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At least 1,153 records · Page 64Linked to original sources
PubMed2002

WNT3-WNT14B and WNT3A-WNT14 gene clusters (Review).

WNT signals are transduced to beta-catenin - TCF pathway, JNK pathway, or Ca2+-releasing pathway through WNT receptors. FRAT1, FRAT2, and PAR-1 are positive regulators of WNT - beta-catenin pathway. APC, AXIN, NKD1, NKD2, and Strabismus (STB1, STB2) are negative regulators of WNT - beta-catenin pathway. Here, biological significance of WNT3-WNT14B/WNT15 gene cluster (human chromosome 17q21) and WNT3A-WNT14 gene cluster (human chromosome 1q42) will be reviewed. Total-amino-acid identity between WNT3 and WNT3A is 84.2%, and that between WNT14 and WNT14B is 61.4%. WNT3A and WNT14B show reciprocal regulation by all-trans retinoic acid in NT2 cells and by beta-estradiol in MCF-7 cells. Exon-intron structures are well conserved between WNT3-WNT14B gene cluster and WNT3A-WNT14 gene cluster, except for the existence of an additional intron in 3'-UTR of WNT3. Capicua pseudogene and AK024248-related sequence are located within intergenic region of human WNT3A-WNT14 gene cluster, but not within intergenic regions of human WNT3-WNT14B gene cluster and mouse Wnt3a-Wnt14 gene cluster. Integration of mouse mammary tumor virus (MMTV) into mouse Wnt3-Wnt14b gene cluster leads to carcinogenesis. Because these WNT gene clusters might be fragile sites in the human genome, implication of WNT3 or WNT3A in cancer as well as implication of WNT14 or WNT14B in connective tissue disease and congenital joint malformation should be elucidated in the future. WNT3, WNT3A, WNT14, and WNT14B might be applicable to tissue engineering of neuron and joint in the field of regenerative medicine, and as an early diagnostic marker in the field of clinical oncology.

Amino Acid Sequence↗
PubMed2002

DOI, an agonist of 5-HT2A/2C serotonin receptor, alters the expression of cyclooxygenase-2 in the rat parietal cortex.

The hallucinogenic effect of DOI, serotonin 5-HT2A/2C receptor agonist, is known to be associated with the activation of cortical 5-HT2 receptors. However, the effect of DOI on excitability of cortical neurons and their subsequent function is still not quite understood. Previous immunohistochemical studies using Fos proteins expression as a marker of neuronal activity showed the involvement of arachidonic acid cascade, particularly cyclooxygenase metabolic pathway, in DOI-induced Fos proteins expression in the rat parietal cortex. DOI increases arachidonic acid release which is transformed itself via acceleration of cyclooxygenase metabolic pathway to biologically active metabolites, such as prostaglandins and thromboxanes. Since cyclooxygenase-2 (COX-2) expression correlates with neuronal activity, it was of interest to investigate whether DOI is capable of influencing the level of COX-2 protein and mRNA expression in the rat parietal cortex. It was observed that neurons which were positive for 5-HT2A receptors showed constitutive COX-2 immunoreactivity. It was found further, that COX-2 protein level was increased at 1 h, and returned to the control level at 3 and 6 h after DOI (5 mg/kg) administration. In contrast, DOI decreased the COX-2 mRNA expression at all tested time points (1 h, 3h and 6h after DOI treatment). The obtained results further support the suggestion that COX-2 activation and possibly arachidonic acid metabolites generated by COX-2 may be considered as important mediators of functional responses generated by activation of cortical 5-HT2A/2C receptors.

Animals↗
PubMedDate not supplied

Fatty acids, calcium and bone metabolism.

Epidemiological, clinical and experimental evidence suggests that fatty acids may have an effect (due to their chemical structure) on calcium metabolism in animals and man. Fatty acid deficiency in animals can lead to a loss of bone calcium and matrix, resulting in marked bone demineralization, and treatment with a mixture of omega-3 and omega-6 polyunsaturated fatty acids can induce significant reduction in some biochemical markers of bone reabsorption. A relationship, between phospholipid fatty acid content, calcium-regulating hormones and intestinal, renal, and bone calcium metabolism alterations, has been reported in patients with renal stones and hypercalciuria. Recent studies have shown specific effects of fatty acids on the gene expression of some bone cytokines. Fatty acids might be involved in calcium metabolism influencing cellular calcium ion transport directly, as second messengers, or generating, through the cyclooxygenase pathway, potential biological mediators which have complex effects on bone remodeling. Experimental and clinical documentation of the specific and indirect effects of fatty acids on calcium and bone metabolism could open up new and interesting clinical prospects.

