Redox Signal Transduction Research Articles

A ratiometric fluorescent probe for sensitively tracking peroxynitrite during drug-induced hepatotoxicity.

As one of the essential components of reactive oxygen species (ROS), peroxynitrite (ONOO-) plays an indispensable role in redox homeostasis and signal transduction processes, and its deviant levels are associated with numerous clinical diseases. Therefore, accurate and rapid detection of intracellular ONOO- levels is crucial for revealing its role in physiological and pathological processes. Herein, we constructed a ratiometric fluorescent probe to detect ONOO- levels in biological systems. The probe represents fast reaction rate (within 15 min), outstanding selectivity, good sensitivity (LOD = 13.32 nM) and stability to ONOO-, and it was successfully used for visualizing endogenous ONOO- in living cells. More importantly, it has also been used for tracking the changes of intracellular ONOO- during drug-induced hepatotoxicity with ratiometric fluorescence.

NIR-II Fluorescence/Photoacoustic Dual Ratiometric Probes with Unique Recognition Site for Quantitatively Visualizing H2S2 in Vivo.

Hydrogen persulfide (H2S2) plays a significant role in redox biology and signal transduction; therefore, quantitative visualization of H2S2 in the deep tissue of living organisms is essential for obtaining reliable information about relevant pathophysiological processes directly. However, currently reported H2S2 probes are unsuitable for this purpose because of their poor selectivity for many polysulfide species or their short wavelength, which hinders precise imaging in deep tissues. Herein, for the first time, we report a unique H2S2-mediated dithiole formation reaction. Based on this reaction, we construct the first NIR-II fluorescence (FL) and photoacoustic (PA) dual-ratiometric probe (NIR-II-H2S2) for quantitatively visualizing H2S2 in vivo. This probe shows dual-ratiometric NIR-II fluorescence (I840/I1000, 107-fold) and photoacoustic (PA800/PA900, 6.5-fold) responses towards Na2S2 species with high specificity, excellent sensitivity (1.8 nM), improved water solubility, and deep-tissue penetration. More importantly, using NIR-II dual-ratiometric FL/PA imaging, we successfully demonstrated that the probe could be used to accurately quantify the fluctuating H2S2 levels in the liver-injury mouse models induced by lipopolysaccharides or metformin drugs. Overall, this study not only presents a promising tool for H2S2-related pathological research, but also provides a unique recognition site that may be generalized for designing more useful H2S2 imaging agents in the future.

NIR‐II Fluorescence/Photoacoustic Dual Ratiometric Probes with Unique Recognition Site for Quantitatively Visualizing H2S2in Vivo

AbstractHydrogen persulfide (H2S2) plays a significant role in redox biology and signal transduction; therefore, quantitative visualization of H2S2 in the deep tissue of living organisms is essential for obtaining reliable information about relevant pathophysiological processes directly. However, currently reported H2S2 probes are unsuitable for this purpose because of their poor selectivity for many polysulfide species or their short wavelength, which hinders precise imaging in deep tissues. Herein, for the first time, we report a unique H2S2‐mediated dithiole formation reaction. Based on this reaction, we construct the first NIR‐II fluorescence (FL) and photoacoustic (PA) dual‐ratiometric probe (NIR‐II‐H2S2) for quantitatively visualizing H2S2 in vivo. This probe shows dual‐ratiometric NIR‐II fluorescence (I840/I1000, 107‐fold) and photoacoustic (PA800/PA900, 6.5‐fold) responses towards Na2S2 species with high specificity, excellent sensitivity (1.8 nM), improved water solubility, and deep‐tissue penetration. More importantly, using NIR‐II dual‐ratiometric FL/PA imaging, we successfully demonstrated that the probe could be used to accurately quantify the fluctuating H2S2 levels in the liver‐injury mouse models induced by lipopolysaccharides or metformin drugs. Overall, this study not only presents a promising tool for H2S2‐related pathological research, but also provides a unique recognition site that may be generalized for designing more useful H2S2 imaging agents in the future.

