Environmental and Genetic Determinants of Ankylosing Spondylitis.

Exposure to heavy metals and lifestyle factors like smoking contribute to the production of free oxygen radicals. This fact, combined with a lowered total antioxidant status, can induce even more damage in the development of ankylosing spondylitis (AS). Despite the fact that some researchers are looking for more genetic factors underlying AS, most studies focus on polymorphisms within the genes encoding the human leukocyte antigen (HLA) system. The biggest challenge is finding the effective treatment of the disease. Genetic factors and the influence of oxidative stress, mineral metabolism disorders, microbiota, and tobacco smoking seem to be of great importance for the development of AS. The data contained in this review constitute valuable information and encourage the initiation and development of research in this area, showing connections between inflammatory disorders leading to the pathogenesis of AS and selected environmental and genetic factors.

11ß-HSD as a New Target in Pharmacotherapy of Metabolic Diseases.

Glucocorticoids (GCs), which are secreted by the adrenal cortex, are important regulators in the metabolism of carbohydrates, lipids, and proteins. For the proper functioning of the body, strict control of their release is necessary, as increased GCs levels may contribute to the development of obesity, type 2 diabetes mellitus, hypertension, cardiovascular diseases, and other pathological conditions contributing to the development of metabolic syndrome. 11ß-hydroxysteroid dehydrogenase type I (11ß-HSD1) locally controls the availability of the active glucocorticoid, namely cortisol and corticosterone, for the glucocorticoid receptor. Therefore, the participation of 11ß-HSD1 in the development of metabolic diseases makes both this enzyme and its inhibitors attractive targets in the pharmacotherapy of the above-mentioned diseases.

Enzymatic Antioxidant Defense and Polymorphic Changes in Male Infertility.

The intensification of oxidative stress and destabilization of the antioxidative defenses of an organism is a consequence of many environmental factors. We considered aspects conditioning male reproductive potential and the functionality of enzymatic antioxidative mechanisms, i.e., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR), and their correlations with Li, Be, B, Na, Mg, Al, P, K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Sr, Mo, Ag, Cd, Sn, Sb, Ba, Hg, Tl, Pb, and malondialdehyde (MDA), as well as genetic polymorphism IL-4v.C589T (rs2243250) in men with infertility (n = 76). A healthy normozoospermic control (n = 87) was also used. We assessed the impact of negative changes driven by oxidative stress on enzymatic antioxidative mechanisms as well as the role of MDA in the overall process. On this basis, we infer connections between disturbances in enzymatic antioxidative defense and reproductive potential. Based on a molecular analysis of the polymorphism of gene IL-4v.C589T (rs2243250) (chromosome 5) (PCR-RFLP), we considered the relationships among particular genotypes with the possibility of occurrence of male infertility. Concentrations of chemical elements were measured in the blood. The activity of antioxidants and MDA levels were measured in serum. In the infertile group, higher GPx activity was noted (6.56 nmoL·min-1·mL-1, control: 4.31 nmoL·min-1·mL-1; p = 0.004), while GR achieved a greater level in the control (17.74 nmoL·min-1·mL-1, infertile: 15.97 nmoL·min-1·mL-1, p = 0.043), which implies diversified efficiency of the first and second lines of defense. The polymorphism of IL-4v.C589T (rs2243250) was not directly connected with infertility because there were not any differences in the frequency of genotypes between the infertile and control group (p = 0.578). An analysis of genotypes CC and TT (polymorphism IL-4v.C589T (rs2243250)) indicated numerous correlations between antioxidants, chemical elements and MDA. Therefore, chemical economy, antioxidative defense and genetic conditions are connected and jointly shape male reproductive potential. Chemical elements influence antioxidative defense and male fertility; the most important modulators appeared to be Na, Ba, Al and B. The polymorphism of gene IL-4v.C589T (rs2243250) has a limited influence on antioxidative defense and the metabolism of chemical elements.

Assessment of the concentration of selected metalloproteinases (MMP-2, MMP-3, MMP-9 and MMP-13) in patients with ulcers as a complication of type 2 diabetes.

