Doxorubicin-induced acute cardiotoxicity is associated with increased oxidative stress, autophagy, and inflammation in a murine model.

Drug-induced cardiotoxicity is a life-threatening side effect of doxorubicin (DOX) treatment that impacts patient prognosis and survival. In the majority of cases, the acute clinical form often remains asymptomatic, with few patients presenting rather nonspecific electrocardiographic abnormalities. While chronic toxicity has been more widely studied, the alterations appearing in acute cardiotoxicity are much less investigated. Thus, our in vivo study aimed to evaluate the process of DOX-induced acute myocardial toxicity by investigating oxidative stress and autophagy markers as mechanisms of myocardial toxicity in correlation with echocardiography and electrocardiography findings. Our results show that both autophagy and oxidative homeostasis were disrupted as soon as 7 days after DOX treatment, alterations that occurred even before the significant increase of NT-proBNP, a clinical marker for cardiac suffering. Moreover, we found a large number of alterations in the electrocardiography and echocardiography of treated rats. These findings suggest that DOX-induced myocardial toxicity started early after treatment initiation, possibly marking the initial phase of the unfolding process of cardiac damage. Further studies are required to completely decipher the mechanisms of DOX-induced cardiotoxicity.

Application of Fuzzy Logic in Oral Cancer Risk Assessment.

BACKGROUND: The mapping of the malignization mechanism is still incomplete, but oxidative stress is strongly correlated to carcinogenesis. In our research, using fuzzy logic, we aimed to estimate the oxidative stress related-cancerization risk of the oral potentially malignant disorders. METHODS: Serum from 16 patients diagnosed (clinical and histopathological) with oral potentially malignant disorders (Dept. of Cranio-Maxillofacial Surgery and Radiology, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj Napoca, Romania) was processed fluorometric for malondialdehyde and proton donors assays (Dept. of Physiology,"Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania). The values were used as inputs, they were associated linguistic terms using MIN-MAX method and 25 IF-THEN inference rules were generated to estimate the output value, the cancerization risk appreciated on a scale from 1 to 10 - IF malondialdehyde is very high and donors protons are very low THEN the cancer risk is reaching the maximum value (Dept. of Industrial Engineering, Faculty of Managerial and Technological Engineering, University of Oradea, Oradea, Romania) (2012-2014). RESULTS: We estimated the cancerization risk of the oral potentially malignant disorders by implementing the multi-criteria decision support system based on serum malondialdehyde and proton donors' values. The risk was estimated as a concrete numerical value on a scale from 1 to 10 depending on the input numerical/linguistic value. CONCLUSION: The multi-criteria decision support system proposed by us, integrated into a more complex computerized decision support system, could be used as an important aid in oral cancer screening and establish future medical decision in oral potentially malignant disorders.

Toxicity and efficiency study of plant extracts-based bleaching agents.

OBJECTIVES: Tooth bleaching is one of the most required dental esthetic treatments. However, it can generate side effects like oral irritation, enamel alteration, tooth sensitivity, especially caused by hydrogen peroxide, the main bleaching component of the commercial products. Therefore, development of new tooth bleaching agents, based on natural products, with comparable esthetic results and lower side effects is needed. The aim of this study was to evaluate the biological effects and bleaching efficacy of four experimental bleaching agents, derived from fruit juices, against the commercially available Opalescence (Ultradent, USA). MATERIALS AND METHODS: Organic acid composition of the gels was characterized by HPLC. Bleaching efficiency was tested by spectrophotometry on composite restorative materials. Biological testing was done in vitro, on human fibroblasts. Cells were exposed to dilutions of the bleaching gel-conditioned medium. Viability was measured by MTS, apoptosis by FACS-AnnexinV FITC/Propidium iodide, NF-kB activation by western blot, malondyaldehide, and superoxide dismutase activity by spectrophotometry. RESULTS: All gels exhibited physical stability and dental bleaching capabilities. Experimental gels induced significantly better viability and apoptosis rates, lower lipid peroxidation, and increased antioxidant defense, compared to Opalescence. CONCLUSIONS: The studied experimental gel formulations exhibited a good safety profile in vitro, as well as bleaching efficiency on restorative composite materials. CLINICAL RELEVANCE: These data open new possibilities for the use of new natural products in dental bleaching treatments that can insure significant esthetic results and lower side effects.