Animals↗
PubMed2003

Slow oscillation in non-lemniscal auditory thalamus.

In the present study, we investigated the oscillatory behavior of the auditory thalamic neurons through in vivo intracellular and extracellular recordings in anesthetized guinea pigs. Repeated acoustic stimulus and cortical electrical stimulation were applied to examine their modulatory effects on the thalamic oscillation. The time course of the spike frequency over each trial was obtained by summing all spikes in the onset period and/or the last time period of 100 or 200 msec in the raster display. Spectral analysis was made on the time course of the spike frequency. A slow-frequency oscillation ranging from 0.03 to 0.25 Hz (mean +/- SD, 0.11 +/- 0.05 Hz) was found in the medial geniculate body (MGB) together with a second rhythm of 5-10 Hz. The oscillation neurons had a mean auditory response latency of 17.3 +/- 0.3 msec, which was significantly longer than that of the non-oscillation neurons in lemniscal MGB (9.0 +/- 1.5 msec, p < 0.001, ANOVA) and similar to the non-oscillation neurons in the non-lemniscal MGB (17.6 +/- 5.4 msec, p = 0.811). They were located in the non-lemniscal nuclei of the auditory thalamus. Cortical stimulation altered the thalamic oscillation, leading to termination of the oscillation or to acceleration of the rhythm of the oscillation (the average rhythm changed from 0.07 +/- 0.03 to 0.11 +/- 0.04 Hz, n = 8, p = 0.066, t test). Acoustic stimulation triggered a more regular rhythm in the oscillation neurons. The present results suggest that only the non-lemniscal auditory thalamus is involved in the slow thalamocortical oscillation. The auditory cortex may control the oscillation of the auditory thalamic neurons.

Acoustic Stimulation↗
PubMed1992

[Tourette's syndrome: psychopathology of development in a model of neuropsychiatric dysfunction in children].

The complex neuropsychiatric disorder described by Gilles de la Tourette is a childhood onset, generally lifelong condition diagnosed on the basis of multiple, everchanging motor and vocal tics. Genetic evidence indicates that the vulnerability to Tourette's Syndrome (TS) is transmitted as an autosomal dominant genetic trait. This vulnerability has a broad range of expression, from full-blown TS to chronic multiple tics; an alternate manifestation may be obsessive compulsive disorder. There is also a broad range of severity, from quite mild to incapacitating. No specific neuroanatomical or neurochemical basis has yet been discovered, but the basal ganglia and dopaminergic systems have been implicated. Children and adults with TS experience the intrusion into consciousness of unwanted and disturbing sensations, thoughts and desires; they repeatedly experience the need, arising from an "alien" force within themselves, to produce sounds and actions which they try to resist but to which they eventually capitulate. Their symptoms elicit strong responses from family and others, as well as themselves. Psychoanalytically guided, clinical study can help illuminate the inner world of individuals with TS and define the pathways between biological vulnerability and clinical expression. Treatment often requires a combination of approaches, including guidance, psychotherapy and, in a minority of cases, the careful use of medication. Over the past decade, TS has served as a model developmental disorder for studying the interactions between biological vulnerability and environmental responses in the emergence of a clinical disorder and in the shaping of a child's character. During the next years, further advances in the study of TS should help clarify basic issues in the transmission of constitutional vulnerability and suggest approaches to prevention and early intervention.

Adult↗
PubMed2005

Expression regulation of MAO isoforms in monocytic cells in response to Th2 cytokines.

