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PubMed2000

Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1.

Cleavage of amyloid precursor protein (APP) by the beta- and gamma-secretases generates the amino and carboxy termini, respectively, of the A beta amyloidogenic peptides A beta40 and A beta42--the major constituents of the amyloid plaques in the brain parenchyma of Alzheimer's disease patients. There is evidence that the polytopic membrane-spanning proteins, presenilin 1 and 2 (PS1 and PS2), are important determinants of gamma-secretase activity: mutations in PS1 and PS2 that are associated with early-onset familial Alzheimer's disease increase the production of A beta42 (refs 4-6), the more amyloidogenic peptide; gamma-secretase activity is reduced in neuronal cultures derived from PS1-deficient mouse embryos; and directed mutagenesis of two conserved aspartates in transmembrane segments of PS1 inactivates the ability of gamma-secretase to catalyse processing of APP within its transmembrane domain. It is unknown, however, whether PS1 (which has little or no homology to any known aspartyl protease) is itself a transmembrane aspartyl protease or a gamma-secretase cofactor, or helps to colocalize gamma-secretase and APP. Here we report photoaffinity labelling of PS1 (and PS2) by potent gamma-secretase inhibitors that were designed to function as transition state analogue inhibitors directed to the active site of an aspartyl protease. This observation indicates that PS1 (and PS2) may contain the active site of gamma-secretase. Interestingly, the intact, single-chain form of wild-type PS1 is not labelled by an active-site-directed photoaffinity probe, suggesting that intact wild-type PS1 may be an aspartyl protease zymogen.

Alzheimer Disease↗
PubMed2005

[Analysis of lactase activities of small intestine mucous membrane by double labeled stable isotope technique in subjects with lactase deficiency].

OBJECTIVE: Low lactase activity in small intestine mucosa is the main reason for the occurrence of lactose malabsorption (LM) and lactose intolerance (LI). It would be the basis for the research on LM and LI to find an accurate method to analyze the activity of lactase. METHODS: In this study, 43 volunteers were selected and divided into LM and LI group according to the results of H2 breath test and symptoms record. Twenty-five grams of 13C-lactose and 0.5 g 2H-glucose in 250ml solution were consumed by all the volunteers. The concentration of total plasma glucose, 13C- glucose and 2H-glucose were measured, the ratio of [13C-glucose]/[2H-glucose] and lactose digestion index (LDI)were calculated which could reflect the lactase activities in the mucous membrane of small intestine. RESULTS: It was found that there was no significant difference in the concentration of total glucose and 13C-glucose, while the LDI in LM group (0.47 +/- 0.15) was significantly higher than LI group (0.34 +/- 0.14). There was no significant relationship between LDI and 6h cumulative breath H2 amount (r = 0.12, P = 0.46). The 13 C-lactose/2 H-glucose challenged test showed there was still residual lactase activity in small intestine. CONCLUSION: It was concluded that 13C-lactose/2H-glucosetest can accurately and sensitively determine the lactase activity on small intestinal mucous membrane and digestible lactose amount.

Adult↗
PubMed2003

Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor.

Phenotype analysis of female mice lacking androgen receptor (AR) deficient (AR-/-) indicates that the development of mammary glands is retarded with reduced ductal branching in the prepubertal stages, and fewer Cap cells in the terminal end buds, as well as decreased lobuloalveolar development in adult females, and fewer milk-producing alveoli in the lactating glands. The defective development of AR-/- mammary glands involves the defects of insulin-like growth factor I-insulin-like growth factor I receptor and mitogen-activated protein kinase (MAPK) signals as well as estrogen receptor (ER) activity. Similar growth retardation and defects in growth factor-mediated Ras/Raf/MAPK cascade and ER signaling are also found in AR-/- MCF7 breast cancer cells. The restoration assays show that AR NH2-terminal/DNA-binding domain, but not the ligand-binding domain, is essential for normal MAPK function in MCF7 cells, and an AR mutant (R608K), found in male breast cancer, is associated with the excessive activation of MAPK. Together, our data provide the first in vivo evidence showing that AR-mediated MAPK and ER activation may play important roles for mammary gland development and MCF7 breast cancer cell proliferation.

