DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity

Hyperthermia induces therapeutic effectiveness and potentiates adjuvant therapy with nontargeted and targeted drugs in an in vitro model of human malignant melanoma

In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an in vitro model of human malignant melanoma and furthermore, to evaluate its therapeutic effectiveness in an adjuvant therapeutic setting characterized by combinational treatments with non-targeted (Dacarbazine & Temozolomide) and targeted (Dabrafenib & Vemurafenib) drugs. Overall, our data showed that both low (43 °C) and high (45 °C) hyperthermic exposures were capable of inducing cell death by activating all apoptotic pathways but in a rather distinct manner. More specifically, low hyperthermia induced extrinsic and intrinsic apoptotic pathways both of which activated caspase 6 only as opposed to high hyperthermia which was mediated by the combined effects of caspases 3, 7 and 6. Furthermore, significant involvement of the ER was evident (under both hyperthermic conditions) suggesting its role in regulating apoptosis via activation of CHOP. Our data revealed that while low hyperthermia activated IRE-1 and ATF6 only, high hyperthermia induced activation of PERK as well suggesting that ultimately these ER stress sensors can lead to the induction of CHOP via different pathways of transmitted signals. Finally, combinational treatment protocols revealed an effect of hyperthermia in potentiating the therapeutic effectiveness of nontargeted as well as targeted drugs utilized in the clinical setting. Overall, our findings support evidence into hyperthermia’s therapeutic potential in treating human malignant melanoma by elucidating the underlying mechanisms of its complex apoptotic induction

Photophysical Properties and Ultrafast Excited-State Dynamics of a New Two-Photon Absorbing Thiopyranyl Probe

Comprehensive linear photophysical and photochemical characterization, two-photon absorption (2PA) properties, and femtosecond excited-state dynamics of a symmetrical fluorene derivative 2-(2,6-bis((E)-2-(7-(diphenylamino)-9,9- dihexyl-9H-fluoren-7-yl)vinyl)-4H-thiopyran-4-ylidene)malononitrile (1) are reported. The linear one-photon absorption (1PA), steady-state fluorescence, excitation, and excitation anisotropy spectra of 1 were investigated in organic solvents of different polarities at room temperature, exhibiting rather complex absorption and emission behavior. The relatively strong 2PA of thiopyranyl 1 was investigated by the open aperture femtosecond Z-scan technique in the main long wavelength 1PA contour with maxima cross sections up to 600-700 GM. Femtosecond dynamics of the excited-state absorption (ESA) and gain processes in 1 exhibited fast complicated relaxation phenomena with a strong dependence on solvent polarity and a weak dependence on excitation wavelength. The nature of the observed transient absorption kinetics was explained based on the short-lived ESA bands of 1 and solvate relaxation phenomena. Quantum chemical calculations, based on density functional theory, were employed for additional analysis of the 1PA and 2PA properties of 1. © 2013 American Chemical Society