BACKGROUND: Th2-cytokines, such as interleukins-4 and -13 (IL-4, IL-13), have been identified as alternative stimuli of monocytes/macrophages. We have recently profiled the gene-expression pattern of IL-4-treated human peripheral monocytes and found that 15-lipoxygenase-1 (15-LOX1) and monoamine oxidase A (MAO-A) are among the five most strongly upregulated gene products in IL-4-treated cells. Transfection of monocytic cells (U937) with 15-LOX1 also induced MAO-A expression. These data suggested that 15-LOX1 products might play a role in the IL4-induced signaling cascade leading to expression of MAO-A in human monocytes. MATERIAL/METHODS: To test this hypothesis we incubated wild-type and 15-LOX1-transfected U937 cells with different concentrations of either IL-4 or 15-LOX-products [13S-H(p)ODE, 15S-H(p)ETE] and quantified the expression of 15-LOX1, MAO-A, and MAO-B by activity assays and real-time RT-PCR. RESULTS: Wild-type U937 cells express neither MAO-A nor MAO-B, but after three days of IL4 treatment, MAO-A mRNA was detected. A similar isoform-specific expression of MAO-A mRNA was observed when U937 cells were transfected with 15-LOX1 or when the cells were incubated with primary 15-LOX1 products (hydroperoxy fatty acids) or H2O2. In contrast, the corresponding hydroxy fatty acids were ineffective. CONCLUSIONS: These data indicate that increased intracellular peroxide concentrations (oxidative stress) induce MAO-A expression in monocytes/macrophages, which normally do not express the enzyme. Our findings also suggest that IL-4-induced upregulation of MAO-A expression in human peripheral monocytes may proceed via 15-LOX1-dependent and 15-LOX1-independent pathways. The biological role of MAO-A expression for monocyte function is discussed.

Arachidonate 15-Lipoxygenase↗
PubMedDate not supplied

Gene expression profiling in chemoresistant variants of three cell lines of different origin.

BACKGROUND: Drug resistance is a major problem in clinical cancer chemotherapy. Several mechanisms of resistance have been identified, but the underlying genomic changes are still poorly understood. MATERIALS AND METHODS: Gene expression profiling, using cDNA microarray, was performed in eight cell lines (K562 leukemia, MCF-7 breast cancer and S1 colon cancer) with acquired resistance against five cytostatic drugs; daunorubicin (DNR), doxorubicin (DOX), vincristine (VCR), etoposide (VP) and mitoxantrone (MX). RESULTS: The resistant cell lines clustered together based on their type of origin. Several genes encoding ABC transporters were highly up-regulated, most notably ABCB1 (MDR1) and ABCB4 in several cell lines and ABCG2 (MXR) specifically in MX-resistant cell lines. A pronounced down-regulation of several histones was noted in the MCF-7-derived resistant sublines. Altered expression was also seen in, e.g., GSTs, topoisomerases, caveolins, annexins and CD44. CONCLUSION: These results will constitute a platform for further studies on specific pathways and biological processes involved in chemotherapy resistance.

Breast Neoplasms↗
PubMed2005

Nitric oxide, S-nitrosylation and neurodegeneration.

Nitric oxide is a critically important signaling molecule, controlling a wide range of pathways and biological processes. Highly reactive nitric oxide mediates its function through reaction with different molecules directly or indirectly. One of these modifications is the S-nitrosylation of cysteine residues in proteins. S-nitrosylation is emerging as an important redox signaling mechanism and has been found to regulate a broad range of biologic, physiologic and cellular functions. One of the major findings in this area recently is the linkage of nitrosative stress to various neurodegenerative disorders. Oxidative stress has long been regarded as a prime mediator in the development of neurodegeneration as various indices of oxidative stress are readily observed in postmortem studies. A causative role for nitrosative stress in neurodegeneration is just now being appreciated. The direct connection of S-nitrosylation to the pathogenesis of Parkinson's disease in recent studies further provide insights into how imbalance in nitric oxide metabolism can contribute to the development of selective injury and disease.

Animals↗
PubMedDate not supplied

Role of cellular immunity in the pathogenesis of autoimmune skin diseases.

The pathomechanism of most autoimmune skin diseases is still elusive; however, recent clinical and basic research is leading novel insights into the cellular and molecular biological underlying pathways. Several types of infectious skin diseases are infiltrated by significant number of gamma/delta T cells and similar observations have been made in selected immune-mediated skin conditions. In particular, a role for gamma/delta T cells has been suggested in discoid lupus erythematosus, contact dermatitis, herpetiformis dermatitis, necrotizing cutaneous vasculitis, and cutaneous lesions of systemic sclerosis. The pathogenesis of these diseases is different and this may suggest multiple potential functions of this subset of T cells in the immune system of the skin. Furthermore, most T cells infiltrating tissue and organs undergoing fibrosis have the potential to produce high levels of interleukin 4. This is particularly true for the CD8+ or CD4+ CD8+ double positive T-cell subsets. Furthermore, leukocyte recruitment is a key event in immunity and a better understanding of the signals involved in autoimmune diseases constitutes a valuable basis for the development of new strategies, which control leukocyte migration and function under pathological conditions.

