The Relevance of Photomutagenicity Testing as a Predictor of Photocarcinogenicity

Today's lifestyle is associated with frequent and intense exposure to ultraviolet radiation (UVR). The tumorigenic effects of UVR are well known. Specifically, the premutagenic lesions of UVB (290-320 nm) are known to be the most important molecular events in UVR tumorigenicity. The less carcinogenic UVA (320-400 nm) mainly generates oxidative damage in the DNA via photody-namic generation of active oxygen species involving endogenous or exogenous photosen sitizers. Several pharmaceuticals are known to act as photosensitizers. Photoinstable phenothiazines, furocoumarins, and fluoroquinolones were shown to be very efficient inducers of chromosomal damage in mammalian cells in culture. Photocar cinogenicity testing in hairless mice of furocoumarins and several fluoroquinolones demonstrated a higher incidence and a shorter latent period for skin tumors compared to UVR alone. These data show a good correlation between the photomutagenic and photocarcinogenic potential of these compounds. Although mammalian cells possess effective repair mechanisms for oxidative damage, photoproducts, and dimers, these repair mechanisms can be overloaded. Eventually, unrepaired damage leads to gene mutations or chromosomal damage in exposed cells and to tumors in the skin. Therefore, in vitro photomutageni-city testing in mammalian cells may be an early and easy-to-measure predictor of the photocarcinogenic potential of a pharmaceutical.

Download Full-text

Tetrandrine Attenuated Doxorubicin-Induced Acute Cardiac Injury in Mice

BioMed Research International ◽

10.1155/2020/2616024 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Gang Li ◽

Wen-Rui Li ◽

Ya-Ge Jin ◽

Qi-Qiang Jie ◽

Cheng-Yu Wang ◽

...

Keyword(s):

Oxidative Damage ◽

Cardiac Function ◽

Cardiac Injury ◽

Whole Body ◽

Oxygen Species ◽

Single Intraperitoneal Injection ◽

Body Wasting ◽

Nrf2 Expression

Oxidative damage is closely involved in the development of doxorubicin- (DOX-) induced cardiotoxicity. It has been reported that tetrandrine can prevent the development of cardiac hypertrophy by suppressing reactive oxygen species- (ROS-) dependent signaling pathways in mice. However, whether tetrandrine could attenuate DOX-related cardiotoxicity remains unclear. To explore the protective effect of tetrandrine, mice were orally given a dose of tetrandrine (50 mg/kg) for 4 days beginning one day before DOX injection. To induce acute cardiac injury, the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg). The data in our study showed that tetrandrine prevented DOX-related whole-body wasting and heart atrophy, decreased markers of cardiac injury, and improved cardiac function in mice. Moreover, tetrandrine supplementation protected the mice against oxidative damage and myocardial apoptotic death. Tetrandrine supplementation also reduced ROS production and improved cell viability after DOX exposure in vitro. We also found that tetrandrine supplementation increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression and activity in vivo and in vitro. The protection of tetrandrine supplementation was blocked by Nrf2 deficiency in mice. In conclusion, our study found that tetrandrine could improve cardiac function and prevent the development of DOX-related cardiac injury through activation of Nrf2.

Download Full-text

Melatonin reduces oxidative damage in mouse granulosa cells via restraining JNK-dependent autophagy

Reproduction ◽

10.1530/rep-18-0002 ◽

2018 ◽

Vol 155 (3) ◽

pp. 307-319 ◽

Cited By ~ 7

Author(s):

Yan Cao ◽

Ming Shen ◽

Yi Jiang ◽

Shao-chen Sun ◽

Honglin Liu

Keyword(s):

Oxidative Stress ◽

Oxidative Damage ◽

Mammalian Cells ◽

Therapeutic Strategies ◽

Oxygen Species ◽

Protective Effects ◽

Follicular Atresia ◽

Direct Role ◽

Jnk Pathway

Oxidative stress-induced granulosa cell (GCs) injury is believed to be a common trigger for follicular atresia. Emerging evidence indicates that excessive autophagy occurs in mammalian cells with oxidative damage. N-acetyl-5-methoxytrypamine (melatonin) has been shown to prevent GCs from oxidative injury, although the exact mechanism remains to be elucidated. Here, we first demonstrated that the suppression of autophagy through the JNK/BCL-2/BECN1 signaling is engaged in melatonin-mediated GCs protection against oxidative damage. Melatonin inhibited the loss of GCs viability, formation of GFP-MAP1LC3B puncta, accumulation of MAP1LC3B-II blots, degradation of SQSTM1 and the expression of BECN1, which was correlated with impaired activation of JNK during oxidative stress. On the other hand, blocking of autophagy and/or JNK also reduced the level of H2O2-induced GCs death, but failed to further restore GCs viability in the presence of melatonin. Particularly, the suppression of autophagy provided no additional protective effects when GCs were pretreated with JNK inhibitor and/or melatonin. Importantly, we found that the enhanced interaction between BCL-2 and BECN1 might be a responsive mechanism for autophagy suppression via the melatonin/JNK pathway. Moreover, blocking the downstream antioxidant system of melatonin using specific inhibitors further confirmed a direct role of melatonin/JNK/autophagy axis in preserving GCs survival without scavenging reactive oxygen species (ROS). Taken together, our findings uncover a novel function of melatonin in preventing GCs from oxidative damage by targeting JNK-mediated autophagy, which might contribute to develop therapeutic strategies for patients with ovulation failure-related disorders.