New Horizons in Micro/Nanoplastic-Induced Oxidative Stress: Overlooked Free Radical Contributions and Microbial Metabolic Dysregulations in Anaerobic Digestion.

Excessive production of reactive oxygen species (ROS) induced by micro/nanoplastics (MPs/NPs) is highly toxic to microbes. However, the mechanisms underlying ROS generation and metabolic regulation within anaerobic guilds remain poorly understood. In this study, we investigated the effects of environmentally relevant levels of polypropylene (PP)-MPs/NPs on oxidative stress and microbial ecology during anaerobic digestion (AD). Electron paramagnetic resonance spectroscopy revealed that PP-MPs/NPs elevated the concentrations of environmentally persistent free radicals (EPFRs) and derived hydroxyl radicals (•OH). EPFRs were identified as the primary contributors to •OH generation, as evidenced by a high Spearman correlation coefficient (r = 0.884, p < 0.001) and free radical-quenching studies. The formation of •OH enhanced ROS production by 86.2-100.9%, resulting in decreased cellular viability and methane production (by 37.5-50.5%) at 100 mg/g TS PP-MPs/NPs. Genome-centric metagenomic and metatranscriptomic analyses suggested that PP-MPs/NPs induced the reassembly of community structures, re-evolution of functional traits, and remodeling of interspecies interactions. Specifically, PP-MPs/NPs induced a shift in methanogen consortia from hydrogenotrophic Methanofollis sp. to acetoclastic and hydrogenotrophic Methanothrix soehngenii, primarily because of the latter's diverse ingestion patterns, electron bifurcation complexes, and ROS-scavenging abilities. Downregulation of genes associated with antioxidative defense systems (i.e., sodN, katA, and osmC) and ROS-driven redox signal transduction pathways (c-di-AMP and phosphorylation signaling pathways) provided insights into the mechanisms underlying ROS-induced microbial metabolic dysregulation. Our findings enhance the understanding of microbial ecological and metabolic traits under MPs/NPs stressors, facilitating the control of MPs/NPs toxicity and the stabilization of AD processes.

Redox Regulation of K+ Channel: Role of Thioredoxin.

Significance: Potassium channels regulate the influx and efflux of K+ ions in various cell types that generate and propagate action potential associated with excitation, contraction, and relaxation of various cell types. Although redox active cysteines are critically important for channel activity, the redox regulation of K+ channels by thioredoxin (Trx) has not been systematically reviewed. Recent Advances: Redox regulation of K+ channel is now increasingly recognized as drug targets in the pathological condition of several cardiovascular disease processes. The role of Trx in regulation of these channels and its implication in pathological conditions have not been adequately reviewed. This review specifically focuses on the redox-regulatory role of Trx on K+ channel structure and function in physiological and pathophysiological conditions. Critical Issues: Ion channels, including K+ channel, have been implicated in the functioning of cardiomyocyte excitation-contraction coupling, vascular hyperpolarization, cellular proliferation, and neuronal stimulation in physiological and pathophysiological conditions. Although oxidation-reduction of ion channels is critically important in their function, the role of Trx, redox regulatory protein in regulation of these channels, and its implication in pathological conditions need to be studied to gain further insight into channel function. Future Directions: Future studies need to map all redox regulatory pathways in channel structure and function using novel mouse models and redox proteomic and signal transduction studies, which modulate various currents and altered excitability of relevant cells implicated in a pathological condition. We are yet at infancy of studies related to redox control of various K+ channels and structured and focused studies with novel animal models. Antioxid. Redox Signal. 41, 818-844.

