Excessive Levels Of Reactive Oxygen Species Research Articles

The transcription factor LBD10 sustains pollen tube growth and integrity by modulating reactive oxygen species homeostasis via the regulation of flavonol biosynthesis in Arabidopsis.

Reproduction in angiosperms relies on the precise growth of pollen tubes, facilitating the delivery of sperm cells to the ovule for double fertilization. LATERAL ORGAN BOUNDARIES DOMAIN10 (LBD10), a plant-specific transcription factor, plays a pivotal role in Arabidopsis pollen development. Here, we uncovered LBD10's function in sustaining pollen tube growth and integrity. The lbd10 mutant exhibited elevated levels of reactive oxygen species (ROS) and hydrogen peroxide (H2O2) in both pollen grains and tubes, leading to compromised pollen tube growth. The inhibition of ROS synthesis and scavenging of excess ROS with an antioxidant treatment each alleviated these defects in lbd10. The lbd10 mutant displayed reduced flavonol accumulation in both pollen grains and tubes. All the altered phenotypes of lbd10 were complemented by expressing LBD10 under its native promoter. Exogenous application of flavonoids recused the defects in pollen tube growth and integrity in lbd10, along with reducing the excess levels of ROS and H2O2. LBD10 directly binds the promoters of key flavonol biosynthesis genes in chromatin and promotes reporter gene expression in Arabidopsis mesophyll protoplasts. Our findings indicate that LBD10 modulates ROS homeostasis by transcriptionally activating genes crucial for flavonol biosynthesis, thereby maintaining pollen tube growth and integrity.

Multitarget Pharmacology of Sulfur-Nitrogen Heterocycles: Anticancer and Antioxidant Perspectives.

Cancer and oxidative stress are interrelated, with reactive oxygen species (ROS) playing crucial roles in physiological processes and oncogenesis. Excessive ROS levels can induce DNA damage, leading to cancer, and disrupt antioxidant defenses, contributing to diseases like diabetes and cardiovascular disorders. Antioxidant mechanisms include enzymes and small molecules that mitigate ROS damage. However, cancer cells often exploit oxidative conditions to evade apoptosis and promote tumor growth. Antioxidant therapy has shown mixed results, with timing and cancer-type influencing outcomes. Multifunctional drugs targeting multiple pathways offer a promising approach, reducing side effects and improving efficacy. Recent research focuses on sulfur-nitrogen heterocyclic derivatives for their dual antioxidant and anticancer properties, potentially enhancing therapeutic efficacy in oncology. The newly synthesized compounds often do not demonstrate both antioxidant and anticancer properties simultaneously. Heterocyclic rings are typically combined with phenyl groups, where hydroxy substitutions enhance antioxidant activity. On the other hand, electron-withdrawing substituents, particularly at the p-position on the phenyl ring, tend to enhance anticancer activity.

Aging-associated Aberrant Mitochondrial Redox Signaling, Physical Activity, and Sarcopenia.

Aging-related alteration of mitochondrial morphology, impairment in metabolic capacity, bioenergetics, and biogenesis are closely associated with loss of muscle mass and function. Mitochondrial Reactive Oxygen Species (ROS) stimulate muscular redox signaling mechanisms. Bioenergetic integrity of mitochondria and redox signaling dynamics deteriorates in aged skeletal muscle. Mitochondrial bioenergetic impairment leads to excessive ROS levels and induces the generation of defective mitochondria. Higher ROS levels may induce senescence or apoptosis. It is not a resolved issue that mitochondrial dysfunction is either the sole reason or a consequence of muscle loss (or both). However, Increasing evidence emphasizes that dysregulated mitochondrial redox signaling has a central role in age-related muscle loss. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox signaling pathways with the expression of antioxidant genes. As the aberrant redox signaling mechanisms in aging skeletal muscle become clearer, new natural and synthetic Nrf2-modulating substances and integrated daily physical activity alternatives are coming into view for preventing muscle loss in the elderly. A comprehensive understanding of the relationship between redox signaling pathways and age-related sarcopenia can help us to prevent sarcopenia and its frailty effects with an optimized exercise program as an innovative non-pharmacological therapeutic approach. A further aspect is necessary to consider both individualized physical training options and alternative Nrf2 signaling modulators. Ameliorating the redox signaling with physical activity and pharmacological interventions may help to prevent sarcopenia and its frailty effects.

