Differential effects of cancer modifying agents during radiation therapy on Ehrlich solid tumor-bearing mice: A comparative investigation of metformin and ascorbic acid.

BACKGROUND: This work was carried out to compare the modifying roles of ascorbic and metformin during Ehrlich (ESC) tumor-bearing mice irradiation. METHODS: Fifty Swiss albino male mice were segmented into seven groups, including one control group and six Ehrlich induced tumors treated with ascorbic, ascorbic plus radiation, metformin, metformin plus radiation, and radiation only. Many tests, including behavioral, biochemical, immunohistochemistry, gene expression, DNA fragmentation, oxidative stress markers, and EPR, were performed to interrogate the modifying effects on tumor and liver tissues. RESULTS: Remarkable apoptosis was found in metformin irradiated animals compared to irradiated ascorbic counterparts. The irradiated metformin mice showed the greatest reduction in PCNA. There was a significant reduction of DNA fragmentation in the liver tissues of the irradiated metformin group. Irradiated metformin and irradiated ascorbic acid animals showed a reduced signal of ERK as well as c-Fos genes. There was a tendency of metformin and metformin irradiated animals to reduce MDA levels in liver tissues. ESC-bearing mice treated with ascorbic or metformin showed an improvement in the spontaneous alternation percentage (SAP%) and improved short-term memory. There was also an improvement in long memory tests. CONCLUSIONS: The study added more preclinical evidence on the utility of metformin in cancer treatment during radiotherapy. Metformin was shown to reduce lipid peroxidation in irradiated healthy tissues, increase tumor cytotoxicity, downregulate critical pathways involved in tumor progression and proliferation, and enhance tumor apoptosis. Controlled clinical trials using metformin are highly warranted.

NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation induced skin injury.

Oxidative stress and lipid peroxidation are major causes of skin injury induced by ultraviolet (UV) irradiation. Ferroptosis is a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids and contributes to kinds of tissue injuries. However, it remains unclear whether the accumulation of lipid peroxides in UV irradiation-induced skin injury could lead to ferroptosis. We generated UV irradiation-induced skin injury mice model to examine the accumulation of the lipid peroxides and iron. Lipid peroxides 4-HNE, the oxidative enzyme COX2, the oxidative DNA damage biomarker 8-OHdG, and the iron level were increased in UV irradiation-induced skin. The accumulation of iron and lipid peroxidation was also observed in UVB-irradiated epidermal keratinocytes without actual ongoing ferroptotic cell death. Ferroptosis was triggered in UV-irradiated keratinocytes stimulated with ferric ammonium citrate (FAC) to mimic the iron overload. Although GPX4 protected UVB-injured keratinocytes against ferroptotic cell death resulted from dysregulation of iron metabolism and the subsequent increase of lipid ROS, keratinocytes enduring constant UVB treatment were markedly sensitized to ferroptosis. Nicotinamide mononucleotide (NMN) which is a direct and potent NAD+ precursor supplement, rescued the imbalanced NAD+/NADH ratio, recruited the production of GSH and promoted resistance to lipid peroxidation in a GPX4-dependent manner. Taken together, our data suggest that NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation-induced skin injury and inhibits oxidative skin damage. NMN or ferroptosis inhibitor might become promising therapeutic approaches for treating oxidative stress-induced skin diseases or disorders.

Contribution of Lipid Oxidation and Ferroptosis to Radiotherapy Efficacy.

Radiotherapy promotes tumor cell death and senescence through the induction of oxidative damage. Recent work has highlighted the importance of lipid peroxidation for radiotherapy efficacy. Excessive lipid peroxidation can promote ferroptosis, a regulated form of cell death. In this review, we address the evidence supporting a role of ferroptosis in response to radiotherapy and discuss the molecular regulators that underlie this interaction. Finally, we postulate on the clinical implications for the intersection of ferroptosis and radiotherapy.

UV induced changes in proteome of rats plasma are reversed by dermally applied cannabidiol.