Lipid droplets-targeting multifunctional fluorescent probe and its application in ferroptosis and bioimaging

Unraveling the inherent association between diseases and hypochlorous acid (HOCl), within the microenvironments of lipid droplets (LD) remains a formidable task due to the scarcity of research on multiple disease models. Intracellular HOCl and microenvironments (such as viscosity and polarity), are crucial in upholding redox balance, orchestrating diffusion, transportation and signal transduction within living cells. Nevertheless, the simultaneous visualization of HOCl alongside viscosity and polarity within the milieu of ferroptosis, inflammation, and neoplasia remains unachieved due to the absence of appropriate analytical tools. In response to this pressing need, we have developed an innovative, multifunctional near infrared (NIR) fluorescent probe, termed NCN, capable of simultaneously monitoring HOCl, viscosity, and polarity within lipid droplets. NCN is characterized by its heightened sensitivity to increased viscosity and decreased polarity, which allows it to target LDs with high specificity. Furthermore, the combined application of HOCl, viscosity, and polarity as diagnostic markers for cancer has been triumphantly demonstrated, encompassing cellular and tissue strata as well as in vivo tumor-bearing mouse models. Therefore, our probe offers a reliable means for understanding LD microenvironments and proposes a promising approach for the diagnostic evaluation of diseases.

From ubiquity to specificity: The diverse functions of bacterial thioredoxin systems.

The thioredoxin (Trx) system, found universally, is responsible for the regeneration of reversibly oxidized protein thiols in living cells. This system is made up of a Trx and a Trx reductase, and it plays a central role in maintaining thiol-based redox homeostasis by reducing oxidized protein thiols, such as disulfide bonds in proteins. Some Trxs also possess a chaperone function that is independent of thiol-disulfide exchange, in addition to their thiol-disulfide reductase activity. These two activities of the Trx system are involved in numerous physiological processes in bacteria. This review describes the diverse physiological roles of the Trx system that have emerged throughout bacterial evolution. The Trx system is essential for responding to oxidative and nitrosative stress. Beyond this primary function, the Trx system also participates in redox regulation and signal transduction, and in controlling metabolism, motility, biofilm formation, and virulence. This range of functions has evolved alongside the diversity of bacterial lifestyles and their specific constraints. This evolution can be characterized by the multiplication of the systems and by the specialization of cofactors or targets to adapt to the constraints of atypical lifestyles, such as photosynthesis, insect endosymbiosis, or spore-forming bacteria.

“Three-key-and-lock” near-infrared fluorescent probe for dual-channel tracking ONOO− in mitochondria and viscosity in lysosomes in ferroptosis and drug-induced liver injury

The processes of ferroptosis and drug-induced liver injury (DILI) correlate closely to oxidative stress in mitochondria which will affect intracellular microenvironmental parameters such as lysosomal viscosity. Therefore, it is of great significance to dynamically monitor ONOO− in mitochondria and viscosity in lysosomes for understanding redox signal transduction but remains challenging. Here we report a near-infrared fluorescent probe, HCy-OH-mito, which has the dual-organelle targeting ability for the detection of ONOO− in mitochondria and viscosity in lysosomes via a “three-key-and-lock” strategy. HCy-OH-mito has been successfully applied to independently and simultaneously label mitochondria and lysosomes in live cells, and monitor the fluctuations of ONOO− in mitochondria and viscosity in lysosomes during ferroptosis and APAP-induced liver injury and in live zebrafish.

Genetic loss of Nrf1 and Nrf2 leads to distinct metabolism reprogramming of HepG2 cells by opposing regulation of the PI3K-AKT-mTOR signalling pathway