Animals↗
PubMed2004

[The decrease of the activity of electron transfer chain of Torulopsis glabrata enhanced pyruvate productivity].

Torulopsis glabrata CCTCC M202019 was mutated by ethidium bromide to screen for respiratory-deficient mutants. Seven mutants that produced pyruvate higher than that of the parent were subjected to the tests of the capability assimilating fermentable substrate (glucose) and non-fermentable substrates (glycerol and acetate) to characterize true respiratory-deficient mutants. Mutants RD-16, RD-17 and RD-18 were unable to assimilate acetate or glycerol and were therefore identified as respiratory-deficient mutants. Compared to the parent strain, the growth the intracellular ATP content of those mutants decreased by 21% - 29% and 15% - 21%, respectively, while the glucose consumption per cell and the pyruvate production per cell of those mutants were enhanced by 20.7% - 30.7% and 30.7% - 55.5%, respectively. Qualitative analysis of cytochromes involved in electron transfer chain showed that mutants RD-16 and RD-18 lacked both cytochrome aa3 and b, while mutant RD-17 lacked cytochrome b. Enzymes analysis indicated that the activities of ATPase, succinate-cytochrome c reductase (complex I ), complex I + III , complex II + III, and complex IV of those mutants decreased by 14.6% - 22.2%, 34% - 41%, 38.6% - 52.6%, 21% - 25%, and 150% - 630%, respectively. However, increased glucose consumption per cell was not observed in those mutants, which might be due to that the NADH generated in glycolysis can not be completely oxidized via electron transfer chain. To avoid the accumulation of NADH, 2.1 mmol/L acetaldehyde was added to the culture broth of mutant RD-17 at 26h of fermentation. Using this strategy, the amount of pyruvate produced increased by 21.6% while the fermentation time was shortened from 62h to 48h.

Acetaldehyde↗
PubMed1990

Kashin-Beck disease: a cross-sectional study in seven villages in the People's Republic of China.

Kashin-Beck disease (KBD) is an endemic disease that occurs in certain parts of the People's Republic of China and in Russia. The etiology of the disease is unknown. Selenium deficiency, mycotoxins, and chelating agents such as humic acid and decaying plant material from walnut tree forests have been suggested as causal agents. The primary lesion of this disease is the selective coagulative necrosis of the hypertrophic chondrocytes at the base of the articular and growth plate cartilages. A cross-sectional study was performed in the People's Republic of China in 7 villages, to focus on information about life styles, food consumption, and environmental factors from the village population where the disease is endemic. A total of 425 children were examined, of which 71 children had KBD. Results of detailed food consumption data analyses showed that certain combinations of food substances high in protein had a protective effect. It was also found that the disease was twice as prevalent in onset in boys as in girls, in the 12-yr-old age group. The overall onset of illness in this group of children ranged from 4 to 13 yr. Either the joints of the fingers or one ankle was affected first. Many of these children also had discolored teeth. However, this finding was unrelated to KBD.

Adolescent↗
PubMed2004

Learning of medical pharmacology via innovation: a personal experience at McMaster and in Asia.

Pharmacology, a discrete preclinical discipline of the traditional medical curriculum, identifies itself distinctly different from the other preclinical or clinical subjects in knowledge base as well as learning/teaching instructions. It exists in series with other pre-clinical courses (e.g., anatomy, biochemistry and physiology), and in parallel with other paraclinical courses such as pathology, microbiology and community medicine. Such arrangement makes learning of pharmacology rather difficult and deficient with regard to its therapeutic relevance and clinical application. In recent years, medical curricula based on clinical cases have emerged as a platform in which pharmacology is one integrated component in a holistic approach to medical education. In this problem-based learning (PBL) model, students learn, with teachers' facilitation, in a student-centered environment, based on self-directed, clinically relevant and case-oriented approach, usually in a small-group tutorial format. In PBL, pharmacology is learned in concert with other subject issues relevant to the case-problem in question, such as anatomy, physiology, pathology, microbiology, population health, behavior science, etc. Students learn via problem-evoked curiosity and motivation, in an environment which encourages free inquiries and intensive discussions in a cooperative rather than competitive atmosphere. Teachers facilitate students' learning objectives rather than deliver pre-packed knowledge and dictate what they think students should learn. A change towards PBL curriculum appears to be beneficial in better preparing the medical students as life-long learners capable of coping with changes in knowledge and skills associated with the progressive and dynamic social/economic transformation in the Asia-Pacific regions. Evidence is presented that this is indeed happening.

