Topically applied fullerenols protect against radiation dermatitis by scavenging reactive oxygen species.
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ABSTRACT:
SUBMITTER: Yin H
PROVIDER: S-EPMC10427596 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:BackgroundOur previous studies showed that vasoconstrictor applied topically to rat skin minutes before irradiation completely prevented radiodermatitis. Here we report on a Phase IIa study of topically applied NG12-1 vasoconstrictor to prevent radiodermatitis in post-lumpectomy breast cancer patients who received at least 40 Gray to the whole breast using standard regimens.MethodsPatients had undergone surgery for Stage Ia, Ib, or IIa infiltrating ductal or lobular carcinoma of the breast or ductal carcinoma in situ. NG12-1 formulation was applied topically to the same 50-cm2 treatment site within the radiation field 20 min before each daily radiotherapy fraction.ResultsScores indicated significant reductions in radiodermatitis at the NG12-1 treatment site versus control areas in the same radiotherapy field. The mean dermatitis score for all subjects was 0.47 (SD 0.24) in the NG12-1-treated area versus 0.72 (SD 0.22) in the control area (P = 0.022). Analysis by two independent investigators indicated radiodermatitis reductions in 9 of the 9 patients with scorable radiodermatitis severity, and one patient with insufficient radiodermatitis to enable scoring. There were no serious adverse events from NG12-1 treatment.ConclusionsThirty, daily, NG12-1 treatments, topically applied minutes before radiotherapy, were well tolerated and conferred statistically significant reductions in radiodermatitis severity (P = 0.022).Trial registrationNCT01263366 ; clinicaltrials.gov.
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Project description:Reactive oxygen species (ROS) are signaling molecules essential for plant responses to abiotic and biotic stimuli as well as for multiple developmental processes. They are produced as byproducts of aerobic metabolism and are affected by adverse environmental conditions. The ROS content is controlled on the side of their production but also by scavenging machinery. Antioxidant enzymes represent a major ROS-scavenging force and are crucial for stress tolerance in plants. Enzymatic antioxidant defense occurs as a series of redox reactions for ROS elimination. Therefore, the deregulation of the antioxidant machinery may lead to the overaccumulation of ROS in plants, with negative consequences both in terms of plant development and resistance to environmental challenges. The transcriptional activation of antioxidant enzymes accompanies the long-term exposure of plants to unfavorable environmental conditions. Fast ROS production requires the immediate mobilization of the antioxidant defense system, which may occur via retrograde signaling, redox-based modifications, and the phosphorylation of ROS detoxifying enzymes. This review aimed to summarize the current knowledge on signaling processes regulating the enzymatic antioxidant capacity of plants.
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Project description:Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb-overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by H2O2 challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.
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Project description:Although many bioactive peptides have been identified from the frog skins, their protective effects and the molecular mechanisms against skin photodamage are still poorly understood. In this study, a novel 20-residue peptide (antioxidin-NV, GWANTLKNVAGGLCKMTGAA) was characterized from the skin of plateau frog Nanorana ventripunctata. Antioxidin-NV obviously decreased skin erythema, thickness and wrinkle formation induced by Ultraviolet (UV) B exposure in hairless mice. In UVB-irradiated keratinocytes (HaCaT cells) and hairless mice, it effectively inhibited DNA damage through reducing p-Histone H2A.X (γH2AX) expression, alleviated cell apoptosis by decreasing the expression of apoptosis-specific protein (cleaved caspase 3), and reduced interleukin-6 (IL-6) production via blocking UVB-activated Toll-like receptor 4 (TLR4)/p38/JNK/NF-κB signaling. In UVB-irradiated human skin fibroblasts (HSF cells) and hairless mice, it effectively restored HSF cells survival rate, and rescued α-SMA accumulation and collagen (especially type I collagen) production by restoring transforming growth factor-β1 (TGF-β1)/Smad2 signaling. We found that antioxidin-NV directly and rapidly scavenged intracellular and mitochondrial ROS in HaCaT cells upon UVB irradiation, and quickly eliminated the artificial free radicals, 2, 2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+). Taken together, antioxidin-NV directly and rapidly scavenged excessive ROS upon UVB irradiation, subsequently alleviated UVB-induced DNA damage, cell apoptosis, and inflammatory response, thus protecting against UVB-induced skin photoaging. These properties makes antioxidin-NV an excellent candidate for the development of novel anti-photoaging agent.