As a vital hallmarker of cancer, the metabolic reprogramming has been shown to play a pivotal role in tumour occurrence, metastasis and drug resistance. Amongst a vast variety of signalling molecules and metabolic enzymes involved in the regulation of cancer metabolism, two key transcription factors Nrf1 and Nrf2 are required for redox signal transduction and metabolic homeostasis. However, the regulatory effects of Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) on the metabolic reprogramming of hepatocellular carcinoma cells have been not well understood to date. Here, we found that the genetic deletion of Nrf1 and Nrf2 from HepG2 cells resulted in distinct metabolic reprogramming. Loss of Nrf1α led to enhanced glycolysis, reduced mitochondrial oxygen consumption, enhanced gluconeogenesis and activation of the pentose phosphate pathway in the hepatocellular carcinoma cells. By striking contrast, loss of Nrf2 attenuated the glycolysis and gluconeogenesis pathways, but with not any significant effects on the pentose phosphate pathway. Moreover, knockout of Nrf1α also caused fat deposition and increased amino acid synthesis and transport, especially serine synthesis, whilst Nrf2 deficiency did not cause fat deposition, but attenuated amino acid synthesis and transport. Further experiments revealed that such distinctive metabolic programming of between Nrf1α−/− and Nrf2−/− resulted from substantial activation of the PI3K-AKT-mTOR signalling pathway upon the loss of Nrf1, leading to increased expression of critical genes for the glucose uptake, glycolysis, the pentose phosphate pathway, and the de novo lipid synthesis, whereas deficiency of Nrf2 resulted in the opposite phenomenon by inhibiting the PI3K-AKT-mTOR pathway. Altogether, these provide a novel insight into the cancer metabolic reprogramming and guide the exploration of a new strategy for targeted cancer therapy.

A Prognostic Activity of Glutaredoxin 1 Protein (Grx1) in Colon Cancer.

Glutaredoxin 1 (Grx1) is an essential enzyme that regulates redox signal transduction and repairs protein oxidation by reversing S-glutathionylation, an oxidative modification of protein cysteine residues. Grx1 removes glutathione from proteins to restore their reduced state (protein-SH) and regulate protein-SSG levels in redox signaling networks. Thus, it can exert an influence on the development of cancer. To further investigate this problem, we performed an analysis of Grx1 expression in colon adenocarcinoma samples from the Polish population of patients with primary colon adenocarcinoma (stages I and II of colon cancer) and those with regional lymph node metastasis (stage III of colon cancer). Our study revealed a significant correlation between the expression of Grx1 protein through immunohistochemical analysis and various clinical characteristics of patients, such as histological grade, depth of invasion, angioinvasion, staging, regional lymph node invasion, and PCNA expression. It was found that almost 88% of patients with stage I had high levels of Grx1 expression, while only 1% of patients with stage III exhibited high levels of Grx1 protein expression. Furthermore, the study discovered that high levels of Grx1 expression were present in samples of colon mucosa without any pathological changes. These results were supported by in vitro analysis conducted on colorectal cancer cell lines that corresponded to stages I, II, and III of colorectal cancer, using qRT-PCR and Western blot.

Recent progress in organelle-targeting fluorescent probes for the detection of peroxynitrite.

Peroxynitrite (ONOO-), as an important reactive nitrogen species, plays a pivotal role in the regulation of intracellular redox homeostasis, signal transduction, cell growth and metabolism, and other physiological processes. Organelles are important for regulating ONOO-, and the dysregulation of ONOO- in organelles is closely related to various diseases. Therefore, it is essential to monitor ONOO- in cellular organelles, including mitochondria, lysosome, endoplasmic reticulum (ER), Golgi apparatus, and lipid droplets. However, the latest advances in organelle-targeting ONOO- fluorescent probes have not been reviewed systematically. In this review, we focus on the design, sensing mechanism, and organelle-targeting imaging applications of ONOO- fluorescent probes that were reported since 2018. This review will help to facilitate the comprehension of organelle-targeting fluorescent probes for the detection of ONOO-.

The relationship of redox signaling with the risk for atherosclerosis.

