote seedling greening. Suppression of GRFs function by overexpressing
caused an accumulation of protochlorophyllide in the dark and severe photobleaching upon light exposure. Additionally, BZR1, PIF4, and GRF7 interact with each other and precisely regulate the expression of chlorophyll biosynthetic genes. Our findings reveal an essential role for BRs in promoting seedling development and survival during the initial emergence of seedlings from subterranean darkness into sunlight.
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