Dual-Targeting EGCG/NO-Supplying protein assembled nanoparticles with Multi-Synergistic effects against atherosclerosis

Limited therapeutic options are available to effectively preventing atherosclerosis. Inflammatory endothelial cells, foamy macrophages, and high protease levels contribute to atherosclerotic plaque formation. Studies have shown that catechins effectively scavenge reactive oxygen species (ROS), inhibit monocyte adhesion and reduce cholesterol levels, while nitric oxide (NO) enhances endothelial function. However, due to the poor stability and bioavailability of catechins and the toxicity from the burst release of current synthetic small molecules NO donor, effective deliveryof these bioactive compounds to treat atherosclerosis is still a challenge. Herein, a catechin/protein-based NO donor co-delivery nanosystem was designed for combinatorial anti-atherosclerotic therapy. We engineered a (−)-epigallocatechin-3-gallate (EGCG)/NO-releasing protein co-assembled nanocomplex based on specific catechin-protein interactions. Furthermore, the nanocomplex was surface modified with fucoidan (Fu), a sulfated polysaccharide with anti-inflammatory activity. This nanocomplex exhibits sensitivity to ROS, pH, and enzymes. The Fu-functionalized nanoparticles specifically accumulates in atherosclerotic plaques mediated by P-selectin on inflamed endothelial cells and scavenger receptor A (SR-A) on foamy macrophages. Under environmental stimuli that simulate the condition of plaque, the nanoparticles are readily activated to release EGCG and NO in response to excess ROS and high protease levels, exerting the multi-synergistic anti-atherosclerosic effects on reducing monocyte adhesion, promoting NO production to proliferate endothelial cells, lowering ROS levels, and decreasing the foam cell formation in vitro, and reducing lipid accumulation, plaque size, and inflammatory cytokines release in high-fat diet-induced atherosclerosis model in ApoE−/− mice. The integration of plaques targeting ability and multiple therapeutic functions can provide an advanced therapeutic strategy foratherosclerosistreatment.

Hydrogen peroxide sensitivity connects the activity of COX5A and NPR3 to the regulation of YAP1 expression.

Reactive oxygen species (ROS) are among the most severe types of cellular stressors with the ability to damage essential cellular biomolecules. Excess levels of ROS are correlated with multiple pathophysiological conditions including neurodegeneration, diabetes, atherosclerosis, and cancer. Failure to regulate the severely imbalanced levels of ROS can ultimately lead to cell death, highlighting the importance of investigating the molecular mechanisms involved in the detoxification procedures that counteract the effects of these compounds in living organisms. One of the most abundant forms of ROS is H2 O2 , mainly produced by the electron transport chain in the mitochondria. Numerous genes have been identified as essential to the process of cellular detoxification. Yeast YAP1, which is homologous to mammalian AP-1 type transcriptional factors, has a key role in oxidative detoxification by upregulating the expression of antioxidant genes in yeast. The current study reveals novel functions for COX5A and NPR3 in H2 O2 -induced stress by demonstrating that their deletions result in a sensitive phenotype. Our follow-up investigations indicate that COX5A and NPR3 regulate the expression of YAP1 through an alternative mode of translation initiation. These novel gene functions expand our understanding of the regulation of gene expression and defense mechanism of yeast against oxidative stress.