Apoptosis↗
PubMed2006

Environmental contaminants in pathogenesis of breast cancer.

This review is an attempt to comprehend the diverse groups of environmental chemical contaminants with a potential for pathogenesis of breast cancer, their probable sources and the possible mechanisms by which these environmental contaminants act and interplay with other risk factors. Estrogens are closely related to the pathogenesis of breast cancer. Oxidative catabolism of estrogen, mediated by various cytochrome P450 enzymes, generates reactive free radicals that can cause oxidative damage. The same enzymes of estrogenic metabolic pathways catalyze biological activation of several environmental (xenobiotic) chemicals. Xenobiotic chemicals may exert their pathological effects through generation of reactive free radicals. Breast tissue can be a target of several xenobiotic agents. DNA-reactive metabolites of different xenobiotic compounds have been detected in breast tissue. Many phase I and II xenobiotic metabolizing enzymes are expressed in both normal and cancerous breast tissues. These enzymes play a significant role in the activation/detoxification of xenobiotic and endogenous compounds including estrogens. More than 30 carcinogenic chemicals are present in tobacco smoke; many of them are fat-soluble, resistant to metabolism and can be stored in breast adipose tissue. Similarly, pesticides are also known to cause oxidative stress; while some act as endocrine disruptor, some are shown to suppress apoptosis in estrogen sensitive cell lines. Reports have shown an association of smoking (both active and passive) and pesticides with breast cancer risk. However, the issues have remained controversial. Different mutagenic substances that are generated in the cooking process e.g., heterocyclic amines and polycyclic aromatic hydrocarbons (PAHs) can be a threat to breast tissue. PAHs and dioxins exert their adverse effects through the aryl hydrocarbon receptor (AhR), which activates several genes involved in the metabolisms of xenobiotic compounds and endogenous estrogens. These chemicals also induce AhR-dependent mitochondrial dysfunction. Many of the environmental pollutants suppress the immune system, which are implicated to risk. A better understanding about the biological effects of different environmental carcinogenic compounds and determination of their impact on rising incidence of breast cancer will be beneficial in improving preventive policy against breast cancer.

Animals↗
PubMed1985

Connections of the mesencephalic, thalamic and telencephalic auditory centers in turtles. Some structural bases for audiosomatic interrelations.

The organization of auditory projections at the mesencephalic, thalamic and telencephalic brain levels was studied utilizing the method of horseradish peroxidase (HRP) transport in two species of the turtle--Emys orbicularis and Testudo horsfieldi. It was shown that the torus semicircularis receives bilateral afferents from the brain stem auditory centers. They arise predominantly from the contralateral cochlear nuclei, the ipsilateral superior olive, the dorsal and ventral nuclei of the lateral lemniscus and from the symmetrical torus semicircularis. These connections appear to be reciprocal. After the enzyme injections correspondingly into the torus semicircularis and n. reuniens anterograde and retrograde HRP transports show that the central nucleus of the torus semicircularis projects to n. reuniens throughout its rostro-caudal extent mainly ipsilaterally. In turn, n. reuniens projects to the medioventral part of the dorsal ventricular ridge. A following common principle of the organization of the auditory system was revealed at the three brain levels explored. Auditory relay centers occupy the most medial positions at every level (n. centralis of the torus semicircularis, n. reuniens, the medioventral part of the dorsal ventricular ridge). Immediately lateral to them are somatic centers (correspondingly, n. intercollicularis, n. ventralis, the central part of the dorsal ventricular ridge). These together with the auditory centers form united functional complexes at every level. In these complexes auditory and somatic projections overlap, thus constituting a basis for the interaction between auditory and somatic afferent inputs. Mesencephalic and thalamic auditory centers were shown to receive direct somatic (cervical spinal) projections and non-direct from the underlying somatic center as well as from the adjacent somatic center at the same level (n. intercollicularis in the mesencephalon, n. ventralis in the thalamus). Somatic centers in the complexes described get no direct auditory projections. Auditory impulses however can enter them via two pathways: along neuron axons from the neighbouring auditory center reaching the adjacent somatic center and along somatic neuron dendrites which pass into the adjacent auditory center. The morphological basis for the auditory-somatic interactions primarily in the auditory center and also in the somatic center was demonstrated in Golgi-like HRP labeled and Golgi-impregnated neurons of these centers. The organization of the auditory-somatic projections at the three brain levels in turtles in to a degree comparable to the auditory system in mammals which is structured according to the core-belt principle.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

