Role of antioxidants in the neurobiology of drug addiction: An update.

Relationships between protective enzymatic and non-enzymatic pro-antioxidant mechanisms and addictive substances use disorders (SUDs) are analyzed here, based on the results of previous research, as well as on the basis of our current own studies. This review introduces new aspects of comparative analysis of associations of pro-antixidant and neurobiological effects in patients taking psychoactive substances and complements very limited knowledge about relationships with SUDs from different regions, mainly Europe. In view of the few studies on relations between antioxidants and neurobiological processes acting in patients taking psychoactive substances, this review is important from the point of view of showing the state of knowledge, directions of diagnosis and treatment, and further research needed explanation. We found significant correlations between chemical elements, pro-antioxidative mechanisms, and lipoperoxidation in the development of disorders associated with use of addictive substances, therefore elements that show most relations (Pr, Na, Mn, Y, Sc, La, Cr, Al, Ca, Sb, Cd, Pb, As, Hg, Ni) may be significant factors shaping SUDs. The action of pro-antioxidant defense and lipid peroxidation depends on the pro-antioxidative activity of ions. We explain the strongest correlations between Mg and Sb, and lipoperoxidation in addicts, which proves their stimulating effect on lipoperoxidation and on the induction of oxidative stress. We discussed which mechanisms and neurobiological processes change susceptibility to SUDs. The innovation of this review is to show that addicted people have lower activity of dismutases and peroxidases than healthy ones, which indicates disorders of antioxidant system and depletion of enzymes after long-term tolerance of stressors. We explain higher level of catalases, reductases, ceruloplasmin, bilirubin, retinol, α-tocopherol and uric acid of addicts. In view of poorly understood factors affecting addiction, analysis of interactions allows for more effective understanding of pathogenetic mechanisms leading to formation of addiction and development the initiation of directed, more effective treatment (pharmacological, hormonal) and may be helpful in the diagnosis of psychoactive changes.

Evaluation of polymorphisms and expression of PTPN22, NLRP1 and TYR genes in vitiligo patients.

Introduction: Vitiligo is a pigmentary disorder associated with a selective loss of melanocytes in the skin, its appendages and mucous membranes. Aim: The aim of the study was to evaluate the association between the rs2476601 polymorphism of the PTPN22 gene, the rs2670660 and rs6502867 polymorphisms of the NLRP1 gene and the rs1847134 and rs1393350 polymorphisms of the TYR gene and vitiligo. Another aim was to compare the gene expression in lesional and symmetrically non-lesional skin of vitiligo patients and healthy controls. Material and methods: The experimental group consisted of 42 patients and the control group consisted of 38 healthy volunteers. The polymorphisms of the genes were assessed with PCR-RFLP technique and gene expression with qRT-PCR technique. Results: We found that the CT genotype of the PTPN22 rs2476601 polymorphism is more frequent in vitiligo patients, in the case of the NLRP1 rs2670660 polymorphism it was the AG genotype, in the NLRP1 rs6502867 polymorphism they were the CT and CC genotypes and in the TYR rs1393350 polymorphism it was the AG genotype. There was no association between vitiligo and the TYR rs1847134 polymorphism. We found statistically significant differences in gene expression in the lesional and symmetrical non-lesional skin of vitiligo patients compared to the control group. Conclusions: Our analysis showed genotypes predisposing to vitiligo. We found that the gene expression is different not only in lesional but also in non-lesional skin of vitiligo patients, what may change the approach to treatment of the disease.

Management of Stable Vitiligo-A Review of the Surgical Approach.

At present, vitiligo is the most common depigmenting skin disorder, characterized by clearly demarcated discolored patches of various shapes and sizes. Depigmentation results from the initial dysfunction and subsequent destruction of melanin-producing cells, called melanocytes, which are located in the basal layer of the epidermis and in hair follicles. This review concludes that the extent of repigmentation, regardless of the treatment method, is greatest in stable localized vitiligo patients. The aim of this review is to provide an overview of the clinical evidence for which the vitiligo treatment method (cellular or tissue) is more effective. The treatment relies on multiple factors, ranging from patient skin predisposition for repigmentation to the experience of the facility performing the procedure. Vitiligo is a significant problem in modern society. Although it is a typically asymptomatic and not life-threatening disease, it may have significant psychological and emotional impacts. Standard treatment relies on pharmacotherapy and phototherapy; however, the treatment of patients with stable vitiligo varies. The stability of vitiligo more than often implies the exhaustion of the potential for skin self-repigmentation. Thus, the surgical methods that distribute normal melanocytes into the skin are crucial elements of these patients' therapy. The most commonly used methods are described in the literature, with an indication of their recent progress and changes. In addition, information on the efficiency of the individual methods at specific locations is compiled in this study, and the prognostic factors indicating repigmentation are presented. Cellular methods are the best therapeutic option for large-sized lesions; although they are more exorbitant than tissue methods, they benefit from more rapid healing times and presenting fewer side effects. Dermoscopy is a valuable tool used to assess the further course of repigmentation, where it is of great value to evaluate the patient prior to and following an operation.

Does HSP90 play an important role in psoriasis?