Cyanidin-3-O-Glucoside Combined with PGC1α Inhibitor Promotes Cancer Cell Death by Inducing Excessive Levels of ROS in Cervical Squamous Cell Carcinoma

Cervical cancer is a global public health problem, particularly in the low-income and middle-income countries. Natural products, such as cyanidin and its derivative cyanidin-3-O-glucoside (C3G), are considered safe and nontoxic food additives, potent therapeutic options for cancer. The present study aims to evaluate the beneficial effects of C3G on cervical squamous cell carcinoma (CSCC) in vitro and explore more potential therapeutic strategies for CSCC. C3G significantly inhibited the cell growth of CSCC cells and induced cancer cell apoptosis in a dose-dependent manner. Meanwhile, C3G promoted cellular reactive oxygen species (ROS) accumulation and decreased mitochondrial membrane potential and mitochondrial mass. The antioxidant regent N-acetyl-L-cysteine (NAC) rescued the effect of C3G on CSCC cells, further demonstrating ROS’s important role in C3G treatment. To explore the underlying mechanism, autophagy-related signaling pathways were investigated, and the results showed that C3G induced cell autophagy but not mitophagy. More importantly, C3G caused a significant activation of mitochondria biogenesis through the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) signaling pathway. C3G synergized with PGC-1α inhibitor SR-18292 induced more severe ROS accumulation and showed more potent inhibition of cell proliferation and mitochondrial membrane potential than C3G treatment alone. Thus, the present study suggests a new potential therapeutic strategy for CSCC based on the synergistic effect of C3G and PGC1α inhibitors.

Reactive oxygen species signalling in the deterioration of quality of mammalian oocytes cultured in vitro: Protective effect of antioxidants

The in vitro fertilization (IVF) is the first choice of infertile couples worldwide to plan for conception. Besides having a significant advancement in IVF procedure, the success rate is still poor. Although several approaches have been tested to improve IVF protocol, minor changes in culture conditions, physical factors and/or drug treatment generate reactive oxygen species (ROS) in oocytes. Due to large size and huge number of mitochondria, oocyte is more susceptible towards ROS-mediated signalling under in vitro culture conditions. Elevation of ROS levels destabilize maturation promoting factor (MPF) that results in meiotic exit from diplotene as well as metaphase-II (M-II) arrest in vitro. Once meiotic exit occurs, these oocytes get further arrested at metaphase-I (M-I) stage or metaphase-III (M-III)-like stage under in vitro culture conditions. The M-I as well as M-III arrested oocytes are not fit for fertilization and limits IVF outcome. Further, the generation of excess levels of ROS cause oxidative stress (OS) that initiate downstream signalling to initiate various death pathways such as apoptosis, autophagy, necroptosis and deteriorates oocyte quality under in vitro culture conditions. The increase of cellular enzymatic antioxidants and/or supplementation of exogenous antioxidants in culture medium protect ROS-induced deterioration of oocyte quality in vitro. Although a growing body of evidence suggests the ROS and OS-mediated deterioration of oocyte quality in vitro, their downstream signalling and related mechanisms remain poorly understood. Hence, this review article summarizes the existing evidences concerning ROS and OS-mediated downstream signalling during deterioration of oocyte quality in vitro. The use of various antioxidants against ROS and OS-mediated impairment of oocyte quality in vitro has also been explored in order to increase the success rate of IVF during assisted reproductive health management.

Cerium-Luteolin Nanocomplexes in Managing Inflammation-Related Diseases by Antioxidant and Immunoregulation.

Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and the antioxidant defense system, plays a pivotal role in inflammation-related diseases. Excessive ROS levels can induce cellular damage and impair normal physiological functions, triggering the release of inflammatory mediators and exacerbating the inflammatory response, ultimately leading to irreversible tissue damage. In this study, we synthesized cerium ion-luteolin nanocomplexes (CeLutNCs) by coordinating Ce ions with the natural product luteolin, aiming to develop a therapeutic agent with excellent antioxidant and immunoregulation properties for ROS-related inflammation treatment. In vitro experiments demonstrated that the prepared CeLutNCs effectively scavenged excess ROS, prevented cell apoptosis, down-regulated levels of important inflammatory cytokines, regulated the response of inflammatory macrophages, and suppressed the activation of the nuclear factor-κ-gene binding (NF-κB) pathway. In an acute kidney injury (AKI) animal model, CeLutNCs exhibited significant efficacy in improving kidney function, repairing damaged renal tissue, and reducing oxidative stress, inflammatory response, and cellular apoptosis. Moreover, the therapeutic potential of CeLutNCs in an acute lung injury (ALI) model was confirmed through the assessment of inflammatory responses and histopathological studies. This study emphasizes the effectiveness of these metal-natural product coordination nanocomplexes as a promising therapeutic approach for preventing AKI and other diseases associated with oxidative stress.

Antioxidant Polymers with Phenolic Pendants for the Mitigation of Cellular Oxidative Stress.

Overproduction of reactive oxygen species (ROS) in cells is a major health concern as it may lead to various diseases through oxidative damage of biomolecules. Commonly used traditional small molecular antioxidants (polyphenols, carotenoids, vitamins, etc.) have inadequate efficacy in lowering excessive levels of ROS due to their poor aqueous solubility and bioavailability. In response to the widespread occurrence of antioxidant polyphenols in various biorenewable resources, we aimed to develop water-soluble antioxidant polymers with side chain phenolic pendants. Four different types of copolymers (P1-P4) containing phenyl rings with different numbers of hydroxy (-OH) substituents (0: phenylalanine, 1: tyrosyl, 2: catechol, or 3: gallol) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization with a desired molar mass (8500-10000 g/mol) and a narrow dispersity (Đ ≤ 1.3). After successful characterizations of P1-P4, their in vitro antioxidant properties were analyzed by different methods, including 2,2-diphenyl-1-picrylhydrazyl (DPPH•), 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS•+), 4,4'-diamino-3,3',5,5'-tetramethylbiphenyl (TMB), and β-carotene (βC) assays. Our results revealed that the gallol pendant polymers can effectively scavenge ROS. Furthermore, electron paramagnetic resonance (EPR) spectroscopy with DPPH• also confirmed the radical quenching ability of the synthesized polymers. The gallol pendant polymers, at a well-tolerated concentration, could effectively penetrate the macrophage cells and restore the H2O2-induced ROS to the basal level. Overall, the present approach demonstrates the efficacy of water-soluble antioxidant polymers with gallol pendants toward the mitigation of cellular oxidative stress.

Non-invasive differentiation of hepatic steatosis and steatohepatitis in a mouse model using nitroxyl radical as an MRI-contrast agent

Drug-induced steatohepatitis is considered more serious than drug-induced hepatic steatosis, so that differentiating between the two is crucial in drug development. In addition, early detection of drug-induced steatohepatitis is considered important since recovery is possible with drug withdrawal. However, no method has been established to differentiate between the two. In the development of drug-induced steatohepatitis, reactive oxygen species (ROS) is excessively generated in the liver. It has been reported that ROS can be monitored with electron spin resonance (ESR) and dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) by using nitroxyl radicals, which are known to participate in various in vivo redox reactions. The decay/reduction rate, which is an index for monitoring nitroxyl radicals, has been reported to be increased in tissues with excessive ROS levels other than liver, but decreased in methionine choline deficient (MCD) diet-induced steatohepatitis with excess ROS. Therefore, looking to differentiate between drug-induced hepatic steatosis and steatohepatitis, we examined whether the reduction rate decreases in steatohepatitis other than the MCD-diet induced disease and whether the decrease could be detected by MRI. We used STAM™ mice in which hepatic steatosis and steatohepatitis developed sequentially under diabetic conditions. 3-carbamoyl-PROXYL (CmP), one of the nitroxyl radicals, was injected intravenously during the MRI procedure and the reduction rate was calculated. The reduction rate was significantly higher in early steatohepatitis than in hepatic steatosis and the control. Excess ROS in early steatohepatitis was detected by an immunohistochemical marker for ROS. Therefore, it was indicated that the increase or decrease in the reduction rate in steatohepatitis differs depending on the model, and early steatohepatitis could be noninvasively differentiated from hepatic steatosis using CmP in MRI. Since the change in direction of the reduction rate in steatohepatitis in clinical studies could be predicted by confirming the reduction rate in preclinical studies, the present method, which can be used consistently in clinical and preclinical studies, warrants consideration as a candidate monitoring method for differentiating between early drug-induced steatohepatitis and hepatic steatosis in drug development.

