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PubMed2007

Fibroblast growth factor receptor 2 tyrosine kinase is required for prostatic morphogenesis and the acquisition of strict androgen dependency for adult tissue homeostasis.

The fibroblast growth factor (FGF) family consists of 22 members and regulates a broad spectrum of biological activities by activating diverse isotypes of FGF receptor tyrosine kinases (FGFRs). Among the FGFs, FGF7 and FGF10 have been implicated in the regulation of prostate development and prostate tissue homeostasis by signaling through the FGFR2 isoform. Using conditional gene ablation with the Cre-LoxP system in mice, we demonstrate a tissue-specific requirement for FGFR2 in urogenital epithelial cells--the precursors of prostatic epithelial cells--for prostatic branching morphogenesis and prostatic growth. Most Fgfr2 conditional null (Fgfr2(cn)) embryos developed only two dorsal prostatic (dp) and two lateral prostatic (lp) lobes. This contrasts to wild-type prostate, which has two anterior prostatic (ap), two dp, two lp and two ventral prostatic (vp) lobes. Unlike wild-type prostates, which are composed of well developed epithelial ductal networks, the Fgfr2(cn) prostates, despite retaining a compartmented tissue structure, exhibited a primitive epithelial architecture. Moreover, although Fgfr2(cn) prostates continued to produce secretory proteins in an androgen-dependent manner, they responded poorly to androgen with respect to tissue homeostasis. The results demonstrate that FGFR2 is important for prostate organogenesis and for the prostate to develop into a strictly androgen-dependent organ with respect to tissue homeostasis but not to the secretory function, implying that androgens may regulate tissue homeostasis and tissue function differently. Therefore, Fgfr2(cn) prostates provide a useful animal model for scrutinizing molecular mechanisms by which androgens regulate prostate growth, homeostasis and function, and may yield clues as to how advanced-tumor prostate cells escape strict androgen regulations.

Androgens↗
PubMed2007

Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene.

UNLABELLED: We report the phenotype of mice with targeted disruption of the Trpv6 (Trpv6 KO) epithelial calcium channel. The mice exhibit disordered Ca(2+) homeostasis, including defective intestinal Ca(2+) absorption, increased urinary Ca(2+) excretion, decreased BMD, deficient weight gain, and reduced fertility. Although our Trpv6 KO affects the closely adjacent EphB6 gene, the phenotype reported here is not related to EphB6 dysfunction. INTRODUCTION: The mechanisms underlying intestinal Ca(2+) absorption are crucial for overall Ca(2+) homeostasis, because diet is the only source of all new Ca(2+) in the body. Trpv6 encodes a Ca(2+)-permeable cation channel responsible for vitamin D-dependent intestinal Ca(2+) absorption. Trpv6 is expressed in the intestine and also in the skin, placenta, kidney, and exocrine organs. MATERIALS AND METHODS: To determine the in vivo function of TRPV6, we generated mice with targeted disruption of the Trpv6 (Trpv6 KO) gene. RESULTS: Trpv6 KO mice are viable but exhibit disordered Ca(2+) homeostasis, including a 60% decrease in intestinal Ca(2+) absorption, deficient weight gain, decreased BMD, and reduced fertility. When kept on a regular (1% Ca(2+)) diet, Trpv6 KO mice have deficient intestinal Ca(2+) absorption, despite elevated levels of serum PTH (3.8-fold) and 1,25-dihydroxyvitamin D (2.4-fold). They also have decreased urinary osmolality and increased Ca(2+) excretion. Their serum Ca(2+) is normal, but when challenged with a low (0.25%) Ca(2+) diet, Trpv6 KO mice fail to further increase serum PTH and vitamin D, ultimately developing hypocalcemia. Trpv6 KO mice have normal urinary deoxypyridinoline excretion, although exhibiting a 9.3% reduction in femoral mineral density at 2 months of age, which is not restored by treatment for 1 month with a high (2%) Ca(2+) "rescue" diet. In addition to their deranged Ca(2+) homeostasis, the skin of Trpv6 KO mice has fewer and thinner layers of stratum corneum, decreased total Ca(2+) content, and loss of the normal Ca(2+) gradient. Twenty percent of all Trpv6 KO animals develop alopecia and dermatitis. CONCLUSIONS: Trpv6 KO mice exhibit an array of abnormalities in multiple tissues/organs. At least some of these are caused by tissue-specific mechanisms. In addition, the kidneys and bones of Trpv6 KO mice do not respond to their elevated levels of PTH and 1,25-dihydroxyvitamin D. These data indicate that the TRPV6 channel plays an important role in Ca(2+) homeostasis and in other tissues not directly involved in this process.