Photodynamic therapy of melanoma using new, synthetic porphyrins and phthalocyanines as photosensitisers - a comparative study.

UNLABELLED: Melanoma, a cancer that arises from melanocytes, is one of the most unresponsive cancers to known therapies and has a tendency to produce early metastases. Several studies showed encouraging results of the efficacy of photodynamic therapy (PDT) in melanoma, in different experimental settings in vitro and in vivo, as well as several clinical reports. AIMS: Our study focuses on testing the antimelanoma efficacy of several new, synthetic photosensitisers (PS), from two different chemical classes, respectively four porphyrins and six phthalocyanines. METHODS: These PS were tested in terms of cell toxicity and phototoxicity against a radial growth phase melanoma cell line (WM35), in vitro. Cells were exposed to different concentrations of the PS for 24h, washed, then irradiatied with red light (630 nm) 75 mJ/cm(2) for the porphyrins and 1 J/cm(2) for the phthalocyanines. Viability was measured using the MTS method. RESULTS: Two of the synthetic porphyrins, TTP and THNP, were active photosensitizers against WM35 melanoma in vitro. Phthalocyanines were effective in producing a dose dependent PDT-induced decrease in viability in a dose-dependent manner. The most efficient was Indium (III) Phthalocyanine chloride, a metal substituted phthalocyanine. CONCLUSIONS: The most efficient photosensitizers for PDT in melanoma cells were the phthalocyanines in terms of tumor cell photokilling and decreased dark toxicity.

Current position of TNF-α in melanomagenesis.

Melanoma is one of the most heterogeneous and immunogenic forms of cancer. Both tumor and stroma cells synthesize many cytokines involved in rapid development and metastasis. One of these cytokines from the tumor milieu is tumor necrosis factor-alpha (TNF-α), which seems to have an intricate role in melanomagenesis. Initially, it was found that TNF-α can induce apoptosis of tumor cells through both extrinsic and intrinsic pathways, in contrast with later studies that revealed its protumoral activity. TNF-α is involved in inflammation, inducing the secretion of survival molecules like antiapoptotic proteins, proangiogenetic factors and metastasis markers. Although there are many therapeutic strategies against melanoma, the prognosis of advanced stages remains poor, due to several tumor resistance mechanisms. TNF seems to be a negative prognostic factor in melanoma surgery and correlates with chemotherapy resistance. However, high intratumoral levels of TNF-α might be beneficial for immunotherapy. Researchers may redirect their studies in the future by double activating of the proinflammatory molecule TNF-α and the immune cells in order to obtain an antitumoral response in metastatic melanoma.

Efficiency of photodynamic therapy on WM35 melanoma with synthetic porphyrins: Role of chemical structure, intracellular targeting and antioxidant defense.

Photodynamic therapy (PDT) could be an adjuvant therapy in melanoma, an aggressive cancer that arises from melanocytes. Several reports showed encouraging results of the efficacy of PDT in melanoma on experimental models and in clinical trials. Therefore, we studied the efficacy of two derivatives of tetraphenylporphyrin (TPP): meso-5,10,15,20-tetrakis (4-hydroxyphenyl) porphyrin (THOPP) and meso-5-(4-hydroxyphenyl)-10,15,20-tris (4-methoxyphenyl) porphyrin (THOMPP) as photosensitizers for PDT, compared to FDA approved delta aminolevulinic acid (ALA) against a lightly pigmented, melanoma cell line, WM35, in vitro. Both porphyrins were more efficient as photosensitizers, compared to ALA, without dark toxicity. The efficiency depended on the intracellular localization and the molecule structure. THOPP, the most efficient porphyrin localized mainly in mitochondria, while THOMPP accumulated in lysosomes; both showed melanosomal localization. The symmetric THOPP molecule was able to generate increased oxidative stress damage and apoptosis. THOPP also induced a low effect on the defense mechanisms like antioxidant enzyme SOD (superoxide dismutase), NF-kB (nuclear transcription factor kB) activation and MITF (microphthalmia transcription factor). The lower efficiency of the asymmetric molecule, THOMPP was probably due to a diminished photoactivation, which led to a lower ROS induced damage, combined with higher activation of the defense mechanisms.

