[Functional polymorphism of genes inactivating catecholamines and emotional deficits in paranoid schizophrenia]. / Funkcjonalny polimorfizm genów enzymów inaktywujacych katecholaminy a deficyty procesów emocjonalnych w schizofrenii paranoidalnej.

AIM: The aim of our work was to assess qualitatively and quantatively emotional deficits in patients diagnosed with schizophrenia following ICD-10 criteria in early and late stages of the schizophrenic process and the evaluation of the relationship between genes polymorphism of enzymes influencing dopaminergic, serotoninergic, and noradrenergic transfer and emotional functioning of the examined patients. METHOD: In our study the following methods have been used: Short Recognition Memory test for Faces (TPRT), Facial Expression Recognition Test (FERT), "Reading the mind in the eyes" Test and psychiatric scales (SAPS, SANS, BDI) and molecular techniques (PCR reaction, RFLP and VNTR techniques). 100 paranoid schizophrenia patients (43 female and 57 man) and 50 healthy controls (30 female and 20 man) were invited to participate in the study. RESULTS: Our results revealed an association between polymorphism of Val158Met COMT and emotional deficits in schizophrenic patients. Furthermore, the relationship between polymorphism of MAO-A and empathy/theory of mind deficit was found. No relationship was elicited between polymorphism of Val158Met COMT and VNTR MAO-A in the promoter area and schizophrenia onset. Allelic distribution of polymorphism of Val158Met COMT and VNTR MAO-A in the promoter area did not differ between the groups. The patients with genotype Val/Val of polymorphism Val158Met COMT showed major emotional deficits. The patients with genotype of 4/4 of polymorphism VNTR MAO-A showed deeper empathy/theory of mind deficits.

Matrix metalloproteinase-9 contributes to the increase of tau protein in serum during acute ischemic stroke.

Previous studies indicate that tau protein, a marker of damage to neurons, is present in the serum of healthy patients at a concentration approximately 40 percent that of patients with ischemic stroke We assumed that increased serum activity of gelatinases (matrix metalloproteinase [MMP]-2 and MMP-9) can influence the level of tau protein in serum, probably due to disruption of the blood-brain barrier. We obtained blood sera from 31 patients admitted within the first 24 hours of ischemic stroke on days 1, 5 and 10, following the onset of stroke. Tau protein was detected in the serum of 12 patients (38.7 percent). The highest MMP-9 activity was recorded on day 5 (p < 0.05). Serum gelatinase activity did not differ between tau protein-positive or -negative individuals. However, a high degree of correlation between mean MMP-9 activity and the maximum tau protein level was observed for patients with detectable tau protein (r = 0.71, p = 0.009). Our study suggests that MMP-9 can increase the tau protein level in the sera of patients during acute ischemic stroke.

Lipids' peroxidation markers in Alzheimer's disease and vascular dementia.

AIM: Although a large body of evidence supports a role of oxidative stress in the etiopathogenesis of dementia, there is still a substantial lack of data regarding the biomarkers of oxidative stress characteristic of Alzheimer's disease (AD) as opposed to different types of dementia. In this study, the level of various oxidative stress parameters were measured in AD, vascular dementia (VaD), and age- and sex-matched control patients. The AD and VaD patients all had similar levels of cognitive impairment as measured by the Mini-Mental State Examination. METHODS: Thirty AD, 19 VaD and 29 controls patients were recruited to the study. Plasma levels of malondialdehyde (MDA), total sulfhydryl (T-SH), calcium (Ca(++)) and magnesium (Mg(++)) were measured. RESULTS: In both AD and VaD groups, the levels of oxidative stress parameters were higher compared with controls. Further, the VaD patients expressed significantly higher levels of plasma parameters of oxidative stress than AD. The difference was noted in MDA, the marker of lipid peroxidation, whereas in VaD the level of MDA was more than 2.8-fold higher than that registered in AD patients. CONCLUSION: Vascular dementia in patients is characteristic of increased levels of oxidative stress, especially lipid peroxidation markers. This finding is relevant to determining the pathophysiology of dementia, particularly in the light of the recently suggested importance of the vascular component in dementia development, in addition to aiding in the diagnosis of VaD following clinical presentation. The study will be continued to compare the character and level of decline in both groups.