UV radiation is known to induce a multiple changes in the metabolism of skin-building cells, what can affect the functioning not only neighboring cells, but also, following signal transduction releasing into the blood vessels, the entire body. Therefore, the aim of this study was to analyze the proteomic disturbances occurred in plasma of chronically UVA/UVB irradiated rats and define the effect on these changes of skin topically applied cannabidiol (CBD). Obtained results showed significant changes in the expression of numerous anti-inflammatory and signaling proteins including: NFκB inhibitor, 14-3-3 protein, protein kinase C, keratin, and protein S100 after UV irradiation and CBD treatment. Moreover, the effects of UVA and UVB were manifested by increased level of lipid peroxidation products-protein adducts formation. CBD partially prevented all of these changes, but in a various degree depending on the UV radiation type. Moreover, topical treatment with CBD resulted in the penetration of CBD into the blood and, as a consequence, in direct modifications to the plasma protein structure by creating CBD adducts with molecules, such as proline-rich protein 30, transcription factor 19, or N-acetylglucosamine-6-sulfatase, what significantly changed the activity of these proteins. In conclusion, it may be suggested that CBD applied topically may be an effective compound against systemic UV-induced oxidative stress, but its effectiveness requires careful analysis of CBD's effects on other tissues of the living organism.

Olive Varieties under UV-B Stress Show Distinct Responses in Terms of Antioxidant Machinery and Isoform/Activity of RubisCO.

In recent decades, atmospheric pollution led to a progressive reduction of the ozone layer with a consequent increase in UV-B radiation. Despite the high adaptation of olive trees to the Mediterranean environment, the progressive increase of UV-B radiation is a risk factor for olive tree cultivation. It is therefore necessary to understand how high levels of UV-B radiation affect olive plants and to identify olive varieties which are better adapted. In this study we analyzed two Italian olive varieties subjected to chronic UV-B stress. We focused on the effects of UV-B radiation on RubisCO, in terms of quantity, enzymatic activity and isoform composition. In addition, we also analyzed changes in the activity of antioxidant enzymes (SOD, CAT, GPox) to get a comprehensive picture of the antioxidant system. We also evaluated the effects of UV-B on the enzyme sucrose synthase. The overall damage at biochemical level was also assessed by analyzing changes in Hsp70, a protein triggered under stress conditions. The results of this work indicate that the varieties (Giarraffa and Olivastra Seggianese) differ significantly in the use of specific antioxidant defense systems, as well as in the activity and isoform composition of RubisCO. Combined with a different use of sucrose synthase, the overall picture shows that Giarraffa optimized the use of GPox and opted for a targeted choice of RubisCO isoforms, in addition to managing the content of sucrose synthase, thereby saving energy during critical stress points.

Plasma membrane permeabilization to explain erythrosine B phototoxicity on in vitro breast cancer cell models.

Lipid oxidation is ubiquitous in cell life under oxygen and essential for photodynamic therapy (PDT) of carcinomas. However, the mechanisms underlying lipid oxidation in rather complex systems such as plasma membranes remain elusive. Herein, Langmuir monolayers were assembled with the lipid extract of glandular breast cancer (MCF7) cells and used to probe the molecular interactions allowing adsorption of the photosensitizer (PS) erythrosine B and subsequent photooxidation outcomes. Surface pressure (π) versus area (cm2/mL) isotherms of MCF7 lipid extract shifted to larger areas upon erythrosine incorporation, driven by secondary interactions that affected the orientation of the carbonyl groups and lipid chain organization. Light-irradiation increased the surface area of the MCF7 lipid extract monolayer containing erythrosine owing to the lipid hydroperoxidation, which may further undergo decomposition, resulting in the chain cleavage of phospholipids and membrane permeabilization. Incorporation of erythrosine by MCF7 cells induced slight toxic effects on in vitro assays, differently of the severe phototoxicity caused by light-irradiation, which significantly decreased cell viability by more than 75% at 2.5 × 10-6 mol/L of erythrosine incubated for 3 and 24 h, reaching nearly 90% at 48 h of incubation. The origin of the phototoxic effects is in the rupture of the plasma membrane shown by the frontal (FSC) and side (SSC) light scattering of flow cytometry. Consistent with hydroperoxide decomposition, membrane permeabilization was also confirmed by cleaved lipids detected in mass spectrometry and subsidizes the necrotic pathway of cell death.