Animals↗
PubMed2003

Homeostasis of intracellular Ca2+ in equine chondrocytes: response to hypotonic shock.

REASONS FOR PERFORMING STUDY: Ca2+ homeostasis in articular chondrocytes affects synthesis and degradation of the cartilage matrix, as well as other cellular functions, thereby contributing to joint integrity. Although it will be affected by mechanical loading, the sensitivity of intracellular Ca2+ concentration ([Ca2+]i) in equine articular chondrocytes to many stimuli remains unknown. HYPOTHESIS: An improved understanding of Ca2+ homeostasis in equine articular chondrocytes, and how it is altered during joint loading and pathology, will be important in understanding how joints respond to mechanical loads. METHODS: [Ca2+]i was determined using the fluorophore fura-2. We examined the effects of hypotonic shock, a perturbation experienced in vivo during mechanical loading cycles. We used inhibitors of Ca2+ transporters to ascertain the important factors in Ca2+ homeostasis. RESULTS: Under isotonic conditions, [Ca2+]i was 148 +/- 23 nmol/l, increasing by 216 +/- 66 nmol/l in response to reduction in extracellular osmolality of 50%. Resting [Ca2+]i, and the increase following hypotonic shock, were decreased by Ca2+ removal; they were both elevated when extracellular [Ca2+] ([Ca2+]o) was raised or following Na+ removal. The hypotonicity-induced rise in [Ca2+]i was inhibited by exposure of cells to gadolinium (Gd3+; 10 micromol/l), an inhibitor of mechanosensitive channels. [Ca2+]i was also elevated following treatment of cells with thapsigargin (10 micromol/l), an inhibitor of the Ca2+ pump of intracellular stores. CONCLUSIONS: A model is presented which interprets these findings in relation to Ca2+ homeostasis in equine articular chondrocytes, including the presence of mechanosensitive channels allowing Ca2+ entry, a Na+/Ca2+ exchanger for removal of intracellular Ca2+ and intracellular stores sensitive to thapsigargin. POTENTIAL RELEVANCE: A more complete understanding of Ca2+ homeostasis in equine chondrocytes may allow development of future therapeutic regimes to ameliorate joint disease.

Animals↗
PubMed2003

Melatonin and energy homeostasis: peripheral versus central regulation.

Melatonin, the hormone of darkness, has been known for a long time to be a major regulator of energy homeostasis in hibernating animals. Much less is known about the role of melatonin in energy homeostasis in non-hibernating animals, including humans. In mammals, two specific melatonin receptor subtypes, MT1 and MT2, have been cloned and are known to be expressed at central and peripheral sites. Although a central regulation of energy homeostasis has been widely accepted for hibernating animals, the exact site of melatonin action remains still poorly defined. Central effects appear to be predominantly mediated by the MT1 subtype. Recently, several groups showed that melatonin may also have a direct effect on peripheral tissues involved in energy homeostasis such as pancreatic beta cell, hepatocytes and adipocytes. Both, the MT1 and MT2 subtypes appear to be involved. The respective contribution of central and peripheral effects of melatonin on energy homeostasis in vivo must be established in future studies.

Animals↗
PubMed2004

[Free radical homeostasis].