Gelatinolytic activity of matrix metalloproteinases 2 and 9 in middle ear cholesteatoma.

BACKGROUND: Cholesteatoma of the middle ear or mastoid is a hyperproliferative disorder of keratinocytes characterized by a progressive bone erosion. Matrix metalloproteinase (MMP)-2 and MMP-9 gelatinases are endopeptidases targeting extracellular protein. Several studies examined the role of gelatinases in the pathogenesis of cholesteatoma, but the biologic mechanism by which cholesteatoma destroys the bone tissue remains unclear. OBJECTIVES: The aim of this study was to characterize the activity of MMP-2 and MMP-9 in human cholesteatoma and external auditory canal skin. METHODS: In the study, specimens of cholesteatoma and middle ear canal skin from 14 patients treated surgically at the Department of Otolaryngology were used. After two-step extraction of MMP-2 and MMP-9 from tissue samples, gelatinolytic activity was assessed with zymography. RESULTS: We noticed the augmentation of MMP-9 (p = .0001) and MMP-2 (p = .046) activity obtained from cholesteatoma in comparison with control skin. The MMP-9 active to latent ratio was significantly higher in cholesteatoma samples versus normal skin. CONCLUSION: The present study indicates that MMP-9 and, to a lesser degree, MMP-2 overexpression may be implicated in the molecular mechanisms of cholesteatoma invasion and bone destruction.

[Genetic polymorphism of a MAO in mental disorders]. / Polimorfizm genu MAO w zaburzeniach psychicznych.

Amin oxydase (monoaminoxydase, MAO) is an enzyme which catalyses chemical reactions of biogenic amines. It plays a crucial role in pathogenesis of mental disorders associated with the dysfunction of the central monoaminergic systems (schizophrenia, affective disorders, some forms of alcohol dependence, and personality disorders). MAO has got two isoforms such as MAO-A and MAO-B. The genes coding of MAO are localised at the short arm of chromosome Xp11. In each sequence of genes there is a probability of functional polymorphism occurrence which leads to a variable expression or a change of MAO activity and it exerts an impact on the onset of some mental disorders, such as: schizophrenia, affective disorders, some forms of alcohol dependence, and personality and behavioural disorders. Dynamic development of psychiatric genetics may have crucial impact on considerable progress in understanding molecular background of mental disorders.

[Genetic polymorphism of COMT in mental disorders]. / Polimorfizm genu COMT w zaburzeniach psychicznych.

Many neurobiochemical studies show abnormalities within dopaminergic neuropathways, particularly altered dopamine transmission in etiopathogenesis of mental disorders. Evaluation of genes associated with the dopaminergic system include five well known subtypes of dopaminergic receptors, dopamine transporter and enzymes associated with the synthesis and degradation of dopamine, such as tyrosine hydroxylase, dopa decarboxylase, monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). None of these genes is 'a' pathognomonic factor of schizophrenia onset. In each sequence of the following genes 'a' functional polymorphism can occur. The polymorphisms of genes MAO-A and COMT have been described in relation to various expression or altered activity of these enzymes, their influence on cognitive functions, affective and anxiety disorders, learning disabilities, aggressive behaviour, eating disorders or gender differences.

[Stress oxidative in schizophrenia]. / Stres oksydacyjny w schizofrenii.