Radon inhalation decreases DNA damage induced by oxidative stress in mouse organs via the activation of antioxidative functions.

Radon inhalation decreases the level of lipid peroxide (LPO); this is attributed to the activation of antioxidative functions. This activation contributes to the beneficial effects of radon therapy, but there are no studies on the risks of radon therapy, such as DNA damage. We evaluated the effect of radon inhalation on DNA damage caused by oxidative stress and explored the underlying mechanisms. Mice were exposed to radon inhalation at concentrations of 2 or 20 kBq/m3 (for one, three, or 10 days). The 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels decreased in the brains of mice that inhaled 20 kBq/m3 radon for three days and in the kidneys of mice that inhaled 2 or 20 kBq/m3 radon for one, three or 10 days. The 8-OHdG levels in the small intestine decreased by approximately 20-40% (2 kBq/m3 for three days or 20 kBq/m3 for one, three or 10 days), but there were no significant differences in the 8-OHdG levels between mice that inhaled a sham treatment and those that inhaled radon. There was no significant change in the levels of 8-oxoguanine DNA glycosylase, which plays an important role in DNA repair. However, the level of Mn-superoxide dismutase (SOD) increased by 15-60% and 15-45% in the small intestine and kidney, respectively, following radon inhalation. These results suggest that Mn-SOD probably plays an important role in the inhibition of oxidative DNA damage.

MHY1485 enhances X-irradiation-induced apoptosis and senescence in tumor cells.

The mammalian target of rapamycin (mTOR) is a sensor of nutrient status and plays an important role in cell growth and metabolism. Although inhibition of mTOR signaling promotes tumor cell death and several mTOR inhibitors have been used clinically, recent reports have shown that co-treatment with MHY1485, an mTOR activator, enhances the anti-cancer effects of anti-PD-1 antibody and 5-fluorouracil. However, it remains unclear whether MHY1485 treatment alters the effects of radiation on tumor cells. In this study, the radiosensitizing effects of MHY1485 were investigated using murine CT26 and LLC cell lines. We examined mTOR signaling, tumor cell growth, colony formation, apoptosis, senescence, oxidative stress, p21 accumulation and endoplasmic reticulum (ER) stress levels in cells treated with MHY1485 and radiation, either alone or together. We found that MHY1485 treatment inhibited growth and colony formation in both cell lines under irradiation and no-irradiation conditions, results that were not fully consistent with MHY1485's known role in activating mTOR signaling. Furthermore, we found that combined treatment with MHY1485 and radiation significantly increased apoptosis and senescence in tumor cells in association with oxidative stress, ER stress and p21 stabilization, compared to radiation treatment alone. Our results suggested that MHY1485 enhances the radiosensitivity of tumor cells by a mechanism that may differ from MHY1485's role in mTOR activation.

UV Effect on Human Anterior Lens Capsule Macro-Molecular Composition Studied by Synchrotron-Based FTIR Micro-Spectroscopy.

Ultraviolet (UV) irradiation is an important risk factor in cataractogenesis. Lens epithelial cells (LECs), which are a highly metabolically active part of the lens, play an important role in UV-induced cataractogenesis. The purpose of this study was to characterize cell compounds such as nucleic acids, proteins, and lipids in human UV C-irradiated anterior lens capsules (LCs) with LECs, as well as to compare them with the control, non-irradiated LCs of patients without cataract, by using synchrotron radiation-based Fourier transform infrared (SR-FTIR) micro-spectroscopy. In order to understand the effect of the UV C on the LC bio-macromolecules in a context of cataractogenesis, we used the SR-FTIR micro-spectroscopy setup installed on the beamline MIRAS at the Spanish synchrotron light source ALBA, where measurements were set to achieve a single-cell resolution with high spectral stability and high photon flux. UV C irradiation of LCs resulted in a significant effect on protein conformation with protein formation of intramolecular parallel ß-sheet structure, lower phosphate and carboxyl bands in fatty acids and amino acids, and oxidative stress markers with significant increase of lipid peroxidation and diminishment of the asymmetric CH3 band.