Download Full-text

Ultraendurance exercise increases the production of reactive oxygen species in isolated mitochondria from human skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.00966.2009 ◽

2010 ◽

Vol 108 (4) ◽

pp. 780-787 ◽

Cited By ~ 47

Author(s):

Kent Sahlin ◽

Irina G. Shabalina ◽

C. Mikael Mattsson ◽

Linda Bakkman ◽

Maria Fernström ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Oxidative Damage ◽

Vastus Lateralis ◽

Reactive Oxygen ◽

Ros Production ◽

Oxygen Species ◽

Work Intensity ◽

Isolated Mitochondria ◽

Mitochondrial Ros

Exercise-induced oxidative stress is important for the muscular adaptation to training but may also cause muscle damage. We hypothesized that prolonged exercise would increase mitochondrial production of reactive oxygen species (ROS) measured in vitro and that this correlates with oxidative damage. Eight male athletes (24–32 yr) performed ultraendurance exercise (kayaking/running/cycling) with an average work intensity of 55% V̇o2peak for 24 h. Muscle biopsies were taken from vastus lateralis before exercise, immediately after exercise, and after 28 h of recovery. The production of H2O2 was measured fluorometrically in isolated mitochondria with the Amplex red and peroxidase system. Succinate-supported mitochondrial H2O2 production was significantly increased after exercise (73% higher, P = 0.025) but restored to the initial level at recovery. Plasma level of free fatty acids (FFA) increased fourfold and exceeded 1.2 mmol/l during the last 6 h of exercise. Plasma FFA at the end of exercise was significantly correlated to mitochondrial ROS production ( r = 0.74, P < 0.05). Mitochondrial content of 4-hydroxy-nonenal-adducts (a marker of oxidative damage) was increased only after recovery and was not correlated with mitochondrial ROS production. Total thiol group level and glutathione peroxidase activity were elevated after recovery. In conclusion, ultraendurance exercise increases ROS production in isolated mitochondria, but this is reversed after 28 h recovery. Mitochondrial ROS production was not correlated with oxidative damage of mitochondrial proteins, which was increased at recovery but not immediately after exercise.

Download Full-text

Synthesis and in vitro Studies of Pyrone Derivatives as Scavengers of Active Oxygen Species

Arzneimittelforschung ◽

10.1055/s-0031-1300131 ◽

2011 ◽

Vol 51 (11) ◽

pp. 877-884

Author(s):

Valérie Weber ◽

Pascal Coudert ◽

Eliane Duroux ◽

Fernand Leal ◽

Jacques Couquelet ◽

...

Keyword(s):

Active Oxygen Species ◽

Active Oxygen ◽

In Vitro Studies ◽

Oxygen Species

Download Full-text

Scavenged Effects of Cu(II) Chelates of Imidazole and Thiazole Derivatives on the Active Oxygen Species in vitro.

Eisei kagaku ◽

10.1248/jhs1956.39.56 ◽

1993 ◽

Vol 39 (1) ◽

pp. 56-62

Author(s):

TERUHISA HIRAYAMA ◽

YASUO MORI ◽

JUNKO KANDA ◽

SATOSHI IKEUCHI ◽

NORIKO TANAKA ◽

...

Keyword(s):

Active Oxygen Species ◽

Active Oxygen ◽

Oxygen Species ◽

Thiazole Derivatives

Download Full-text

Selective oxidation of histidine residues in proteins or peptides through the copper(II)-catalysed autoxidation of glucosone

Biochemical Journal ◽

10.1042/bj2850667 ◽

1992 ◽

Vol 285 (2) ◽

pp. 667-671 ◽

Cited By ~ 16

Author(s):

R Z Cheng ◽

K Uchida ◽

S Kawakishi

Keyword(s):

Oxidative Damage ◽

Active Oxygen Species ◽

Oxidative Degradation ◽

Imidazole Ring ◽

Active Oxygen ◽

Oxygen Species ◽

Selective Degradation ◽

Sugar Moiety ◽

Amadori Compound ◽

Model Protein

Glucosone has been identified as the main intermediate sugar moiety product of the copper(II)-catalysed autoxidation of the Amadori compound [Kawakishi, Tsunehiro & Uchida (1991) Carbohydr. Res. 211, 167-171]. Oxidative fragmentation of the model protein, especially selective degradation of the histidine residue in protein or peptides mediated by the copper(II)-catalysed autoxidation of glucosone, is discussed in this paper. The oxidative damage to protein could be retarded by catalase (EC 1.11.1.16) and EDTA, while superoxide dismutase (EC 1.15.1.1) and hydroxyradical scavengers showed little effect. Through the process of the oxidative degradation of N-benzoylhistidine and other histidine-containing peptides, the oxidation of the imidazole ring in histidine caused by the glucosone-copper(II) system was the same as that by the ascorbate-copper(II) system. These facts suggest that the copper-catalysed autoxidation of glucosone could generate some active-oxygen species causing oxidative damage to protein similar to that caused by the ascorbate-copper(II) system.