Etiopathogenesis of schizophrenia development is unknown yet in 1% of human population. There is damaged metabolism of biological membranes, abused production of free radicals and altered activity of antioxidant enzymes in patients with schizophrenia. Recently, a study showed that many of the genes and proteins whose expression is modified in the schizophrenic brain are related to glutathione and oxidative stress pathways. According to the researchers changes in permeability of biological membranes in brain could involve the pathophisiology of all--subtypes of schizophrenia as a result of oxidative stress. Brain is particularly sensitive to oxidative damage. There is a lot of phospholipids and polyunsaturated fatty acids in brain tissue under physiological conditions. The changes in polyunsaturated fatty acids metabolism, increased lipid peroxidation and the presence of oxidative stress are found in schizophrenia. They can course to appear instabilities of neuron membranes or even cell death owing to oxidative stress. Mainly to getting to know the molecular disease mechanism is associated with a disorder of the brain. The results suggest that at least some of the schizophrenia disease process can be traced in peripheral tissue like plasma, blood cells or liver. In various types of schizophrenia antipsychotic treatment affects oxidative state of erythrocyte membranes in a different way. Research into changes of antioxidant enzymes level during the treatment of typical and atypical neuroleptic drugs could contribute to widening the knowledge on the reasons of undesirable effects during pharmacotherapy with typical neuroleptic drugs.

Activity of matrix metalloproteinase-2 and -9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium.

BACKGROUND AND AIM: Matrix metalloproteinase-2 and -9 (MMP-2 and -9) are proteolytic enzymes degrading extracellular matrix proteins, mainly collagen type IV. Recent reports show that these proteases may be implicated in the growth of uterine leiomyoma. The aim of the present study was to evaluate the activity of MMP-2 and MMP-9, the contents of their tissue inhibitors (TIMP-1 and TIMP-2) and the immunolocalization of collagen type IV in uterine leiomyoma and corresponding myometrium. MATERIALS AND METHODS: Material for the study comprised specimens of uterine leiomyomas and corresponding myometrium derived from 20 hysterectomized women. The activity of MMP-2 and MMP-9 in tissue extracts was evaluated by semi-quantitative zymography. TIMPs were measured by enzyme-linked inmmunosorbent assay. Protein immunohistochemistry was applied for detection of collagen type IV. RESULTS: Activity and activation ratio of MMP-2 were significantly higher in leiomyomas than myometrium. The activity of MMP-9 was weak and did not differ between the investigated tissues. Contents of TIPM-1 and TIPM-2 were similar in both tissues. In both leiomyomas and myometrium, collagen type IV was localized in the extracellular matrix embedding bundles of smooth muscle cells, but was absent in areas of extracellular matrix accumulation within leiomyomas and in larger septa separating muscle fibers in normal myometrium. CONCLUSION: MMP-2 may be implicated in pathogenesis of leiomyoma.

[Activity of matrix metalloproteinases -2 and -9 (MMP-2 and MMP-9) and content of their tissue inhibitors in endometrial cancer--a preliminary study]. / Aktywnosc metaloproteaz macierzowych -2 i -9 (MMP-2 i MMP-9) oraz zawartosc ich tkankowych inhibitorów w raku blony sluzowej macicy--doniesienie wstepne.

OBJECTIVES: Matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) are enzymes degrading collagen type IV and other components of the basement membrane. Their activity is suppressed by tissue inhibitors of metalloproteinases--TIMP-1 and TIMP-2. Substantial evidence indicates that MMP2 and MMP-9 play an important role in the spread of malignant tumours. The aim of the study was to evaluate the activity of MMP-2 and MMP-9 and contents of their inhibitors: TIMP-1 and TIMP-2 in endometrial cancer and normal endometrium. MATERIAL AND METHODS: Material for the study comprised 28 samples of endometrial cancers and 15 samples of normal endmetrium. A two-step method for extraction of MMPs was applied. The activity of MMP-2 and MMP-9 was measured with semi-quantitative zymography. TIMP-1 and TIMP-2 contents were measured with ELISA method. RESULTS: Mean activity and activation ratio of MMP-9 was significantly higher in endometrial cancers compared with normal myometrium, whereas mean activity and activation ratio of MMP-2 did not differ significantly between investigated groups. Mean content of TIMP-1 and TIMP-2 did not differ between cancer and control tissues. No unequivocal association between activity of investigated MMPs or contents of their inhibitors and clinicopathological features of endometrial cancers was observed. CONCLUSIONS: Results of the study suggest that MMP-9 may play an important role in the progression of endometrial cancer, whereas MMP-2 does not seem to be involved in this process. Action of MMP-9 may be further enhanced by relative deficiency of TIMP-1.