ROS responsive nanoparticles mediated inhibition of monocarboxylic acid transporters to enhance chemoimmunotherapy by overcoming low immune response in osteosarcoma

Maintaining intracellular pH homeostasis and regulating the acidity of the tumor microenvironment (TME) are critical for the proliferation and progression of highly glycolytic-dependent cancer cells. This is primarily achieved through the activity of monocarboxylate transporters 1 (MCT1) and monocarboxylate transporters 4 (MCT4), which promotes metabolic symbiosis among tumor cells and enables immune evasion. Consequently, targeting monocarboxylic acid transporters (MCTs) offers an effective strategy for cancer treatment. However, the widespread expression of MCTs and the potential toxicity of MCT inhibitors on normal cells have hindered their clinical utility. Herein, we designed reactive oxygen species (ROS)-sensitive nanoparticles loaded with the MCT1/4 inhibitor syrosingopine (Syro) and cisplatin (IV) prodrugs for the treatment of osteosarcoma. The nanoparticles could efficiently accumulate in the tumor cells and achieve abundant production of ROS, therefore enhancing therapeutic efficacy with the delivery of cisplatin and Syro. The excessive ROS levels induced severe endoplasmic reticulum (ER) stress, triggered immunogenic cell death (ICD), and activated adaptive immunity. This study demonstrates a safe and effective nano-delivery system that enhances tumor chemoimmunotherapy by reshaping lactate distribution in TME, thereby providing an effective new treatment strategy for osteosarcoma.

Effects and Mechanisms of Non-Thermal Plasma-Mediated ROS and Its Applications in Animal Husbandry and Biomedicine.

Non-thermal plasma (NTP) is an ionized gas composed of neutral and charged reactive species, electric fields, and ultraviolet radiation. NTP presents a relatively low discharge temperature because it is characterized by the fact that the temperature values of ions and neutral particles are much lower than that of electrons. Reactive species (atoms, radicals, ions, electrons) are produced in NTP and delivered to biological objects induce a set of biochemical processes in cells or tissues. NTP can mediate reactive oxygen species (ROS) levels in an intensity- and time-dependent manner. ROS homeostasis plays an important role in animal health. Relatively low or physiological levels of ROS mediated by NTP promote cell proliferation and differentiation, while high or excessive levels of ROS mediated by NTP cause oxidative stress damage and even cell death. NTP treatment under appropriate conditions not only produces moderate levels of exogenous ROS directly and stimulates intracellular ROS generation, but also can regulate intracellular ROS levels indirectly, which affect the redox state in different cells and tissues of animals. However, the treatment condition of NTP need to be optimized and the potential mechanism of NTP-mediated ROS in different biological targets is still unclear. Over the past ten decades, interest in the application of NTP technology in biology and medical sciences has been rapidly growing. There is significant optimism that NTP can be developed for a wide range of applications such as wound healing, oral treatment, cancer therapy, and biomedical materials because of its safety, non-toxicity, and high efficiency. Moreover, the combined application of NTP with other methods is currently a hot research topic because of more effective effects on sterilization and anti-cancer abilities. Interestingly, NTP technology has presented great application potential in the animal husbandry field in recent years. However, the wide applications of NTP are related to different and complicated mechanisms, and whether NTP-mediated ROS play a critical role in its application need to be clarified. Therefore, this review mainly summarizes the effects of ROS on animal health, the mechanisms of NTP-mediated ROS levels through antioxidant clearance and ROS generation, and the potential applications of NTP-mediated ROS in animal growth and breeding, animal health, animal-derived food safety, and biomedical fields including would healing, oral treatment, cancer therapy, and biomaterials. This will provide a theoretical basis for promoting the healthy development of animal husbandry and the prevention and treatment of diseases in both animals and human beings.