Formulation of Novel Liquid Crystal (LC) Formulations with Skin-Permeation-Enhancing Abilities of Plantago lanceolata (PL) Extract and Their Assessment on HaCaT Cells.

Exposure to reactive oxygen species can easily result in serious diseases, such as hyperproliferative skin disorders or skin cancer. Herbal extracts are widely used as antioxidant sources in different compositions. The importance of antioxidant therapy in inflammatory conditions has increased. Innovative formulations can be used to improve the effects of these phytopharmacons. The bioactive compounds of Plantago lanceolata (PL) possess different effects, such as anti-inflammatory, antioxidant, and bactericidal pharmacological effects. The objective of this study was to formulate novel liquid crystal (LC) compositions to protect Plantago lanceolata extract from hydrolysis and to improve its effect. Since safety is an important aspect of pharmaceutical formulations, the biological properties of applied excipients and blends were evaluated using assorted in vitro methods on HaCaT cells. According to the antecedent toxicity screening evaluation, three surfactants were selected (Gelucire 44/14, Labrasol, and Lauroglycol 90) for the formulation. The dissolution rate of PL from the PL-LC systems was evaluated using a Franz diffusion chamber apparatus. The antioxidant properties of the PL-LC systems were evaluated with 2,2-diphenyl-1-picrylhydrazyl (DPPH) and malondialdehyde (MDA) assessments. Our results suggest that these compositions use a nontraditional, rapid-permeation pathway for the delivery of drugs, as the applied penetration enhancers reversibly alter the barrier properties of the outer stratum corneum. These excipients can be safe and highly tolerable thus, they could improve the patient's experience and promote adherence.

Photobiomodulation and Oxidative Stress: 980 nm Diode Laser Light Regulates Mitochondrial Activity and Reactive Oxygen Species Production.

Photobiomodulation with 808 nm laser light electively stimulates Complexes III and IV of the mitochondrial respiratory chain, while Complexes I and II are not affected. At the wavelength of 1064 nm, Complexes I, III, and IV are excited, while Complex II and some mitochondrial matrix enzymes seem to be not receptive to photons at that wavelength. Complex IV was also activated by 633 nm. The mechanism of action of wavelengths in the range 900-1000 nm on mitochondria is less understood or not described. Oxidative stress from reactive oxygen species (ROS) generated by mitochondrial activity is an inescapable consequence of aerobic metabolism. The antioxidant enzyme system for ROS scavenging can keep them under control. However, alterations in mitochondrial activity can cause an increment of ROS production. ROS and ATP can play a role in cell death, cell proliferation, and cell cycle arrest. In our work, bovine liver isolated mitochondria were irradiated for 60 sec, in continuous wave mode with 980 nm and powers from 0.1 to 1.4 W (0.1 W increment at every step) to generate energies from 6 to 84 J, fluences from 7.7 to 107.7 J/cm2, power densities from 0.13 to 1.79 W/cm2, and spot size 0.78 cm2. The control was equal to 0 W. The activity of the mitochondria's complexes, Krebs cycle enzymes, ATP production, oxygen consumption, generation of ROS, and oxidative stress were detected. Lower powers (0.1-0.2 W) showed an inhibitory effect; those that were intermediate (0.3-0.7 W) did not display an effect, and the higher powers (0.8-1.1 W) induced an increment of ATP synthesis. Increasing the power (1.2-1.4 W) recovered the ATP production to the control level. The interaction occurred on Complexes III and IV, as well as ATP production and oxygen consumption. Results showed that 0.1 W uncoupled the respiratory chain and induced higher oxidative stress and drastic inhibition of ATP production. Conversely, 0.8 W kept mitochondria coupled and induced an increase of ATP production by increments of Complex III and IV activities. An augmentation of oxidative stress was also observed, probably as a consequence of the increased oxygen consumption and mitochondrial isolation experimental conditions. No effect was observed using 0.5 W, and no effect was observed on the enzymes of the Krebs cycle.

2-acetylphenothiazine protects L929 fibroblasts against UVB-induced oxidative damage.