Although free radicals have reactive chemical properties, the characteristics of free radical homeostasis have been maintained during the evolution of oxygen-requiring organisms. These characteristics are implicated in performing diverse physiological functions and none of deleterious effects resulting from neat balance of production and scavenging of free radicals, as well as the repair of radical-induced damage of bio-macromolecules under physiological conditions. Nutrients and their metabolites along with "essential" antioxidants play crucial roles in maintaining free radical homeostasis. Glutathione homeostasis interrelates synergistically with free radical homeostasis. Free radical homeostasis should be maintained well in healthy humans at different ages and under various living conditions in order that oxidative stress and its induced oxidative damage will be prevented or ameliorated before aging.

Animals↗
PubMed2005

[TRPM7: a protein responsible for magnesium homeostasis in a cell].

Magnesium is an important cofactor in biological processes. For many years it has been considered that magnesium homeostasis in a cell is regulated by its eflux from a cell and not by its influx. It has also been considered that the Na+/Mg2+ antiport plays the main role. In recent years, many experiments have been carried out to understand the mechanisms of Mg2+ transport in an organism. These experiments have led to some new conclusions. It was confirmed that the level of magnesium in a cell is probably also regulated by its influx to the cell. One of the last scientific findings is the discovery of the TRPM (transient receptor potential melastatin) protein family. TRPM6 and TRPM7, bifunctional proteins with kinase and ion channel activities, are responsible for magnesium homeostasis. The discovery of these proteins led to a better understanding of magnesium homeostasis. It was confirmed that TRPM6 protein is responsible for homeostasis in the whole organism and that TRPM7 may regulate the level of magnesium in the cell. TRPM7 also has other functions. One of those newly recognized is the phosphorylation of annexin 1. However, many activities and functions of TRPM7 have not yet been described. This paper is a review of knowledge of TRPM7 transmembrane protein, which is responsible for the magnesium homeostasis in the cell. It briefly presents the main functions and structure of TRPM7. It also describes the mechanisms of its biological activity.

Animals↗
PubMed1993

Homeostasis of zinc in marginal human zinc deficiency: role of absorption and endogenous excretion of zinc.

Although biochemical and immunologic aspects of mild or marginal human zinc deficiency have been well characterized, there is a paucity of data regarding the effects of prolonged marginal zinc deficiency on zinc homeostasis. It appears that human beings are able to maintain zinc homeostasis by increasing efficiency of zinc absorption and decreasing endogenous excretion of zinc when they are subjected to short-term dietary zinc restriction. However, a mild deficiency of zinc in human beings under usual circumstances is an outcome of chronic exposure to diets low in zinc lasting for many months and years. Therefore, it is important to determine whether or not the adapted zinc homeostasis during the short duration of dietary zinc deprivation is also maintained during a prolonged period of dietary zinc restriction. We assessed the efficiency of zinc absorption as well as endogenous zinc excretion during a 6-month period of dietary zinc restriction (63.1 mumol/day) in human volunteers by using a stable zinc (70Zn). Prolonged marginal zinc deficiency did not impair the functional role of endogenous zinc excretion in zinc homeostasis, but efficiency of zinc absorption was not sustained and decreased in the majority of our volunteers when the zinc-restricted diet was continued for 6 months. Such altered mechanisms of zinc homeostasis suggest that chronic human zinc deficiency warrants reassessment of dietary zinc requirement to preserve normal zinc status in the subsets of population that are vulnerable to zinc deficiency.

Adult↗
PubMedDate not supplied

[The interrelationship of changes in carbohydrate-energy metabolism and potassium homeostasis in children with diffuse suppurative peritonitis].

The parameters of potassium homeostasis (potassium concentration in the plasma, red cells, and urine and potassium to sodium ratio in the urine) and of carbohydrate-energy metabolism (CEM) assessed from the activities of the key enzymes of glycolysis and pentose phosphate route of glucose oxidation were determined in 52 patients on day 2 postoperation. Relationships between potassium metabolism and CEM status were revealed in children with diffuse peritonitis. Disorders in potassium homeostasis were associated with CEM changes. In children with a favorable course of the disease the adaptation changes in the metabolic system, characterized by increased intensity of glucose oxidation and intactness of cellular energy homeostasis, permit the maintenance of potassium homeostasis at optimal potassemia of low therapeutic value. In case of a lethal outcome failure of therapeutic measures aimed at correction of potassium homeostasis is coupled with CEM disorders manifesting by reduced glucose oxidation after the pentose phosphate route, reduced concentration of adenyl nucleotides, disordered membrane permeability, and accumulation of organic acids.