The Antioxidant Activity of Undaria pinnatifida Sporophyll Extract Obtained Using Ultrasonication: A Focus on Crude Polysaccharide Extraction Using Ethanol Precipitation.

Undaria pinnatifida, a marine biological resource from which antioxidants such as polysaccharides can be obtained, is primarily distributed in the coastal areas of East Asia. Reactive oxygen species (ROS) are essential for physiological processes; however, excess ROS levels in the body result in cellular oxidative damage. Several extraction methods exist; however, factors such as long extraction times and high temperatures degrade polysaccharides. Therefore, this study aimed to increase the yield of U. pinnatifida sporophyll extract (UPE), a U. pinnatifida byproduct, using ultrasonication, an environmentally friendly extraction method, and identify UPE components with antioxidant activity. UPE_2, 4, 6, and 8 extracts were obtained at extraction times of 2, 4, 6, and 8 h, respectively. UPE_8 had the highest yield (31.91%) and polysaccharide (69.22%), polyphenol, (8.59 GAE μg/mg), and fucoxanthin contents (2.3 μg/g). UPE_8 showed the greatest protective and inhibitory effects on ROS generation in H2O2-damaged Vero cells. Ethanol precipitation of UPE_8 confirmed that UPE_8P (precipitate) had superior antioxidant activity in Vero cells compared to UPE_8S (supernatant). UPE_8P contained a large amount of polysaccharides, a major contributor to the antioxidant activity of UPE_8. This study shows that UPE_8 obtained using ultrasonication can be a functional food ingredient with excellent antioxidant activity.

Manoalide Induces Intrinsic Apoptosis by Oxidative Stress and Mitochondrial Dysfunction in Human Osteosarcoma Cells.

Osteosarcoma (OS) is the most common primary malignant bone tumor that produces immature osteoid. Metastatic OS has a poor prognosis with a death rate of >70%. Manoalide is a natural sesterterpenoid isolated from marine sponges. It is a phospholipase A2 inhibitor with anti-inflammatory, analgesic, and anti-cancer properties. This study aimed to investigate the mechanism and effect of manoalide on OS cells. Our experiments showed that manoalide induced cytotoxicity in 143B and MG63 cells (human osteosarcoma). Treatment with manoalide at concentrations of 10, 20, and 40 µM for 24 and 48 h reduced MG63 cell viability to 45.13-4.40% (p < 0.01). Meanwhile, manoalide caused reactive oxygen species (ROS) overproduction and disrupted antioxidant proteins, activating the apoptotic proteins caspase-9/-3 and PARP (Poly (ADP-ribose) polymerase). Excessive levels of ROS in the mitochondria affected oxidative phosphorylation, ATP generation, and membrane potential (ΔΨm). Additionally, manoalide down-regulated mitochondrial fusion protein and up-regulated mitochondrial fission protein, resulting in mitochondrial fragmentation and impaired function. On the contrary, a pre-treatment with n-acetyl-l-cysteine ameliorated manoalide-induced apoptosis, ROS, and antioxidant proteins in OS cells. Overall, our findings show that manoalide induces oxidative stress, mitochondrial dysfunction, and apoptosis, causing the cell death of OS cells, showing potential as an innovative alternative treatment in human OS.