Oxidative balance plays a pivotal role in physiological homeostasis, and many diseases, particularly age-related conditions, are closely associated with oxidative imbalance. While the strategic role of oxidative regulation in various diseases is well-established, the specific involvement of oxidative stress in atherosclerosis remains elusive. Atherosclerosis is a chronic inflammatory disorder characterized by plaque formation within the arteries. Alterations in the oxidative status of vascular tissues are linked to the onset, progression, and outcome of atherosclerosis. This review examines the role of redox signaling in atherosclerosis, including its impact on risk factors such as dyslipidemia, hyperglycemia, inflammation, and unhealthy lifestyle, along with dysregulation, vascular homeostasis, immune system interaction, and therapeutic considerations. Understanding redox signal transduction and the regulation of redox signaling will offer valuable insights into the pathogenesis of atherosclerosis and guide the development of novel therapeutic strategies.

Reactive oxygen species- and nitric oxide-dependent regulation of ion and metal homeostasis in plants.

Deterioration and impoverishment of soil, caused by environmental pollution and climate change, result in reduced crop productivity. To adapt to hostile soils, plants have developed a complex network of factors involved in stress sensing, signal transduction, and adaptive responses. The chemical properties of reactive oxygen species (ROS) and reactive nitrogen species (RNS) allow them to participate in integrating the perception of external signals by fine-tuning protein redox regulation and signal transduction, triggering specific gene expression. Here, we update and summarize progress in understanding the mechanistic basis of ROS and RNS production at the subcellular level in plants and their role in the regulation of ion channels/transporters at both transcriptional and post-translational levels. We have also carried out an in silico analysis of different redox-dependent modifications of ion channels/transporters and identified cysteine and tyrosine targets of nitric oxide in metal transporters. Further, we summarize possible ROS- and RNS-dependent sensors involved in metal stress sensing, such as kinases and phosphatases, as well as some ROS/RNS-regulated transcription factors that could be involved in metal homeostasis. Understanding ROS- and RNS-dependent signaling events is crucial to designing new strategies to fortify crops and improve plant tolerance of nutritional imbalance and metal toxicity.

Investigating Lysosomal Reactive Sulphur Species with Small Molecular Fluorescent Probes

AbstractReactive sulphur species (RSS) play a vital role in cellular redox homeostasis and signal transduction. The lysosome is a vital organelle in eukaryotic cells involved in phagocytosis, digestion and degradation of proteins or damaged organelles, repair of cell membrane and energy metabolism. Lysosomal RSS are closely associated with normal functions of the lysosome, and abnormal RSS homeostasis may lead to lysosomal dysfunction and some serious diseases. Thus, real‐time visualization of lysosomal RSS is of great significance. Due to the prominent advantages of fluorescence imaging technology, many small molecular fluorescent probes for detecting lysosomal RSS have been developed. Herein, we have systematically summarized the versatile small molecular and lysosome‐targetable fluorescent probes available for detecting RSS, including their chemical structures, response mechanisms and bioapplications. In addition, we have highlighted the current status, challenges and developmental prospects for RSS‐responsive small molecular fluorescent probes. We sincerely hope that this review can instruct researchers interested in constructing new fluorescent probes for RSS and draw attention toward the significance of lysosomal RSS.

Glutathione and Glutaredoxin-Key Players in Cellular Redox Homeostasis and Signaling.