Introduction: Impaired chronic wound healing is a great challenge for modern medicine. This process causes ulceration especially in the course of diseases such as type II diabetes mellitus. Aim: This study assesses the concentration of selected matrix metalloproteinases in the example of metalloproteinase 2, 3, 9, 13 in patients with impaired healing of chronic wounds as a complication of type 2 diabetes. Material and methods: Nineteen people took part in the assessment of wound healing in patients with type 2 diabetes. The control group consisted of 21 healthy people. In the blood serum the concentration of MMP-2, MMP-3, MMP-9 and MMP-13 was determined. Results: The concentrations of MMP-2 and MMP-3 in the group of patients with ulcers were significantly higher (61% and 84% accordingly) compared to those in the control group without chronic wounds. No statistically significant differences in MMP-9 and MMP-13 concentrations were observed between the study and control groups. Conclusions: The increase in MMP-2 concentration, which is particularly active in the degradation of type IV collagen, which is the main component of the basal membranes, in patients with type 2 diabetes may impede and delay the healing of chronic wounds and thus contribute to the intensification of vascular complications. In turn, the increase in MMP-3 concentration, which plays a significant role in vascular diseases, in patients with type 2 diabetes may lead to intensification of atherosclerotic changes involving the arteries of the lower extremities and ulceration.

Concentration of proinflammatory cytokines in patients with ulcers as a complication of type 2 diabetes mellitus.

INTRODUCTION: Difficult healing of chronic wounds is a serious problem for modern medicine. It leads to ulceration, especially in conditions such as diabetic foot syndrome or chronic venous insufficiency. This may be a result of chemical, physical, thermal or biological factors, among others. Analysis of mediators and molecular factors released by the abovementioned structure helps to better understand the mechanism of healing of chronic wounds and the formation of ulcers. AIM: To assess excretion of selected cytokines in patients with ulcerations as a complication of diabetes mellitus type 2. MATERIAL AND METHODS: Seventeen patients aged 68-87 took part in the assessment of wound healing in patients with ulceration in the course of diabetes mellitus type 2. The control group consisted of 21 healthy patients aged 32-62. In the blood serum bFGF, TNF-α, IL-4, TGF-ß1, TGF-ß2 and TGF-ß3 were determined. RESULTS: A significant difference was found in bFGF, IL-4, TGF-ß1, TGF-ß2, and TGF-ß3 levels. Concentration of bFGF was 12% lower in patients with ulcers than in the non-ulcerated control group (p = 0.013). IL-4 concentration was 46% lower in patients with ulcers than in the non-ulcerated control group (p = 0.002). TGF-ß1, TGF-ß2 and TGF-ß3 concentrations were also lower in the group of patients with ulcers compared to those in the non-ulcerated control group. CONCLUSIONS: Reduced concentrations of selected cytokines and growth factors may indicate abnormal activity of the cells that secrete them and affect the healing process of chronic wounds, hindering and delaying the healing process.

Novel 2-(Adamantan-1-ylamino)Thiazol-4(5H)-One Derivatives and Their Inhibitory Activity towards 11ß-HSD1-Synthesis, Molecular Docking and In Vitro Studies.

A common mechanism in which glucocorticoids participate is suggested in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing's syndrome. The enzyme involved in the control of the availability of cortisol, the active form of the glucocorticoid for the glucocorticoid receptor, is 11ß-HSD1. Inhibition of 11ß-HSD1 activity may bring beneficial results for the alleviation of the course of metabolic diseases such as metabolic syndrome, Cushing's syndrome or type 2 diabetes. In this work, we obtained 10 novel 2-(adamantan-1-ylamino)thiazol-4(5H)-one derivatives containing different substituents at C-5 of thiazole ring and tested their activity towards inhibition of two 11ß-HSD isoforms. For most of them, over 50% inhibition of 11ß-HSD1 and less than 45% inhibition of 11ß-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11ß-HSD1 correctly reproduced the experimental IC50 values for analyzed compounds. The most active compound 2-(adamantan-1-ylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one (3i) inhibits the activity of isoform 1 by 82.82%. This value is comparable to the known inhibitor-carbenoxolone. The IC50 value is twice the value determined by us for carbenoxolone, however inhibition of the enzyme isoform 2 to a lesser extent makes it an excellent material for further tests.

A Novel N-Tert-Butyl Derivatives of Pseudothiohydantoin as Potential Target in Anti-Cancer Therapy.