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Project description:Soil salinity is a major environmental stress that restricts the growth and yield of crops. Mining the key genes involved in the balance of rice salt tolerance and yield will be extremely important for us to cultivate salt-tolerance rice varieties. In this study, we report a WUSCHEL-related homeobox (WOX) gene, quiescent-center-specific homeobox (OsQHB), positively regulates yield-related traits and negatively regulates salt tolerance in rice. Mutation in OsQHB led to a decrease in plant height, tiller number, panicle length, grain length and grain width, and an increase in salt tolerance. Transcriptome and qPCR analysis showed that reactive oxygen species (ROS) scavenging-related genes were regulated by OsQHB. Moreover, the osqhb mutants have higher ROS-scavenging enzymes activities and lower accumulation of ROS and malondialdehyde (MDA) under salt stress. Thus, our findings provide new insights into the role of rice WOX gene family in rice development and salt tolerance, and suggest that OsQHB is a valuable target for improving rice production in environments characterized by salt stress.
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Project description:The large yellow croaker (Larimichthys crocea), which is an economically important mariculture fish in China, is often exposed to environmental hypoxia. Reactive oxygen species (ROS) homeostasis is essential for the maintenance of normal physiological conditions in an organism. Direct evidence that environmental hypoxia leads to ROS overproduction is scarce in marine fish. Furthermore, the sources of ROS overproduction in marine fish under hypoxic stress are poorly known. In this study, we investigated the effects of hypoxia on redox homeostasis in L. crocea and the impact of impaired redox homeostasis on fish. We first confirmed that hypoxia drove ROS production mainly via the mitochondrial electron transport chain and NADPH oxidase complex pathways in L. crocea and its cell line (large yellow croaker fry (LYCF) cells). We subsequently detected a marked increase in the antioxidant systems of the fish. However, imbalance between the pro-oxidation and antioxidation systems ultimately led to excessive ROS and oxidative stress. Cell viability showed a remarkable decrease while oxidative indicators, such as malondialdehyde, protein carbonylation, and 8-hydroxy-2 deoxyguanosine, showed a significant increase after hypoxia, accompanied by tissue damage. N-acetylcysteine (NAC) reduced ROS levels, alleviated oxidative damage, and improved cell viability in vitro. Appropriate uptake of ROS scavengers (e.g., NAC and elamipretide Szeto-Schiller-31) and inhibitors (e.g., apocynin, diphenylene iodonium, and 5-hydroxydecanoate) may be effective at overcoming hypoxic toxicity. Our findings highlight previously unstudied strategies of hypoxic toxicity resistance in marine fish.
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Project description:Flavonoids are a class of specialized metabolites with subclasses including flavonols and anthocyanins, which have unique properties as antioxidants. Flavonoids modulate plant development, but whether and how they impact lateral root development is unclear. We examined potential roles for flavonols in this process using Arabidopsis thaliana mutants with defects in genes encoding key enzymes in flavonoid biosynthesis. We observed the tt4 and fls1 mutants, which produce no flavonols, have increased lateral root emergence. The tt4 root phenotype was reversed by genetic and chemical complementation. To more specifically define the flavonoids involved, we tested an array of flavonoid biosynthetic mutants, eliminating roles for anthocyanins and the flavonols quercetin and isorhamnetin in modulating lateral root development. Instead, two tt7 mutant alleles, with defects in a branchpoint enzyme blocking quercetin biosynthesis, formed reduced numbers of lateral roots and tt7-2 had elevated levels of kaempferol. Using a flavonol-specific dye, we observed that in the tt7-2 mutant, kaempferol accumulated within lateral root primordia at higher levels than wild-type. These data are consistent with kaempferol, or downstream derivatives, acting as a negative regulator of lateral root emergence. We examined ROS accumulation using ROS-responsive probes and found reduced fluorescence of a superoxide-selective probe within the primordia of tt7-2 compared with wild-type, but not in the tt4 mutant, consistent with opposite effects of these mutants on lateral root emergence. These results support a model in which increased level of kaempferol in the lateral root primordia of tt7-2 reduces superoxide concentration and ROS-stimulated lateral root emergence.