[The role of matrix metalloproteinases and tissue inhibitors of metalloproteinases in invasion of tumours of neuroepithelial tissue]. / Rola metaloproteaz macierzy i tkankowych inhibitorów metaloproteaz w inwazji nowotworów pochodzenia neuroepitelialnego.

Tumour invasion requires degradation of extracellular matrix components and migration of cells through degraded structures into surrounding tissues. Matrix metalloproteinases (MMP) constitute a family of zinc and calcium-dependent endopeptidases that play a key role in the breakdown of extracellular matrix, and in processing of cytokines, growth factors, chemokines and cell surface receptors. Their activity is regulated at the levels of transcription, activation and inhibition by tissue inhibitors of metalloproteinases (TIMP). Changes in expression of MMP and TIMP are implicated in tumour invasion, because they may contribute to both migration of tumour cells and angiogenesis. Alterations of MMP expression observed in brain tumours arouse interest in the development and evaluation of synthetic matrix metalloproteinase inhibitors as antitumour agents.

[Lack of prognostic significance of carcinoembryonic antigen (CEA) preoperative serum levels in patients with advanced larynx cancer]. / Brak wartosci diagnostycznej przedoperacyjnego oznaczania steienia antygenu rakowo-plodowego (CEA) w surowicy pacjentów z zaawansowanym rakiem krtani.

The purpose of this study was to identify the relationship between preoperative serum levels of carcinoembryonic antigen (CEA) and clinicopathological features in advanced stage of larynx cancer. The mean CEA serum concentrations were below cutoff value, which exclude the CEA as a serum marker in diagnosis of larynx cancer. However, significant correlations were found between CEA levels and tumor size, lymph node metastasis and clinical stage of the disease. The pretreatment CEA level was increased above cut-off value only in 6% of tested patients and thereby is not a prognostic factor in larynx cancer.

[Squamous cell carcinoma antigen levels in patients with laryngeal cancer]. / Antygen raka plaskonablonkowego w surowicy krwi pacjentów z rakiem krtani.

Squamous cell carcinoma antigen (SCCAg) is one of the most common markers used in diagnosis of head and neck cancer and larynx cancer. We tested correlations between level of SCC Ag and tumor size, presence of lymph node metastasis, clinical advances of tumour and histopathological diagnosis. Pretreatment level of SCC antigen was evaluated in 34 patients with squamous cell carcinoma of the larynx. Microparticle enzyme immunoassay was used to measure the SCCAg level. Elevated SCCAg serum levels were found in 41% of patients. The magnitude of the marker elevations were correlated with lymph node metastases (N0 versus N2, and N1 versus N2). Our date indicate that in patients with larynx cancer SCCAg does not appear to be a sensitive marker in the primary diagnosis. However, seem to be useful marker for monitoring nodal invasion.

[Diagnostic value of tissue polypeptide antigen in serum of larynx cancer patients]. / Wartosc diagnostyczna oznaczania tkankowego antygenu polipeptydowego w surowicy chorych na raka krtani.

UNLABELLED: Tissue polypeptide antigen (TPA) is a serological tumour marker used in the diagnosis, management and follow-up of patients with head and neck cancer. The aim of this study was to evaluate the diagnostic and prognostic significance of pretreatment TPA serum levels in patients with larynx cancer. The predicting ability of this tumour marker with respect to histological type, pathological state and lymph node metastasis was also assessed. MATERIALS AND METHOD: Concentrations of the TPA in the serum from 35 patients were measured by immunoradiometric assay. RESULTS: The results showed the sensitivity value for the group of 35 patients was 29.4%, but in clinical stage IV was 70%. TPA levels correlate with T classification and lymph node metastasis. In T4 tumors it was significantly higher than in T2 (p=0.047). TPA levels were significantly higher in patients with nodal invasion and were generally lower in patients with spinocellular carcinoma (p=0.0048). CONCLUSION: Our date indicate that TPA is of limited usefulness in the primary diagnosis in patients with larynx cancer, but is useful in detecting lymph node metastasis.

NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth.

Glutamate antagonists limit the growth of human cancers in vitro. The mechanism of anticancer action of NMDA antagonists is not known, however. In this article, we report that the NMDA antagonist dizocilpine inhibits the extracellular signal-regulated kinase 1/2 pathway, an intracellular signaling cascade that is activated by growth factors and controls the proliferation of cancer cells. Dizocilpine reduces the phosphorylation of cAMP-responsive element binding protein, suppresses the expression of cyclin D1, up-regulates the cell cycle regulators and tumor suppressor proteins p21 and p53, and increases the number of lung adenocarcinoma cells in the G(2) and S phases of the cell cycle. Silencing of the tumor suppressor protein p21 abolishes antiproliferative action of dizocilpine. Consistent with inhibition of the extracellular signal-regulated kinase 1/2-signaling cascade, dizocilpine reverses the stimulation of proliferation induced by epidermal, insulin, and basic fibroblast growth factors in lung adenocarcinoma cells. Furthermore, dizocilpine prolongs the survival of mice with metastatic lung adenocarcinoma and slows the growth of neuroblastoma and rhabdomyosarcoma in mice. These findings reveal the mechanism of antiproliferative action of dizocilpine and indicate that it may be useful in the therapy of human cancers.

[Histone deacetylase inhibitors as a new generation of anti-cancer agents]. / Inhibitory deacetylaz histonów jako potencjalne cytostatyki nowej generacji.

The acetylation and deacetylation of histones mediated by histone acetylases and deacetylases influence DNA accessibility to factors regulating replication, repair, and transcription. Histone deacetylases inhibitors (HDI) are inducers of growth arrest, differentiation, and/or apoptosis of many tumors cells by altering the transcription of a small number of genes. The selective tumor specificity of these compounds underscores their potential as new agents for the treatment of cancer. Several HDI have shown anti-tumor activity in vitro and in vivo with remarkably low toxicity in preclinical studies and are currently in phase I and II clinical trials. This review summarizes the molecular mechanism of action of HDI and its clinical application in the treatment of cancer.

[Role of matrix metalloproteinases in the pathogenesis of multiple sclerosis]. / Rola metaloproteinaz macierzy zewnatrzkomórkowej w patogenezie stwardnienia rozsianego.

Multiple sclerosis (MS) is an autoimmune disease whose features include a massive lymphocyte recruitment into the central nervous system and segmental demyelinization of the white matter. One of the MS development factors is an increase of matrix metalloproteinases (MMPs) activity with a coincidental decrease of tissue inhibitors of MMPs (TIMPs) activity. Investigations of serum, cerebrospinal fluid and brain tissue of patients showed an increase of MMP-1, -2, -3, -7, -9 and MMP-12 activity. MMPs disrupt the blood-brain barrier (BBB), increase lymphocyte migration into the central nervous system and are involved in degradation of myelin proteins. MMPs induce the appearance of an active form of tumor necrosis factor alpha, a strong proinflammatory cytokine. The drugs used in MS treatment decrease MMPs expression. Multiple actions of MMPs prove their involvement in the pathogenesis and treatment of MS.

Catalase, superoxide dismutase, and glutathione peroxidase activities in various rat tissues after carbon tetrachloride intoxication.

BACKGROUND: The aim of this study was to determine the possible relationship between the activity of three different antioxidant enzymes--peroxidase superoxide dismutase, catalase, and glutathione peroxidase--and carbon tetrachloride-induced injury. METHODS: Male Wistar rats weighing 200-250 g were used in the experiments. Rats of the experimental groups were given carbon tetrachloride 0.5 ml/kg i.p. in olive oil (5 mmol/kg body mass) for 1 or 3 days. Control group rats were injected with olive oil only for the same period. Brain, liver, kidney, and heart supernatants were used for measurement of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) activities. RESULTS: No statistically significant changes in SOD and GPX activities were observed in the liver after CCl4 administration, but catalase activity was significantly increased after 24 h and remained at that level during the course of the study. In the brain, SOD and catalase activities decreased after 24 h of experiment, but GPX activity statistically significantly increased at all time points studied. Increased activities of SOD, catalase, and GPX were found in heart after CCl4 intoxication. The CCl4 injection in our experiment caused a reduction of SOD and catalase activities and increased GPX activity in the kidney. CONCLUSIONS: The results suggest that change in antioxidant enzyme activities may be relevant to the ability of the liver and other investigated organs to cope with oxidative stress during CCl4 poisoning.