Tumors are currently more and more common all over the world; hence, attempts are being made to explain the biochemical processes underlying their development. The search for new therapeutic pathways, with particular emphasis on enzymatic activity and its modulation regulating the level of glucocorticosteroids, may contribute to the development and implementation of new therapeutic options in the treatment process. Our research focuses on understanding the role of 11ß-HSD1 and 11ß-HSD2 as factors involved in the differentiation and proliferation of neoplastic cells. In this work, we obtained the 9 novel N-tert-butyl substituted 2-aminothiazol-4(5H)-one (pseudothiohydantoin) derivatives, differing in the substituents at C-5 of the thiazole ring. The inhibitory activity and selectivity of the obtained derivatives in relation to two isoforms of 11ß-HSD were evaluated. The highest inhibitory activity for 11ß-HSD1 showed compound 3h, containing the cyclohexane substituent at the 5-position of the thiazole ring in the spiro system (82.5% at a conc. 10 µM). On the other hand, the derivative 3f with the phenyl substituent at C-5 showed the highest inhibition of 11ß-HSD2 (53.57% at a conc. of 10 µM). A low selectivity in the inhibition of 11ß-HSD2 was observed but, unlike 18ß-glycyrrhetinic acid, these compounds were found to inhibit the activity of 11ß-HSD2 to a greater extent than 11ß-HSD1, which makes them attractive for further research on their anti-cancer activity.

Synthesis of Novel 2-(Isopropylamino)thiazol-4(5H)-one Derivatives and Their Inhibitory Activity of 11ß-HSD1 and 11ß-HSD2 in Aspect of Carcinogenesis Prevention.

Glucocorticoid metabolism at the tissue level is regulated by two isoenzymes 11ß-hydroxysteroid dehydrogenase (11ß-HSD), which mutually convert biologically active cortisol and inactive cortisone. Recent research is focused on the role of 11ß-HSD1 and 11ß-HSD2 as autocrine factors of tumor cell proliferation and differentiation. Herein, we report the synthesis of novel 2-(isopropylamino)thiazol-4(5H)-one derivatives and their inhibitory activity for 11ß-HSD1 and 11ß-HSD2. The derivative containing the spiro system of thiazole and cyclohexane rings shows the highest degree of 11ß-HSD1 inhibition (54.53% at 10 µM) and is the most selective inhibitor of this enzyme among the tested compounds. In turn, derivatives containing ethyl and n-propyl group at C-5 of thiazole ring inhibit the activity of 11ß-HSD2 to a high degree (47.08 and 54.59% at 10 µM respectively) and are completely selective. Inhibition of the activity of these enzymes may have a significant impact on the process of formation and course of tumors. Therefore, these compounds can be considered as potential pharmaceuticals supporting anti-cancer therapy.

Application of ELISA Technique and Human Microsomes in the Search for 11ß-Hydroxysteroid Dehydrogenase Inhibitors.

The metabolic syndrome is defined by impaired carbohydrate metabolism and lipid disorders and often accompanied by hypertension, all of which will lead to obesity and insulin resistance. Glucocorticoids play a regulatory role in the metabolism of proteins, lipids, and carbohydrates. There is growing evidence for a role of glucocorticoids in the development of the metabolic syndrome. The most important factor that regulates the access of endogenous glucocorticoids to receptors after release of glucocorticoids and their diffusion into the cytoplasm of target cells is the steroid metabolism involving a microsomal enzyme, 11ß-hydroxysteroid dehydrogenase (11ß-HSD). The changes in intracellular glucocorticoid metabolism in the pathogenesis of obesity indicate the participation of modulation by 11ß-HSD1, which may represent a new therapeutic target for the treatment of diseases such as type 2 diabetes, visceral obesity, or atherosclerosis. The aim of our study was to determine the fast and effective method to assess inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase. The material for this study was human liver and kidney microsomes. In this study we used ELISA technique using 96-well microplates coated with antibodies which were specific for analyzed enzymes. The method can quickly and efficiently measure the inhibition of both 11ß-HSD1 and 11ß-HSD2. This method can be used to search for and determine inhibitors of this enzyme. Cortisone and cortisol were used as the substrates for corresponding enzyme assays. Furthermore, 3-N-allyl-2-thiouracil derivatives were used by us for comparison purposes in developing the method, although, due to their structure, those derivatives have not previously been considered as potential inhibitors of 11ß-HSD1. 3-N-Allyl-2-thiouracil derivatives are a group worth considering, because by modifying their structure (e.g., by introducing other substituents into the pyrimidine ring) it will be possible to obtain an increase in the activity of compounds in this regard. In conclusion, this study shows an efficient and fast method of determining inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase.