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Project description:Apart from natural products and synthesis, phenolic compounds can be produced from the depolymerization of lignin, a major waste in biofuel and paper production. This process yields a plethora of aryl propanoid phenolic derivatives with broad biological activities, especially antioxidant properties. Due to its versatility, our study focuses on investigating the antioxidant mechanisms of several phenolic compounds obtained from renewable and abundant resources, namely, syringol (Hs), 4-allylsyringol (HAs), 4-propenylsyringol (HPns), and 4-propylsyringol (HPs). Employing the density functional theory (DFT) approach in conjunction with the QM-ORSA protocol, we aim to explore the reactivity of these compounds in neutralizing hydroperoxyl radicals in physiological and non-polar media. Kinetic and thermodynamic parameter calculations on the antioxidant activity of these compounds were also included in this study. Additionally, our research utilizes the activation strain model (ASM) for the first time to explain the reactivity of the HT and RAF mechanisms in the peroxyl radical scavenging process. It is predicted that HPs has the best rate constant in both media (1.13 × 108 M-1 s-1 and 1.75 × 108 M-1 s-1, respectively). Through ASM analysis, it is observed that the increase in the interaction energy due to the formation of intermolecular hydrogen bonds during the reaction is an important feature for accelerating the hydrogen transfer process. Furthermore, by examining the physicochemical and toxicity parameters, only Hs is not suitable for further investigation as a therapeutic agent because of potential toxicity and mutagenicity. However, overall, all compounds are considered potent HOO˙ scavengers in lipid-rich environments compared to previously studied antioxidants.
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Project description:A broad-spectrum reactive oxygen species (ROS)-scavenging hybrid material (CASCADE) was developed by sequential adsorption of heparin (HEP) and poly(L-lysine) (PLL) polyelectrolytes together with superoxide dismutase (SOD) and horseradish peroxidase (HRP) antioxidant enzymes on layered double hydroxide (LDH) nanoclay support. The synthetic conditions were optimized so that CASCADE possessed remarkable structural (no enzyme leakage) and colloidal (excellent resistance against salt-induced aggregation) stability. The obtained composite was active in decomposition of both superoxide radical anions and hydrogen peroxide in biochemical assays revealing that the strong electrostatic interaction with the functionalized support led to high enzyme loadings, nevertheless, it did not interfere with the native enzyme conformation. In vitro tests demonstrated that ROS generated in human cervical adenocarcinoma cells were successfully consumed by the hybrid material. The cellular uptake was not accompanied with any toxicity effects, which makes the developed CASCADE a promising candidate for treatment of oxidative stress-related diseases.
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Project description:Hypoxia, excessive reactive oxygen species (ROS), and impaired angiogenesis are prominent obstacles to wound healing following trauma and surgical procedures, often leading to the development of keloids and hypertrophic scars. To address these challenges, a novel approach has been proposed, involving the development of a cascade enzymatic reaction-based nanocarriers-laden wound dressing. This advanced technology incorporates superoxide dismutase modified oxygen nanobubbles and catalase modified oxygen nanobubbles within an alginate hydrogel matrix. The oxygen nano chamber functions through a cascade reaction between superoxide dismutase and catalase, wherein excessive superoxide in the wound environment is enzymatically decomposed into hydrogen peroxide, and this hydrogen peroxide is subsequently converted into oxygen by catalase. This enzymatic cascade effectively controls wound inflammation and hypoxia, mitigating the risk of keloid formation. Concurrently, the oxygen nanobubbles release oxygen continuously, thus providing a sustained supply of oxygen to the wound site. The oxygen release from this dynamic system stimulates fibroblast proliferation, fosters the formation of new blood vessels, and contributes to the overall wound healing process. In the rat full-thickness wound model, the cascade reaction-based nano oxygen chamber displayed a notable capacity to expedite wound healing without scarring. Furthermore, in the pilot study of porcine full-thickness wound healing, a notable acceleration of tissue repair was observed in the conceived cascade reaction-based gel treated group within the 3 days post-surgery, which represents the proliferation stage of healing process. These achievements hold significant importance in ensuring the complete functional recovery of tissues, thereby highlighting its potential as a promising approach for enhancing wound healing outcomes.
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