Ultraviolet B (UVB) light corresponds to 5% of ultraviolet radiation. It is more genotoxic and mutagenic than UVA and causes direct and indirect cellular damage through the generation of reactive oxygen species (ROS). Even after radiation, ROS generation may continue through activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) enzyme. Long-term exposure can progress to premature skin aging and photocarcinogenesis. To prevent damage that is caused by UVB radiation, several studies have focused on the topical administration of compounds that have antioxidant properties. 2-Acetylphenothiazine (ML171) is a potent and selective inhibitor of NOX1. The present study investigated the antioxidant potential and photoprotective ability of ML171 in UVB-irradiated L929 fibroblasts. ML171 had considerable antioxidant activity in both the DPPH• and xanthine/luminol/xanthine oxidase assays. ML171 did not induce cytotoxicity in L929 fibroblasts and increased the viability of UVB-irradiated cells. ML171 also inhibited ROS production, the enzymatic activity of NOX, depolarization of the mitochondrial membrane, and DNA damage. Additionally, ML171 protected cell membrane integrity and induced fibroblast migration. These results suggest that the incorporation of ML171 in topical administration systems may be a promising strategy to mitigate UVB-induced oxidative damage in L929 fibroblasts.

Radioiodine therapy of Graves' disease.

Graves' disease (GD), the most common cause of hyperthyroidism, is an autoimmune disease directly caused by circulating autoantibodies that bind and activate the TSH receptor, inducing metabolic activation of the thyroid gland; this may be associated with important cardiac (atrial fibrillation) and ocular (ophthalmopathy) complications. Treating GD with real curative intent implies the full elimination of the functioning thyroid parenchyma using surgery or radioactive iodine therapy (RAI). RAI has been used in humans with hyperthyroidism since 1941, thanks to the pioneering work of a physician (Dr. Saul Hertz) and a physicist (Dr. Arthur Roberts). The rationale of RAI is based on the effect of radiation of 131I on target cells leading to DNA damage, both directly, through breakage of molecular bonds, and indirectly through the formation of free radicals. In particular, irradiation causes a broad spectrum of cellular damage due to the production of reactive oxygen species and lipid peroxidation of the plasma membrane. Thus, RAI-related cellular death takes place through both apoptosis and necrosis. The aim of this review was to summarize indications, efficacy, safety profile, and dosimetric aspects of RAI treatment in patients affected by GD.

Obacunone protects retinal pigment epithelium cells from ultra-violet radiation-induced oxidative injury.

Ultra-violet (UV) radiation (UVR) causes significant oxidative injury to retinal pigment epithelium (RPE) cells. Obacunone is a highly oxygenated triterpenoid limonoid compound with various pharmacological properties. Its potential effect in RPE cells has not been studied thus far. Here in ARPE-19 cells and primary murine RPE cells, obacunone potently inhibited UVR-induced reactive oxygen species accumulation, mitochondrial depolarization, lipid peroxidation and single strand DNA accumulation. UVR-induced RPE cell death and apoptosis were largely alleviated by obacunone. Obacunone activated Nrf2 signaling cascade in RPE cells, causing Keap1-Nrf2 disassociation, Nrf2 protein stabilization and nuclear translocation. It promoted transcription and expression of antioxidant responsive element-dependent genes. Nrf2 silencing or CRISPR/Cas9-induced Nrf2 knockout almost reversed obacunone-induced RPE cytoprotection against UVR. Forced activation of Nrf2 cascade, by Keap1 knockout, similarly protected RPE cells from UVR. Importantly, obacunone failed to offer further RPE cytoprotection against UVR in Keap1-knockout cells. In vivo, intravitreal injection of obacunone largely inhibited light-induced retinal damage. Collectively, obacunone protects RPE cells from UVR-induced oxidative injury through activation of Nrf2 signaling cascade.

Antioxidant activity of curcumin protects against the radiation-induced micronuclei formation in cultured human peripheral blood lymphocytes exposed to various doses of γ-Radiation.