Aluminum-doped carbon quantum dots and carbon nanosheets from electrochemical peeled-off MAX phase and their antioxidant ability

Excessive reactive oxygen species levels will cause great harm to the human body, so it’s important to develop a highly effective antioxidant to balance their level. In this study, metal-doped carbon nanomaterials-Al-doped carbon quantum dots (Al-CQDs) and carbon nanosheets (Al-CNSs) were first peeled off from the MAX phase by electrochemical approach. The detailed stripped mechanism was analyzed and demonstrated. The as-prepared Al-CQDs and Al-CNSs exhibited improved antioxidant activity by hydroxyl radicals (·OH) scavenging test, due to the Al doping and thus the improved charge transport ability. As a kind of environment-friendly and non-toxic material, metal-doped carbon nanomaterials could have great application prospects in the field of antioxidants.

Mitochondria Quality Control and Male Fertility.

Mitochondria are pivotal to cellular homeostasis, performing vital functions such as bioenergetics, biosynthesis, and cell signalling. Proper maintenance of these processes is crucial to prevent disease development and ensure optimal cell function. Mitochondrial dynamics, including fission, fusion, biogenesis, mitophagy, and apoptosis, maintain mitochondrial quality control, which is essential for overall cell health. In male reproduction, mitochondria play a pivotal role in germ cell development and any defects in mitochondrial quality can have serious consequences on male fertility. Reactive oxygen species (ROS) also play a crucial role in sperm capacitation, but excessive ROS levels can trigger oxidative damage. Any imbalance between ROS and sperm quality control, caused by non-communicable diseases or environmental factors, can lead to an increase in oxidative stress, cell damage, and apoptosis, which in turn affect sperm concentration, quality, and motility. Therefore, assessing mitochondrial functionality and quality control is essential to gain valuable insights into male infertility. In sum, proper mitochondrial functionality is essential for overall health, and particularly important for male fertility. The assessment of mitochondrial functionality and quality control can provide crucial information for the study and management of male infertility and may lead to the development of new strategies for its management.

Lower Concentrations of the Glyphosate-Based Herbicide Roundup® Cause Developmental Defects in Artemia salina.

Roundup® is the most used glyphosate-based herbicide. During agricultural use it may directly contaminate existing aquatic ecosystems, posing severe concerns for the safety of nontarget terrestrial and aquatic organisms. We investigated the outcome of exposure to different concentrations of glyphosate in Roundup on cyst hatchability, toxicity, and teratogenic effects in the aquatic crustacean Artemia salina that inhabits diverse types of salt waters and, as a filter feeder, carries a greater risk of being exposed to pollutants. We found that exposure to 144 and 288 μg/ml glyphosate in Roundup resulted in cysts unable to complete diapause, and hatchability was completely inhibited during all exposure times tested (17-48 h). A glyphosate concentration of 288 μg/ml in Roundup was lethal to A. salina nauplii, and the lower concentrations (9, 18, 36, 72 μg/ml) had no significant effects on viability. In addition, sublethal and environmentally safe concentrations of glyphosate (0.72 μg/ml) in Roundup affected the early development of A. salina nauplii, with significantly decreased body lengths and reduced widths of the tail, abdomen, and head. The increased level of catalase activity observed in nauplii exposed to 0.72 μg/ml glyphosate for 24 h and those exposed to 7.2 and 72 μg/ml glyphosate for 48 h may be linked to excessive reactive oxygen species levels that had been induced by Roundup. In conclusion, Roundup containing >72 μg/ml glyphosate totally inhibited hatching of cysts and exerted toxic effects on A. salina nauplii. The increased prevalence of developmental defects in the nauplii observed at 0.72 μg/ml glyphosate signifies possible teratogenicity of Roundup exposure even at environmentally relevant concentrations of glyphosate, possibly due to disturbance of the antioxidant defenses, which needs further investigation. Environ Toxicol Chem 2023;00:1-9. © 2023 SETAC.

Transient Receptor Potential Ankyrin 1 (TRPA1) Channel as a Sensor of Oxidative Stress in Cancer Cells.