Introduction: Psoriasis is a chronic, inflammatory skin disease. Environmental, genetic, autoinflammatory and autoimmune factors play a role in the pathogenesis of disease. It is believed that heat shock protein 90 (HSP90) is an interleukin-17 (IL-17) receptor, which plays an essential role in the psoriasis pathogenesis. Aim: To evaluate the expression of the gene encoding HSP90 protein in keratinocytes of patients with psoriasis depending on its duration, recurrences, exacerbating factors, therapy form, and the coexistence of metabolic disorders and cardiovascular diseases. Material and methods: Skin samples from 40 psoriatic patients were investigated in this study. Control skin biopsies were collected from 20 healthy volunteers. HSP90 expression level was measured by qRT-PCR reaction. Results: This study has shown an increased mRNA expression of HSP90 in psoriatic patients as compared to healthy volunteers. A positive correlation of HSP90 expression and the frequency of exacerbations was found. A negative correlation between the HSP90 activity and the age of patients was demonstrated in the coexistence of psoriasis with hyperlipidaemia or diabetes. Among the factors exacerbating psoriasis, acute infections induced HSP90 expression most significantly. Conclusions: HSP90 plays a role in the pathogenesis of psoriasis. The expression of HSP90 increases with the frequency of exacerbations of psoriasis throughout the year. Hyperlipidaemia or diabetes associated with psoriasis in young adults, and acute infections and emotional stress increase the expression of HSP90. The expression of HSP90 in psoriatic patients is not dependent on the type of psoriasis, comorbidity of cardiovascular diseases, smoking and alcohol addiction.

Paclitaxel and the dietary flavonoid fisetin: a synergistic combination that induces mitotic catastrophe and autophagic cell death in A549 non-small cell lung cancer cells.

BACKGROUND: The use of the dietary polyphenols as chemosensitizing agents to enhance the efficacy of conventional cytostatic drugs has recently gained the attention of scientists and clinicians as a plausible approach for overcoming the limitations of chemotherapy (e.g. drug resistance and cytotoxicity). The aim of this study was to investigate whether a naturally occurring diet-based flavonoid, fisetin, at physiologically attainable concentrations, could act synergistically with clinically achievable doses of paclitaxel to produce growth inhibitory and/or pro-death effects on A549 non-small cell lung cancer cells, and if it does, what mechanisms might be involved. METHODS: The drug-drug interactions were analyzed based on the combination index method of Chou and Talalay and the data from MTT assays. To provide some insights into the mechanism underlying the synergistic action of fisetin and paclitaxel, selected morphological, biochemical and molecular parameters were examined, including the morphology of cell nuclei and mitotic spindles, the pattern of LC3-II immunostaining, the formation of autophagic vacuoles at the electron and fluorescence microscopic level, the disruption of cell membrane asymmetry/integrity, cell cycle progression and the expression level of LC3-II, Bax, Bcl-2 and caspase-3 mRNA. RESULTS: Here, we reported the first experimental evidence for the existence of synergism between fisetin and paclitaxel in the in vitro model of non-small cell lung cancer. This synergism was, at least partially, ascribed to the induction of mitotic catastrophe. The switch from the cytoprotective autophagy to the autophagic cell death was also implicated in the mechanism of the synergistic action of fisetin and paclitaxel in the A549 cells. In addition, we revealed that the synergism between fisetin and paclitaxel was cell line-specific as well as that fisetin synergizes with arsenic trioxide, but not with mitoxantrone and methotrexate in the A549 cells. CONCLUSIONS: Our results provide rationale for further testing of fisetin in the combination with paclitaxel or arsenic trioxide to obtain detailed insights into the mechanism of their synergistic action as well as to evaluate their toxicity towards normal cells in an animal model in vivo. We conclude that this study is potentially interesting for the development of novel chemotherapeutic approach to non-small cell lung cancer.

Correlation of SATB1 expression with clinical course of cutaneous T-cell lymphomas.

Cutaneous T-cell lymphomas (CTCLs) are slowly progressive diseases with a poor prognosis. There are no specific prognostic factors in development of cutaneous lymphomas. SATB1 protein controls expression of many genes, including the cellular cycle and apoptosis. The subject of our study was the expression of SATB1 protein in the skin sample in patients with mycosis fungoides and Sezary syndrome and its correlation with clinical course. Immunohistochemical reaction with SATB1 antibody was observed in 29 cases of mycosis fungoides of different stages (15 patients) and two cases of Sezary syndrome. SATB1 expression was observed in 22 cases of mycosis fungoides, 7 of which were in the patch stage, 11 were in the plaque stage and 4 were in the tumor stage. SATB1 expression was not found in 2 cases of the patch stage, 4 cases of the plaque stage and one case of the tumor stage. Negative reaction was confirmed in both cases of the Sezary syndrome. There were no changes in SATB1 expression during progression of the disease. A group of patients with the positive reaction of the SATB1 is characterized by a noticeably longer time to progression between the stages. The SATB1 expression seems to be a potential prognosis factor confirming the inner heterogeneous features of CTCLs.

Transplantation of cultured autologous melanocytes: hope or danger?

Cultured human melanocytes are increasingly being used in the treatment of vitiligo. The growth media contain various types of mitogenic factors, both recombinant human (e.g., rhbFGF and rhSCF) and synthetic (e.g., TPA). High concentrations of mitogenic factors accelerate the cell cycle, and consequently may increase the risk of carcinogenesis of transplanted cells. Mutations of genes of the RAS/RAF/MEK/ERK signaling pathway are very often found in the early stages of the development of melanoma. TPA is considered to be an oncogenic factor, but so far there is no evidence to show that it is responsible for damage to the genetic material of cultured melanocytes. The aim of our study was to assess the risk of the development of mutations in selected genes of the RAS/RAF/MEK/ERK signaling pathway during the culturing of melanocytes in various growth media. Based on the results obtained, it can be concluded that TPA and high concentrations of other growth factors intensify the proliferation of melanocytes, without the risk of damage to the HRAS (exon 1 and 2), KRAS (exon 1 and 2), NRAS (exon 1 and 2), and BRAF (exon 11 and 15) genes. In order to assess the total safety of the transplantation of cultured melanocytes, it is necessary to carry out further studies on other signaling pathways as well as carry out biological tests on an animal model.