Download Full-text

ChemInform Abstract: Synthesis and in vitro Studies of Pyrone Derivatives as Scavengers of Active Oxygen Species.

ChemInform ◽

10.1002/chin.200210121 ◽

2010 ◽

Vol 33 (10) ◽

pp. no-no

Author(s):

Valerie Weber ◽

Pascal Coudert ◽

Eliane Duroux ◽

Fernand Leal ◽

Jacques Couquelet ◽

...

Keyword(s):

Active Oxygen Species ◽

Active Oxygen ◽

In Vitro Studies ◽

Oxygen Species

Download Full-text

Oxidative Stress, Mutations and Chromosomal Aberrations Induced by In Vitro and In Vivo Exposure to Furan

International Journal of Molecular Sciences ◽

10.3390/ijms22189687 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9687

Author(s):

Maria Teresa Russo ◽

Gabriele De Luca ◽

Nieves Palma ◽

Paola Leopardi ◽

Paolo Degan ◽

...

Keyword(s):

Thermal Processing ◽

Mammalian Cells ◽

Mutagenic Activity ◽

Critical Role ◽

Dna Lesions ◽

Sufficient Evidence ◽

Chromosomal Damage ◽

Vast Number

Furan is a volatile compound that is formed in foods during thermal processing. It is classified as a possible human carcinogen by international authorities based on sufficient evidence of carcinogenicity from studies in experimental animals. Although a vast number of studies both in vitro and in vivo have been performed to investigate furan genotoxicity, the results are inconsistent, and its carcinogenic mode of action remains to be clarified. Here, we address the mutagenic and clastogenic activity of furan and its prime reactive metabolite cis-2 butene-1,4-dial (BDA) in mammalian cells in culture and in mouse animal models in a search for DNA lesions responsible of these effects. To this aim, Fanconi anemia-derived human cell lines defective in the repair of DNA inter-strand crosslinks (ICLs) and Ogg1−/− mice defective in the removal of 8-hydroxyguanine from DNA, were used. We show that both furan and BDA present a weak (if any) mutagenic activity but are clear inducers of clastogenic damage. ICLs are strongly indicated as key lesions for chromosomal damage whereas oxidized base lesions are unlikely to play a critical role.

Download Full-text

Principles for assessing the genotoxicity of carbon nanomaterials in vitro (on the example of carbon nanotubes) (literature review)

Токсикологический вестник ◽

10.36946/0869-7922-2021-29-6-16-23 ◽

2021 ◽

Vol 29 (6) ◽

pp. 16-23

Author(s):

Gulnaz Faezovna Gabidinova ◽

Gyuzel Abdulkhalimovna Timerbulatova ◽

Liliya Minvagizovna Fatkhutdinova

Keyword(s):

Carbon Nanomaterials ◽

Physicochemical Characterization ◽

Gene Mutations ◽

Micronucleus Assay ◽

Bibliographic Databases ◽

Chromosomal Damage ◽

Colorimetric Test ◽

Wide Range ◽

Dna Strand

Introduction. Genotoxicity of nanomaterials (NM) is becoming a major concern when investigating new NM for their safety. Each mutagen is considered to be potentially carcinogenic, therefore a genotoxicity assessment is necessary. However, a clear strategy for assessing the genotoxic effect of NM has not yet been developed. Material and methods. The material for the analysis have included literature sources from the bibliographic databases PubMed, Scopus, RSCI. Results. Physicochemical characterization of NM is carried out using high-resolution microscopic and light scattering methods. Before testing for genotoxicity, it is necessary to know the cytotoxicity of the tested NM in order to select the appropriate concentration range. The most important and significant tests are based on the cell viability. MTT assay is a colorimetric test that evaluates the metabolic activity of cells. In addition, viability can be determined using microscopy, flow cytometry, determination of lactate dehydrogenase. Genotoxicity evaluation can be carried out only after the preliminary steps. The strategy should include genotoxicity endpoints: DNA damage, gene mutations, chromosomal damage. The in vitro mammalian gene mutation test, usually performed using mouse lymphoma cells, detects a wide range of genetic damage, including gene deletions. The most common test for detecting chromosomal damage is an in vitro micronucleus assay. DNA strand breaks are most often assessed using the comet DNA assay. Conclusion. Compulsory stages in the study of the genotoxicity of nanomaterials should be preliminary studies, including physicochemical characterization and assessment of cytotoxicity, as well as the study of the endpoints of genotoxicity and potential mechanisms.

Download Full-text