PURPOSE: Ionizing radiations trigger the formation of free radicals that damage DNA and cause cell death. DNA damage may be simply evaluated by micronucleus assay and the pharmacophores that impede free radicals could effectively reduce the DNA damage initiated by irradiation. Therefore, it was desired to determine the capacity of curcumin to alleviate micronuclei formation in human peripheral blood lymphocytes (HPBLs) exposed to 0-4 Gy of γ-radiation. MATERIALS AND METHODS: HPBLs were exposed to 3 Gy after 30 minutes of 0.125, 0.25, 0.5, 1, 2, 5, 10, 20 or 50 µg/mL curcumin treatment or with 0.5 µg/mL curcumin 30 minutes early to 0, 0.5, 1, 2, 3 or 4 Gy 60Co γ-irradiation. Cytokinesis of HPBLs was blocked by cytochalasin B and micronuclei scored. The ability of curcumin to suppress free radical induction in vitro was determined by standard methods. RESULTS: HPBLs treated with different concentrations of curcumin before 3 Gy irradiation alleviated the micronuclei formation depending on curcumin concentration and the lowest micronuclei were detected at 0.5 µg/mL curcumin when compared to 3 Gy irradiation alone. Increasing curcumin concentration caused a gradual rise in micronuclei, and the significant increases were detected at 10-50 µg/mL curcumin than 3 Gy irradiation alone. Irradiation of HPBLs to different doses of γ-rays caused a significant rise in micronuclei depending on radiation dose, whereas HPBLs treated with 0.5 µg/mL curcumin 30 minutes before irradiation to different doses of γ-rays significantly reduced frequencies of HPBLs with one, two, or more micronuclei. Curcumin treatment inhibited the formation of hydroxyl (OH), 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), 2,2'-diphenyl-1-picrylhydrazyl (DPPH), and (nitric oxide) NO free radicals in a concentration-related way. CONCLUSIONS: Curcumin when treated at a dose of 0.5 µg/mL attenuated micronuclei formation after γ-irradiation by inhibiting the formation of radiation-induced free radicals.

Hematopoietic protection and mechanisms of ferrostatin-1 on hematopoietic acute radiation syndrome of mice.

PURPOSE: Baicalein (an anti-ferroptosis drug) was recently reported to synergistically improve the survival rate of mice following a high dose of total body irradiation with anti-apoptosis and anti-necroptosis drugs. At the same time, our group has demonstrated that ferrostatin-1, a ferroptosis inhibitor, improves the survival rate of a mouse model of hematopoietic acute radiation syndrome to 60% for 150 days (p < .001). These phenomena suggest that ferroptosis inhibition can mitigate radiation damage. In this study, we continued to study the mechanisms by which ferrostatin-1 alleviated radiation-induced ferroptosis and subsequent hematopoietic acute radiation syndrome. MATERIALS AND METHODS: Male ICR mice (8-10 weeks old) were exposed to doses of 0, 8, or 10 Gy irradiated from a 137Cs source. Ferrostatin-1 was intraperitoneally injected into mice 72 h post-irradiation. Bone marrow mononuclear cells (BMMCs) and peripheral blood cells were counted. The changes in iron-related parameters, lipid metabolic enzymes, lipid peroxidation repair molecules (glutathione peroxidase 4, glutathione, and coenzyme Q10), and inflammatory factors (TNF-α, IL-6, and IL-1ß) were evaluated using biochemical or antibody techniques. RESULTS: Ferrostatin-1 increased the number of red and white blood cells, lymphocytes, and monocytes in the peripheral blood after total body irradiation in mice by mitigating the ferroptosis of BMMCs. Total body irradiation induced ferroptosis in BMMCs by increasing the iron and lipid peroxidation levels and depleting the acyl-CoA synthetase long-chain family member 4 (ASCL4), lipoxygenase 15, glutathione peroxidase 4, and glutathione levels. Ferroptotic BMMCs did not release TNF-α, IL-6, or IL-1ß at the early stage of radiation exposure. Ferrostatin-1 mitigated the lipid peroxidation of radiation-induced ferroptosis by attenuating increases in levels of hemosiderin and liable iron pool and decreases in levels of ASCL4 and glutathione peroxidase 4. CONCLUSIONS: The onset of total body irradiation-induced ferroptosis in BMMCs involved changes in iron, lipid metabolic enzymes, and anti-lipid peroxidation molecules. Ferrostatin-1 could be a potential radiation mitigation agent by acting on these targets.