This Special Issue of Antioxidants on Glutathione (GSH) and Glutaredoxin (Grx) was designed to collect review articles and original research studies focused on advancing the current understanding of the roles of the GSH/Grx system in cellular homeostasis and disease processes. The tripeptide glutathione (GSH) is the most abundant non-enzymatic antioxidant/nucleophilic molecule in cells. In addition to various metabolic reactions involving GSH and its oxidized counterpart GSSG, oxidative post-translational modification (PTM) of proteins has been a focal point of keen interest in the redox field over the last few decades. In particular, the S-glutathionylation of proteins (protein-SSG formation), i.e., mixed disulfides between GSH and protein thiols, has been studied extensively. This reversible PTM can act as a regulatory switch to interconvert inactive and active forms of proteins, thereby mediating cell signaling and redox homeostasis. The unique architecture of the GSH molecule enhances its relative abundance in cells and contributes to the glutathionyl specificity of the primary catalytic activity of the glutaredoxin enzymes, which play central roles in redox homeostasis and signaling, and in iron metabolism in eukaryotes and prokaryotes under physiological and pathophysiological conditions. The class-1 glutaredoxins are characterized as cytosolic GSH-dependent oxidoreductases that catalyze reversible protein S-glutathionylation specifically, thereby contributing to the regulation of redox signal transduction and/or the protection of protein thiols from irreversible oxidation. This Special Issue includes nine other articles: three original studies and six review papers. Together, these ten articles support the central theme that GSH/Grx is a unique system for regulating thiol-redox hemostasis and redox-signal transduction, and the dysregulation of the GSH/Grx system is implicated in the onset and progression of various diseases involving oxidative stress. Within this context, it is important to appreciate the complementary functions of the GSH/Grx and thioredoxin systems not only in thiol-disulfide regulation but also in reversible S-nitrosylation. Several potential clinical applications have emerged from a thorough understanding of the GSH/Grx redox regulatory system at the molecular level, and in various cell types in vitro and in vivo, including, among others, the concept that elevating Grx content/activity could serve as an anti-fibrotic intervention; and discovering small molecules that mimic the inhibitory effects of S-glutathionylation on dimer association could identify novel anti-viral agents that impact the key protease activities of the HIV and SARS-CoV-2 viruses. Thus, this Special Issue on Glutathione and Glutaredoxin has focused attention and advanced understanding of an important aspect of redox biology, as well as spawning questions worthy of future study.

Structural insights into redox signal transduction mechanisms in the control of nitrogen fixation by the NifLA system

NifL is a conformationally dynamic flavoprotein responsible for regulating the activity of the σ54-dependent activator NifA to control the transcription of nitrogen fixation (nif) genes in response to intracellular oxygen, cellular energy, or nitrogen availability. The NifL-NifA two-component system is the master regulatory system for nitrogen fixation. NifL serves as a sensory protein, undergoing signal-dependent conformational changes that modulate its interaction with NifA, forming the NifL-NifA complex, which inhibits NifA activity in conditions unsuitable for nitrogen fixation. While NifL-NifA regulation is well understood, these conformationally flexible proteins have eluded previous attempts at structure determination. In work described here, we advance a structural model of the NifL dimer supported by a combination of scattering techniques and mass spectrometry (MS)-coupled structural analyses that report on the average structure in solution. Using a combination of small angle X-ray scattering-derived electron density maps and MS-coupled surface labeling, we investigate the conformational dynamics responsible for NifL oxygen and energy responses. Our results reveal conformational differences in the structure of NifL under reduced and oxidized conditions that provide the basis for a model for modulating NifLA complex formation in the regulation of nitrogen fixation in response to oxygen in the model diazotroph, Azotobacter vinelandii.

Inhibition of HAdV-14 induced apoptosis by selenocystine through ROS-mediated PARP and p53 signaling pathways

BackgroundHuman Adenovirus (HAdV) can cause severe respiratory symptoms in people with low immunity and there is no targeted treatment for adenovirus infection. Anti-adenoviral drugs have high clinical significance for inhibiting adenovirus infection. Selenium (Se) plays an important role in anti-oxidation, redox signal transduction, and redox homeostasis. The excellent biological activity of Se is mainly achieved by being converted into selenocystine (SeC). Se participates in the active sites of various selenoproteins in the form of SeC. The ability of SeC to resist the virus has raised high awareness due to its unique antioxidative activity in recent years. The antiviral ability of the SeC was determined by detecting the infection rate of the virus in the cells. MethodsThe experiment mainly investigated the antiviral mechanism of SeC by locating the virus in the cell, detecting the generation of ROS, observing the DNA status of the cell, and monitoring the mitochondrial membrane potential. ResultsIn the present study, SeC was designed to resist A549 cells infections caused by HAdV-14. SeC could prevent HAdV-14 from causing cell apoptosis-related to DNA damage. SeC significantly inhibited ROS generation and protect the cells from oxidative damage induced by ROS against HAdV-14. SeC induced the increase of antiviral cytokines such as IL-6 and IL-8 by activating the Jak2 signaling pathway, and repaired DNA lesions by suppressing ATR, p53, and PARP signaling pathways. ConclusionSeC might provide an effective selenium species with antiviral properties for the therapies against HAdV-14.