Acid-Base Equilibrium↗
PubMedDate not supplied

[The prenatal mechanisms of gas homeostasis].

This article discusses the physiological mechanisms of blood gas homeostasis in the prenatal period. Support of gas homeostasis is one of the most important systems providing for normal growth and development of an embryo. In the first period, the gas homeostasis of an embryo is provided by mother's organism. However, later this function is transferred to fetus. The satisfactory results depend, above all, on the adaptive changes in blood circulation. Simultaneously, the second chain of the functional systems is developing. After birth it is generally used in the form of the respiratory and general movements in response to breathing motivation. It can also appear in the prenatal period in case of deviation of the internal environment parameters to the extent when the adaptive changes in blood circulation are inadequate to compensate for gas deficit. In a fetus the breathing motivation is in most cases expressed in patterns or successive series of movements. Movement patterns have no direct adaptive role, because the result of the actions is evaluated and directed not by reverse afferentation accompanying the movement, but by its possible result modified by the humoral system. Formation of the second part of functional system supporting gas homeostasis, is significantly impacted by the situation and the starting stimulus. This is clear from the fetus response to contact with air. In this situation the adaptive behavior provides the successful birth of an organism. Under the impact of breathing motivation, the fetus demonstrates the ability to afferent synthesis of inner irritation with autostimulus, which comes from external environment (perception of gravitation, locomotion of swimming and walking, negative reaction to water, defensive reaction, etc.). Nasal contact with air produces the breathing movements typical for a newborn. The paper discusses the steps of maturation of the components of the functional system supporting gas homeostasis, the central elements of the process, the role of respiration movements after gas exchange is maintained by lungs, the role of the lung gas exchange in displays of the functional system in question, and other regularities of systemogenesis.

Animals↗
PubMed2006

Epidermal homeostasis in long-term scaffold-enforced skin equivalents.

Epidermal homeostasis is understood as the maintenance of epidermal tissue structure and function by a fine tuned regulatory mechanism balancing proliferation and cell loss by desquamation and apoptosis. The lack of appropriate experimental models has largely prevented a better understanding of the regulatory mechanisms controlling epidermal tissue homeostasis in human skin. Keratinocyte culture studies had revealed a strict dependency of regular epidermal differentiation on dermal interactions only accomplishable in three-dimensional skin models. As major drawbacks, conventional models, employing collagen hydrogels as dermal equivalents (DEs) exhibit a rather poor stability and limited lifespan. Here, we present an improved stabilized in vitro-model for long-term growth and differentiation of keratinocytes providing the basis for tissue homeostasis. Keratinocytes were grown on DEs reinforced by modified hyaluronic acid fibers (Hyalograft-3D) and colonized with skin fibroblasts, producing genuine dermis-type matrix. These skin equivalents (SEs) develop superior epidermal architecture with regular differentiation and ultrastructure. Critical aspects of differentiation, still unbalanced in early stages, are renormalized, most strikingly the coexpression of keratins K1/K10, downregulation of regeneration-associated keratins (K16), and restriction of K15 to the basal layer. The strict localization of integrins to basal cells underlining restored tissue polarity, the drop of keratinocyte growth rates towards physiological levels and the rapid formation of a mature basement membrane with abundant anchoring fibrils are altogether features fulfilling the criteria of tissue homeostasis. Therefore, these scaffold-based SEs not only allow for studying homeostasis control but also for the first time provide proper experimental conditions for establishing a stem cell niche in vitro.

Adult↗
PubMed1986

Risk homeostasis theory and traffic accident data.