[Vasoactive intestinal polypeptide: a potential neurotransmitter].

A review of current advances in anatomy, physiology and pharmacology of vasoactive intestinal polypeptide (VIP) is presented. VIP is a basic 28-aminoacid peptide of molecular weight 3300. Nerves immunoreactive to VIP are in the heart, lung, digestive and genitourinary tract, eye, skin, ovaries and thyroid gland. In the central nervous system VIP-ergic neurons are found primarily in telencephalic areas. Here, VIP provokes the excitation, vasodilatation and together with noradrenaline participates in the regulation of cortical energy metabolism. VIP-ergic neurons are mainly present in afferent pathways of the spinal cord with higher density in the sacral segments. Anatomic distribution of VIP-ergic neurons suggests involvement in pain transmission and integration of the sacral autonomic reflex pathways. The biologic effects of VIP in periphery are the vasodilatation, relaxation of smooth muscle and influence on exocrine glands secretion. In the endocrine system VIP stimulates the secretion of different hormones (prolaction, growth hormone, oxytocin, vasopressin, ovarial and thyroid hormones). VIP-ergic innervation is changed in some organs during the diseases of those organs. Practical exploatation of this knowledge is limited at present because effective, non-polypeptide agonists and antagonists are not available yet.

Humans↗
PubMed1986

Aromatase inhibitors for treatment of breast cancer: current concepts and new perspectives.

Estrogens provide the major hormonal support for endocrine-dependent human mammary neoplasms. In postmenopausal women, the extraglandular aromatization of the adrenal prehormone, androstenedione to estrone is the major pathway for estrogen biosynthesis. Estrone can then be converted into estradiol or into an inactive conjugate, estrone sulfate. Recent data suggest that the estrogens may also be synthesized in situ by human breast tumors, either from androstenedione via aromatase, or from estrone sulfate via the enzyme, sulfatase. Our enzyme kinetic studies support the predominance of the sulfatase pathway for in situ estrogen biosynthesis. The ability of estrone sulfate to stimulate colony formation of the nitrosomethylurea-induced rat mammary tumor in the clonogenic assay, suggests that this in situ pathway has biologic relevance. Aromatase inhibitors can be used to suppress the levels of circulating estrone, estrone sulfate, and estradiol in postmenopausal women. Aminoglutethimide, the major inhibitor currently used clinically, acts in a competitive fashion and blocks cholesterol side chain cleavage and 11 beta-hydroxylase as well as aromatase. Clinical studies indicate that the combination of aminoglutethimide plus replacement glucocorticoid causes breast tumor regression with the same frequency and for the same duration as surgical ablative therapies such as adrenalectomy or hypophysectomy. Aminoglutethimide also induces a similar rate of tumor regression as achieved with the antiestrogen, tamoxifen. However, because tamoxifen is associated with fewer side effects, this antiestrogen is to be preferred over use of aminoglutethimide as first-line hormonal treatment for women with breast cancer. Several specific suicide inhibitors of aminoglutethimide such as 4-hydroxy-androstenedione are being developed and have proven effective in early clinical trials with breast cancer patients. Further development of active aromatase inhibitors should allow precise control of estradiol levels in women with breast cancer. This ability to perform an 'estrogen clamp' may allow new strategies to be developed in which hormone depletion followed by repletion can produce a synchronization of tumor cell DNA synthesis. If achievable, such manipulations may allow potentiation of the effects of cytotoxic chemotherapy. This latter concept is currently being rigorously tested in basic and in clinical investigative studies.

Adrenalectomy↗