Influence of metallothioneins on zinc and copper distribution in brain tumours.

Metallothioneins take part in the homeostasis of the ions of the metals which are necessary for the proper metabolism of the organism (zinc, copper), in biosynthesis regulation of the zinc-containing proteins and also in the detoxication of metals from the tissues. They also protect the tissue from the effects of free radicals, radiation, electrophilic pharmacological agents used in the cancer therapy and from mutagens. The experimental materials were brain astrocytomas, benign gliomas and malignant gliomas. The levels of the metallothionein were determined by cadmium-haemoglobin affinity assay using the cadmium isotope (109Cd). The values of zinc and copper were determined by means of atomic absorption spectrophotometry. In our studies, the level of metallothioneins in the group of malignant neoplasms was slightly higher than the level of these proteins in the group of benign neoplasms. The correlation coefficient of the studied parameters proved an interrelation between the levels of zinc and copper and the content of metallothioneins. In malignant neoplasms, the level of zinc showed a positive relationship with the metallothionein level, whereas the copper content showed an inverse relationship. There was a statistical difference, but no significant difference, in the levels of copper between malignant and benign groups.

The influence of hypomagnesemia on erythrocyte antioxidant enzyme defence system in mice.

The effect of magnesium deficiency on antioxidant defence system was studied in RBC of mice suffering from hypomagnesemia. The animals were kept for 8, 15 and 22 days on magnesium-deficient diet with consequent reduction of magnesium level in plasma by 38% at the first 8 days and by 64% after 22 days of experiment. The activities of the most important antioxidant enzymes, catalase, glutathione peroxidase, superoxide dismutase, glutathione reductase, glutahione S-transferase were assayed in hemolysates. The level of reduced glutathione in erythrocytes was measured as well. Apart from catalase, the activities of antioxidant enzymes were decreasing. The activity of superoxide dismutase decreased gradually during the experiment and on the 15th and 22nd day of experiment was significantly (P < 0, 05) lowered by 30 and 32% respectively. The catalase activity was increased on each point of the experiment with the peak value up to 149% on 15th day, and by 32% on 22nd day. Glutathione peroxidase activity was insignificantly reduced. The reduction of Glutatione reductase and Glutathione S-transferase activities by 24 and 21%, respectively, were observed after 8 days of the experiment with a further downward tendency. The reduced glutathione was significantly depleted after 8 days by 33% and was kept on that level in the course of the study. These findings support previous reports on the hypomagnesemia--induced alteration in endogenous enzyme antioxidant defences and glutathione redox cycle of mice.

Activity of matrix metalloproteinases-2 and -9 in advanced laryngeal cancer.

OBJECTIVES: Matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) are proteolytic enzymes that digest collagen type IV and other components of the basement membrane. They play a key role in local invasion and the formation of distant metastases by malignant tumors. The aim of this study was to evaluate the activity of MMP-2 and MMP-9 in stage III and IV laryngeal cancers. STUDY DESIGN: In the study we used specimens of laryngeal cancer and surrounding normal mucosa obtained from 23 patients undergoing surgical treatment as a primary therapy. After extraction of MMP-2 and MMP-9 from tissue samples, their activity was assessed with zymography. RESULTS: Greater activity of MMP-2 and MMP-9 and a higher active/latent MMP-2 ratio were found in cancer compared with normal mucosa. Moreover, N2 tumors revealed greater activity of MMP-2 in comparison with N1 and N0 tumors. CONCLUSIONS: Results of the study indicate that both MMP-2 and MMP-9 may be involved in the expansion of laryngeal cancer. MMP-2 may also play an important role in the lymphatic spread of some laryngeal tumors.