The risk homeostasis theory posits, in essence, that a control mechanism analogous to the thermal homeostatic system in warm-blooded animals tends to keep risk per unit time constant, and, as a consequence, the number of traffic accidents per unit time of driving also tends to remain constant, essentially independent of changes in the traffic safety system. It is the purpose of the present research to examine the validity of this claim using a wide variety of traffic accident data. All the data examined are found to be incompatible with the risk homeostasis theory. The only specific field accident data offered in the literature to support the risk homeostasis theory are found to, in fact, refute the theory. The accident data provide evidence that a rich variety of user responses occur. While it is possible for users to collectively respond in such a way that safety benefits are completely cancelled, such a response is not particularly common; it is certainly not universally occurring, as suggested by the risk homeostasis theory. It is concluded that the risk homeostasis theory should be rejected because there is no convincing evidence supporting it and much evidence refuting it.

Accidents, Traffic↗
PubMed2006

Metabolomic profiling of heat stress: hardening and recovery of homeostasis in Drosophila.

Frequent exposure of terrestrial insects to temperature variation has led to the evolution of protective biochemical and physiological mechanisms, such as the heat shock response, which markedly increases the tolerance to heat stress. Insight into such mechanisms has, so far, mainly relied on selective studies of specific compounds or characteristics or studies at the genomic or proteomic levels. In the present study, we have used untargeted NMR metabolomic profiling to examine the biological response to heat stress in Drosophila melanogaster. The metabolite profile was analyzed during recovery after exposure to different thermal stress treatments and compared with untreated controls. Both moderate and severe heat stress gave clear effects on the metabolite profiles. The profiles clearly demonstrated that hardening by moderate heat stress led to a faster reestablishment of metabolite homeostasis after subsequent heat stress. Several metabolites were identified as responsive to heat stress and could be related to known physiological and biochemical responses. The time course of the recovery of metabolite homeostasis mirrored general changes in gene expression, showing that recovery follows the same temporal pattern at these two biological levels. Finally, our data show that heat hardening permits a quicker return to homeostasis, rather than a reduction of the acute metabolic perturbation and that the reestablishment of homeostasis is important for obtaining maximal heat-hardening effect. The results display the power of NMR metabolomic profiling for characterization of the instantaneous physiological condition, enabling direct visualization of the perturbation of and return to homeostasis.

Adaptation, Physiological↗
PubMed2023

Metabolomic profiling of glucose homeostasis in African Americans: the Insulin Resistance Atherosclerosis Family Study (IRAS-FS).

INTRODUCTION: African Americans are at increased risk for type 2 diabetes. OBJECTIVES: This work aimed to examine metabolomic signature of glucose homeostasis in African Americans. METHODS: We used an untargeted liquid chromatography-mass spectrometry metabolomic approach to comprehensively profile 727 plasma metabolites among 571 African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) and investigate the associations between these metabolites and both the dynamic (SI, insulin sensitivity; AIR, acute insulin response; DI, disposition index; and SG, glucose effectiveness) and basal (HOMA-IR and HOMA-B) measures of glucose homeostasis using univariate and regularized regression models. We also compared the results with our previous findings in the IRAS-FS Mexican Americans. RESULTS: We confirmed increased plasma metabolite levels of branched-chain amino acids and their metabolic derivatives, 2-aminoadipate, 2-hydroxybutyrate, glutamate, arginine and its metabolic derivatives, carbohydrate metabolites, and medium- and long-chain fatty acids were associated with insulin resistance, while increased plasma metabolite levels in the glycine, serine and threonine metabolic pathway were associated with insulin sensitivity. We also observed a differential ancestral effect of glutamate on glucose homeostasis with significantly stronger effects observed in African Americans than those previously observed in Mexican Americans. CONCLUSION: We extended the observations that metabolites are useful biomarkers in the identification of prediabetes in individuals at risk of type 2 diabetes in African Americans. We revealed, for the first time, differential ancestral effect of certain metabolites (i.e., glutamate) on glucose homeostasis traits. Our study highlights the need for additional comprehensive metabolomic studies in well-characterized multiethnic cohorts.