Grape seed extract effects in brain after hypobaric hypoxia.

Hypoxia induces a wide range of deleterious effects at the cellular level due to an increased production of reactive oxygen species (ROS). Polyphenols from grape seeds, which are potent antioxidants might protect the brain against oxidative stress produced by hypobaric hypoxia. The brain effects of three doses of grape seed extract intraperitoneally (i.p.) administered in rats after exposure to hypobaric hypoxia corresponding to 5500 m altitude were investigated. Some oxygen and nitrogen reactive species, inflammatory cytokine (IL-6) and molecules involved in angiogenesis (vascular endothelial growth factor [VEGF], matrix metalloproteinase 2 [MMP2], and tissue inhibitors of metalloproteinase 1 [TIMP1]) were determined. Forty-two rats were divided in seven groups: group 1, control; groups 2, 3, and 4 were exposed to hypobaric hypoxia for 24 h in a hypobaric chamber; groups 5, 6, and 7 were exposed to hypobaric hypoxia for 5 days. After returning to normal atmospheric pressure, rats from groups 2 and 5 were sacrificed without other treatment. Animals from groups 3 and 6 were i.p treated with carboxymethyl cellulose (CMC) vehicle and those from groups 4 and 7 were i.p. treated with grape seed extract (GSE) (50 mg gallic acid equivalents/kg body weight in 0.5 mL CMC suspension/animal). The treatment was applied at 2, 24, and 72 h from returning to normoxia. Hypobaric hypoxia produced increased brain levels of ROS, nitric oxide (NO), IL-6, and VEGF after both time intervals (P<.05). The MMP2 concentration was significantly increased in groups treated only with vehicle, whereas TIMP1 was slightly changed. GSE produced a significant reduction of ROS and NO levels proving its antioxidant capacity. It also decreased IL-6 and MMP2 concentrations to values similar to controls. The VEGF concentration was also significantly reduced. These effects are indicative for anti-inflammatory and antiangiogenic properties of GSE.

New nanomaterials for the improvement of psoriatic lesions.

The main purpose of the present paper is to emphasize the non-invasive effect of some new prepared nanomaterials on skin diseases (psoriasis) together with the procedures to obtain them. These new materials are based on gold nanoparticles and natural compounds extracted from native plants of the Adoxaceae family (European cranberrybush -Viburnum opulus L. and European black elderberry -Sambucus nigra L.) and possess a known anti-inflammatory activity mainly due to their high content of anthocyanins and other polyphenols. The nanomaterials were characterized by transmission electron microscopy (TEM), UV-Vis spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX) and thermogravimetric analysis (TGA). Studies in vivo and in vitro were made in order to determine the toxicity of the products. Based on the obtained nanomaterials, specific dermatological creams were prepared. Their effect on psoriatic lesions, in comparison with the hydrocortisone creams, was studied.

Photodynamic therapy--indications and limits in malignant tumors treatment.

Photodynamic therapy (PDT) is a very promising technique used for the treatment of a variety of solid neoplasms, based on the formation of singlet oxygen induced by a photosensitizer after irradiation with visible light. The mechanism of interaction of the photosensitizers and light is discussed, along with the effects produced in the target tissue. PDT has been approved in many countries for the treatment of lung, esophageal, bladder, skin and head and neck cancers. The antitumor effects of this treatment result from the combination of direct tumor cell photodamage, destruction of tumor vasculature and activation of an immune response. The present status of clinical PDT is discussed along with the newer photosensitizers being used and their clinical roles. Despite the promising results from earlier clinical trials of PDT considerable additional work is needed to bring this new modality of treatment into modern clinical practice.