Assessment of the State of the Natural Antioxidant Barrier of a Body in Patients Complaining about the Presence of Tinnitus.

BACKGROUND: Tinnitus is defined as a phantom auditory perception, i.e., sound experience despite the lack of acoustic stimuli in the environment. The aim of this study was to assess the state of the natural antioxidant barrier of a body in patients complaining about the presence of tinnitus. MATERIAL AND METHODS: The study included a total of 51 patients aged from 20 to 62 years with diagnosed idiopathic tinnitus and 19 healthy subjects as a control group. All patients underwent the audiometric tone test, speech audiometry, distortion otoacoustic emission product testing, study of evoked auditory potentials of short latency, and biochemical analysis of venous blood concerning values of activity or concentration of glutathione, glutathione peroxidase, S-transferase, glutathione reductase superoxide dismutase, malondialdehyde, and ceruloplasmin as the selected parameters of oxidative stress. RESULTS: Disorders of the auditory pathway were not only limited to the cochlea but also covered its further episodes. Mean values of activity or concentration of the selected parameters of oxidative stress in the study and control groups showed reduced effectiveness of the body's natural antioxidant barrier. DISCUSSION: Patients complaining about the presence of tinnitus showed reduced effectiveness of the body's natural antioxidant barrier compared to the control group. CONCLUSIONS: The main indication to undertake further research on the functioning of the antioxidant barrier in people suffering from ailments in the form of tinnitus is to determine a suitable therapy aimed at improving the quality of life of these patients, which might be the administration of antioxidant medications.

Change of the State of the Natural Antioxidant Barrier of a Body and Psychological Parameters in Patients Aged above 60.

BACKGROUND: The goal of this study is to assess the natural antioxidant barrier of the organism and selected psychological aspects of the aging process in patients above 60 years old. METHODS: The study included a total of 52 patients aged above 60 (mean age 67 ± 3.4) and 32 healthy subjects (mean age 22 ± 3.4) as a control group. All patients underwent psychological assessment using Test of Attentional Performance version 2.3 (TAP 2.3, four subtests: alertness, cross-modal integration, neglect with central task, and working memory) and biochemical analysis of venous blood concerning values of the selected parameters of oxidative stress (HT, GSH, GPXOS, GPXRBC, GRRBC1, SODRBC1, MDARBC1, NO2-/NO3-, and CP). RESULTS: Disorders of attention were observed mainly in elderly people, but an assumption that elderly people have developed more efficient ways of working memory use than younger people may be true. Results showed the reduced effectiveness of the body's natural antioxidant barrier in elderly people. Moderate positive and negative correlations among parameters of oxidative stress and psychological parameters were observed in the control group. DISCUSSION: Intensification of the attention deficits and oxidative stress may be observed as one of the pathogenic factors of age-dependent diseases.

Immunohistochemical localization of selected pro-inflammatory factors in uterine myomas and myometrium in women of various ages.

Uterine myomas represent one of the most frequently manifested benign tumors in women. They originate from smooth muscle cells of myometrium or its blood vessels. Many studies suggest that inflammation and pro-inflammatory factors may play a role in the carcinogenesis with an involvement of the transcription factor NF-kappaB which activity can be controlled by various environmental factors, including many cytokines. The aim of the study was to investigate the expression of NF-B, interleukin-1ß (IL-1ß), tumor necrosis factor a (TNF-α), cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) in myometrium and uterine myomas of women of various age. The expression of NF-kappaB, selected cytokines and enzymes was estimated in women of reproductive or perimenopausal age by semiquantitative immunohistochemistry. The expression of the examined proteins was higher in myomas than in control myometrium and was dependent on the size of myomas and the age of women. However, the expression of the cytoplasmic NF-kappaB observed in uterine myomas was independent on the size of myomas and no significant differences were observed in the number of stained nuclei between control and myoma groups. Thus, the expression of proinflammatory factors in myomas was not accompanied by the nuclear activation of NF-kappaB p65. The results of our study indicate that the examined factors may be involved in the pathogenesis of benign tumors and not only malignant diseases.