Humans↗
PubMed2000

Cell population dynamics (apoptosis, mitosis, and cell-cell communication) during disruption of homeostasis.

The sequence of events involved in maintenance of homeostasis must encompass mechanisms within single cells as well as interactions between cells within a population. To investigate the interaction among these inter- and intracellular mechanisms, disruption of homeostasis by serum deprivation was performed in WB-F344, a normal diploid epithelial cell line. Changes in cell-cell communication (gap junction function) at the population level and in individual cells were monitored using the scrape load/dye transfer and fluorescence redistribution after photobleaching assays. Apoptosis and mitosis were measured using internucleosomal DNA ladder assays and fluorescence-activated cell sorting. The results indicate that a common element in early apoptosis and early mitosis is sustained gap junction function. As cell life (mitosis) and cell death (apoptosis) progressed, a common process of change in gap junction function occurred. A transient stimulation of mitosis concomitant with increased apoptosis was also observed during serum deprivation. Gap junctions may play a regulatory role during initiation of these opposite yet equally important mechanisms of maintaining homeostasis. This model system is useful for further studies on the relationships among inter- and intracellular mechanisms of homeostasis.

Animals↗
PubMed1997

T-cell homeostasis in HIV-1 infection.

Failure of T-cell homeostasis is an important feature of HIV-1 infection. Substantial evidence indicates that T-cell homeostasis is independent of CD4+ and CD8+ subsets, and this may contribute to the decline of CD4+ T cells to low levels in this disease. Moreover, failure of T-cell homeostasis appears to precede the development of clinically-defined AIDS by approximately 1.5 to 2 years and is thus an important milestone in HIV-1 disease progression. We argue that T-cell turnover and depletion of memory cells in HIV-1 infection can be viewed as the reverse of the process by which immune reconstitution occurs after stem cell transplantation, and that changes in the functional level of T-cell memory may be critical to both processes. An understanding of the relationship between T-cell memory and regeneration of lost T cells may help preserve and/or reconstitute immune system homeostasis in HIV-1-infected individuals.

Disease Progression↗
PubMed1993

Comparative effects of two polychlorinated biphenyl congeners on calcium homeostasis in rat cerebellar granule cells.

Some polychlorinated biphenyls (PCBs) have been reported to alter locomotor activity and decrease brain dopamine function in laboratory animals. PCBs with ortho- and/or parachlorine substitutions and varying number of chlorinations are known to decrease cell dopamine content in vitro and have been detected in brains of animals exposed to PCBs, suggesting that the neurotoxicity could be mediated by ortho-substituted congeners. Dopamine or other neurotransmitter uptake and release phenomena are dependent on the maintenance of intracellular Ca2+ homeostasis, and perturbations in Ca2+ homeostasis could lead to altered cell function and/or death. We compared the effects of two PCB congeners on Ca2+ homeostasis in cerebellar granule cells: 2,2'-dichlorobiphenyl (DCBP), a putative neurotoxic congener, and 3,3',4,4',5-pentachlorobiphenyl (PCBP), a presumed nonneurotoxic congener. In cerebellar granule cells (6-8 days in vitro), DCBP was cytotoxic as indicated by a significant increase in LDH leakage at 200 microM after 2 hr of exposure and at 100 microM after 4 hr exposure. PCBP, on the other hand, did not affect LDH leakage even at 200 microM for up to 4 hr. Although both congeners increased cerebellar granule cell [Ca2+]i, DCPB was more effective in increasing [Ca2+]i to a greater extent than PCBP. The increase in [Ca2+]i produced by both congeners was not transient, but a steady rise was observed with time. To understand cellular Ca(2+)-buffering capacity, Ca2+ sequestration and Ca2+ extrusion were studied in mitochondria, microsomes, and synaptosomes, isolated from adult rat cerebellum. DCBP was a potent inhibitor of 45Ca2+ uptake by mitochondria (IC50 = 6.17 +/- 0.53 microM) and microsomes (IC50 = 7.61 +/- 0.35 microM). PCBP inhibited Ca2+ sequestration by mitochondria (68% of control) and microsomes (72% of control), but the effects were much less than those produced by equivalent concentrations of DCBP. Synaptosomal Ca(2+)-ATPase was inhibited by DCBP, but not by PCBP. These results indicate that at concentrations where cytotoxicity in cerebellar granule cells was not observed, DCBP increased intracellular [Ca2+]i, and at the same concentrations, Ca2+ sequestration by intracellular organelles and Ca(2+)-ATPase in synaptic plasma membrane were inhibited. Although PCBP increased [Ca2+]i in cerebellar granule cells to some extent, it was not potent in affecting Ca2+ sequestration or Ca2+ extrusion in adult cerebellar components. Hence, PCBP-induced slight increase of [Ca2+]i levels in the cells might have been associated with effective Ca2+ sequestration by intracellular organelles, as seen in cerebellar preparations. The results of this study support the hypothesis that the position of chlorine substitution on the biphenyl ring and/or number of chlorine substitutions may have significant implications for predicting potential effects of PCB congeners in the nervous system, and perturbations in Ca2+ homeostasis might play a significant role in the neuroactivity of PCBs.