H2S regulates redox signaling downstream of cardiac β-adrenergic receptors in a G6PD-dependent manner

Stimulating β-adrenergic receptors (β-AR) culminates in pathological hypertrophy – a condition underlying multiple cardiovascular diseases (CVDs). The ensuing signal transduction network appears to involve mutually communicating phosphorylation-cascades and redox signaling modules, although the regulators of redox signaling processes remain largely unknown. We previously showed that H2S-induced Glucose-6-phosphate dehydrogenase (G6PD) activity is critical for suppressing cardiac hypertrophy in response to adrenergic stimulation. Here, we extended our findings and identified novel H2S-dependent pathways constraining β-AR-induced pathological hypertrophy. We demonstrated that H2S regulated early redox signal transduction processes – including suppression of cue-dependent production of reactive oxygen species (ROS) and oxidation of cysteine thiols (R-SOH) on critical signaling intermediates (including AKT1/2/3 & ERK1/2). Consistently, the maintenance of intracellular levels of H2S dampened the transcriptional signature associated with pathological hypertrophy upon β-AR-stimulation, as demonstrated by RNA-seq analysis. We further prove that H2S remodels cell metabolism by promoting G6PD activity to enforce changes in the redox state that favor physiological cardiomyocyte growth over pathological hypertrophy. Thus, our data suggest that G6PD is an effector of H2S-mediated suppression of pathological hypertrophy and that the accumulation of ROS in the G6PD-deficient background can drive maladaptive remodeling. Our study reveals an adaptive role for H2S relevant to basic and translational studies. Identifying adaptive signaling mediators of the β-AR-induced hypertrophy may reveal new therapeutic targets and routes for CVD therapy optimization.

Multifunctional Fluorescent Probe for Simultaneous Detection of ONOO-, Viscosity, and Polarity and Its Application in Ferroptosis and Cancer Models.

Intracellular peroxynitrite anions (ONOO-) and microenvironments (such as viscosity and polarity) play an important role in maintaining redox homeostasis, regulating diffusion, transportation, and signal transduction in living cells. The abnormality of these factors is often closely related to various physiological/pathological processes. However, owing to the lack of suitable probes, the simultaneous visualization of ONOO-, viscosity, and polarity in ferroptosis and cancer models has not been achieved. To meet urgent needs, we presented a multifunctional near-infrared (NIR) fluorescent probe, named MQA-P, for simultaneously detecting ONOO-, viscosity, and polarity within mitochondria. The probe exhibited a remarkable turn-on response to ONOO- with the far-red emission of about 645 nm and was highly sensitive to viscosity/polarity in the NIR channel with λem > 704 nm. Facilitated by MQA-P, for the first time, we revealed that erastin-induced ferroptosis was accompanied by a significant upregulation of ONOO- and an increase of viscosity (or decrease of polarity) at the same time. Moreover, the concurrent use of ONOO-, viscosity, and polarity for the diagnosis of cancer has been successfully achieved not only at cell/tissue levels but also in tumor mice models. Compared with detecting only one factor, this simultaneous detection of multimarkers provides a more sensitive and reliable method/tool for tracking ferroptosis-related pathological processes and cancer diagnosis, holding great potential in preclinical research, medical diagnosis, and imaging-guided surgery.

The cellular redox status and signal transduction in cadmium-induced acclimation responses

The cellular redox status and signal transduction in cadmium-induced acclimation responses