Moderate levels of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), fuel tumor metastasis and invasion in a variety of cancer types. Conversely, excessive ROS levels can impair tumor growth and metastasis by triggering cancer cell death. In order to cope with the oxidative stress imposed by the tumor microenvironment, malignant cells exploit a sophisticated network of antioxidant defense mechanisms. Targeting the antioxidant capacity of cancer cells or enhancing their sensitivity to ROS-dependent cell death represent a promising strategy for alternative anticancer treatments. Transient Receptor Potential Ankyrin 1 (TRPA1) is a redox-sensitive non-selective cation channel that mediates extracellular Ca2+ entry upon an increase in intracellular ROS levels. The ensuing increase in intracellular Ca2+ concentration can in turn engage a non-canonical antioxidant defense program or induce mitochondrial Ca2+ dysfunction and apoptotic cell death depending on the cancer type. Herein, we sought to describe the opposing effects of ROS-dependent TRPA1 activation on cancer cell fate and propose the pharmacological manipulation of TRPA1 as an alternative therapeutic strategy to enhance cancer cell sensitivity to oxidative stress.

Repurposing Sulfasalazine as a Radiosensitizer in Hypoxic Human Colorectal Cancer.

xCT overexpression in cancer cells has been linked to tumor growth, metastasis and treatment resistance. Sulfasalazine (SSZ), an FDA-approved drug for the treatment of rheumatoid sarthritis, and inflammatory bowel diseases, has anticancer properties via inhibition of xCT, leading to the disruption of redox homeostasis. Since reactive oxygen species (ROS) are pivotal for the efficacy of radiotherapy (RT), elevated levels of ROS are associated with improved RT outcomes. In this study, the influence of SSZ treatment on the radiosensitivity of human colorectal cancer (CRC) cells was investigated. Our principal finding in human HCT116 and DLD-1 cells was that SSZ enhances the radiosensitivity of hypoxic CRC cells but does not alter the intrinsic radiosensitivity. The radiosensitizing effect was attributed to the depletion of glutathione and thioredoxin reductase levels. In turn, the reduction leads to excessive levels of ROS, increased DNA damage, and ferroptosis induction. Confirmation of these findings was performed in 3D models and in DLD-1 xenografts. Taken together, this study is a stepping stone for applying SSZ as a radiosensitizer in the clinic and confirms that xCT in cancer cells is a valid radiobiological target.

Elevated ROS levels during the early development of Angelman syndrome alter the apoptotic capacity of the developing neural precursor cells

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder caused by the maternally inherited loss of function of the UBE3A gene. AS is characterized by a developmental delay, lack of speech, motor dysfunction, epilepsy, autistic features, happy demeanor, and intellectual disability. While the cellular roles of UBE3A are not fully understood, studies suggest that the lack of UBE3A function is associated with elevated levels of reactive oxygen species (ROS). Despite the accumulating evidence emphasizing the importance of ROS during early brain development and its involvement in different neurodevelopmental disorders, up to date, the levels of ROS in AS neural precursor cells (NPCs) and the consequences on AS embryonic neural development have not been elucidated. In this study we show multifaceted mitochondrial aberration in AS brain-derived embryonic NPCs, which exhibit elevated mitochondrial membrane potential (ΔΨm), lower levels of endogenous reduced glutathione, excessive mitochondrial ROS (mROS) levels, and increased apoptosis compared to wild-type (WT) littermates. In addition, we report that glutathione replenishment by glutathione-reduced ethyl ester (GSH-EE) corrects the excessive mROS levels and attenuates the enhanced apoptosis in AS NPCs. Studying the glutathione redox imbalance and mitochondrial abnormalities in embryonic AS NPCs provides an essential insight into the involvement of UBE3A in early neural development, information that can serve as a powerful avenue towards a broader view of AS pathogenesis. Moreover, since mitochondrial dysfunction and elevated ROS levels were associated with other neurodevelopmental disorders, the findings herein suggest some potential shared underlying mechanisms for these disorders as well.