Broadening horizons: the role of ferroptosis in cancer.

The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFß1) can induce ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate ferroptosis. Herein, we present the key molecular mechanisms of ferroptosis, describe the crosstalk between ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy.

Amphora algae with low-level ionizing radiation exposure ameliorate D-galactosamine-induced inflammatory impairment in rat kidney.

d-Galactosamine (d-GalN) is a well-known toxin that causes many metabolic and morphological abnormalities resulting in advanced renal failure and liver damage. Occupational exposure to low-level ionizing radiation (<1 Gy) was shown to enhance cell protection via attenuating an established inflammatory process. The present study was therefore aimed to investigate the protective impact of Amphora coffaeiformis extract and low dose gamma radiation against d-GalN induced renal damage in rats. Forty-eight adult male Swiss albino rats were distributed equally into eight groups. The measurements included antioxidants activities (superoxide dismutase, catalase and glutathione peroxidase) as well as lipid peroxidation level in kidney tissue. Also, kidney function tests and inflammatory markers (tumor necrosis factor alpha and nuclear factor kappa-light-chain-enhancer of activated B cells) were measured. Additionally, relative quantification of kidney nuclear factor erythroid 2-related factor 2 (Nrf-2) gene was estimated. Histopathological examination was also performed in kidney tissue. The results revealed decreases in antioxidant activities and downregulation of Nrf-2 expression accompanied by increases in lipid peroxidation level, kidney function tests and inflammatory markers in d-GaIN group. The treatment with Amphora algal extract and low dose gamma radiation ameliorated the previous measurements which were harmony with histopathological findings. In conclusion, A coffaeiformis extract and low dose gamma radiation provided marked functional and histological effects in the treating acute renal damage induced by d-GalN in rats.

Exogenous γ-aminobutyric acid (GABA)-induced signaling events and field performance associated with mitigation of drought stress in Phaseolus vulgaris L.

Not much information is available to substantiate the possible role of γ -aminobutyric acid (GABA) signaling in mitigating water-deficit stress in snap bean (Phaseolus vulgaris L.) plants under semiarid conditions. Present work aims to investigate the role of exogenous GABA (foliar application; 0.5, 1 and 2 mM) in amelioration of drought stress and improvement of field performance on snap bean plants raised under two drip irrigation regimes (100% and 70% of water requirements). Water stress led to significant reduction in plant growth, leaf relative water content (RWC), cell membrane stability index (CMSI), nutrient uptake (N, P, K, Ca, Fe and Zn), pod yield and its content from protein and total soluble solids (TSS). Meanwhile, lipid peroxidation (malondialdehyde content- MDA), osmolyte content (free amino acids- FAA, proline, soluble sugars) antioxidative defense (activity of superoxide dismutase- SOD, catalase- CAT, peroxidase- POX and ascorbate peroxidase- APX) and the pod fiber content exhibited significantly increase due to water stress. Exogenous GABA application (especially at 2 mM) revealed partial normalization of the effects of drought stress in snap bean plants. GABA-induced mitigation of drought stress was manifested by improvement in growth, water status, membrane integrity, osmotic adjustment, antioxidant defense and nutrient acquisition. Furthermore, GABA application during water stress in snap bean plants resulted in improvement of field performance being manifested by increased pod yield and its quality attributes. To sum up, exogenous GABA appears to function as an effective priming molecule to alleviate drought stress in snap bean plants under semiarid conditions.

Tanned or Sunburned: How Excessive Light Triggers Plant Cell Death.

Plants often encounter light intensities exceeding the capacity of photosynthesis (excessive light) mainly due to biotic and abiotic factors, which lower CO2 fixation and reduce light energy sinks. Under excessive light, the photosynthetic electron transport chain generates damaging molecules, hence leading to photooxidative stress and eventually to cell death. In this review, we summarize the mechanisms linking the excessive absorption of light energy in chloroplasts to programmed cell death in plant leaves. We highlight the importance of reactive carbonyl species generated by lipid photooxidation, their detoxification, and the integrating role of the endoplasmic reticulum in the adoption of phototolerance or cell-death pathways. Finally, we invite the scientific community to standardize the conditions of excessive light treatments.