Animals↗
PubMed2005

Alteration of thyroid hormone homeostasis by antiepileptic drugs in humans: involvement of glucuronosyltransferase induction.

RATIONALE: The aim of this review article is to analyse which antiepileptic drugs (AEDs) alter thyroid hormone homeostasis in humans and when this can be explained, at least partially, by the induction of the glucuronoconjugation pathways. METHODS: Electronic databases were searched which have provided more than 300 articles. These have been integrated with fundamental books and personal information by experts in the different areas examined. RESULTS: Alteration of thyroid hormone homeostasis by phenobarbital/primidone, phenytoin, and carbamazepine clearly occurs in humans. However, it is not associated with thyroid-stimulating hormone (TSH) increase and the clinical significance of altered serum concentrations of thyroid hormones by these antiepileptic drugs has remained unclear. The published information on the effect of the other antiepileptic drugs examined in this review article on thyroid hormones is lacking (felbamate, pregabalin, zonisamide) or limited. Oxcarbazepine appears to have some effects. Topiramate would need further investigations as well as gabapentin. Levetiracetam, tiagabine, vigabatrine, and lamotrigine do not alter at all, or only minimally, thyroid hormone homeostasis. CONCLUSION: Concerning the antiepileptic drugs which alter thyroid hormone homeostasis, it is highly probable that the mechanism of induction of uridine diphosphate glucuronosyltransferases (UGT) is involved, at least partially, in such an alteration. However, it is not possible to estimate the relative contribution of the UGT induction by these drugs on the total alteration observed in thyroid hormone levels, as other mechanisms not investigated, or not examined in the present article, could contribute.

Anticonvulsants↗
PubMed2007

Copper homeostasis gene discovery in Drosophila melanogaster.

Recent studies have shown a high level of conservation between Drosophila melanogaster and mammalian copper homeostasis mechanisms. These studies have also demonstrated the efficiency with which this species can be used to characterize novel genes, at both the cellular and whole organism level. As a versatile and inexpensive model organism, Drosophila is also particularly useful for gene discovery applications and thus has the potential to be extremely useful in identifying novel copper homeostasis genes and putative disease genes. In order to assess the suitability of Drosophila for this purpose, three screening approaches have been investigated. These include an analysis of the global transcriptional response to copper in both adult flies and an embryonic cell line using DNA microarray analysis. Two mutagenesis-based screens were also utilized. Several candidate copper homeostasis genes have been identified through this work. In addition, the results of each screen were carefully analyzed to identify any factors influencing efficiency and sensitivity. These are discussed here with the aim of maximizing the efficiency of future screens and the most suitable approaches are outlined. Building on this information, there is great potential for the further use of Drosophila for copper homeostasis gene discovery.

Animals↗