Asia↗
PubMed2004

TNF alpha-induced Ras activation due to ethanol promotes hepatocyte proliferation independently of liver injury in the mouse.

Tumor necrosis factor alpha (TNFalpha) has been shown to be both proapoptotic and mitogenic for hepatocytes and necessary for alcohol-induced liver injury. Ras, a known proto-oncogene, is very important in the regulation of cellular responses to TNFalpha. Therefore, the purpose of this study was to investigate the role of Ras in alcohol-induced pathogenesis. Male C57Bl/6 mice were fed ethanol or high-fat control diet via intragastric cannulation for 4 weeks. Ras activity was increased significantly after 4 weeks of ethanol and correlated with an increase in pathologic features. However, in mice deficient in the receptor-type 1 for TNFalpha (TNFR1(-/-)), ethanol-induced liver injury and the increase in Ras activity were significantly blunted compared with wild-type mice. Furthermore, it was demonstrated that H-, K-, and R-Ras isoforms were increased after ethanol exposure in wild-type mice. In TNFR1(-/-) mice, R-Ras activity remained elevated by ethanol, whereas H-Ras and K-Ras activity was blunted significantly under these conditions. Interestingly, hepatocellular proliferation, which was elevated approximately fivefold after 4 weeks of chronic ethanol in wild-type mice, was also blunted in TNFR1(-/-) mice given ethanol. Inhibition of Ras with adenovirus containing a dominant-negative Ras had no effect on ethanol-induced liver injury, but significantly blunted ethanol-induced hepatocyte proliferation by more than 50%. Overexpression of mitochondrial superoxide dismutase using recombinant adenovirus blunted lipid peroxidation and attenuated hepatic injury resulting from ethanol, but had no effect on Ras activation and hepatocyte proliferation caused by ethanol. In conclusion, these data support the hypotheses that hepatocellular oxidative stress leads to cell death and that TNFalpha-induced Ras activation is important in hepatic proliferation in response to ethanol-induced liver injury.

Adenoviridae↗
PubMed2002

Intact active bone transplantation synergizes with anti-CD40 ligand therapy to induce B cell tolerance.

Blockade of T cell costimulatory pathways can result in the prolongation of allograft survival through the suppression of Th1 responses; however, late allograft rejection is usually accompanied by an emerging allograft-specific humoral response. We have recently determined that intact active bone (IAB) fragments transplanted under the kidney capsule can synergize with transient anti-CD40 ligand (CD40L) treatment to induce robust donor-specific allograft tolerance and suppress the alloantibody response. In this study, we take advantage of the ability of galactosyltransferase-deficient knockout (GT-Ko) mice to respond to the carbohydrate epitope, galactose-alpha1,3-galactose (Gal), to investigate whether IAB plus transient anti-CD40L therapy directly tolerize B cell responses. GT-Ko mice tolerized to Gal-expressing C3H hearts and IAB plus transient anti-CD40L therapy were challenged with pig kidney membranes that express high levels of Gal. The anti-Gal IgM and IgG responses were significantly suppressed in IAB-tolerant mice compared with controls, while the non-Gal anti-pig Ab responses were comparable. The anti-pig T cell cytokine response (IFN-gamma and IL-4) was comparable in IAB-tolerant and control mice. The tolerant state for the anti-Gal IgM response could be reversed with repeated immunization, whereas the tolerant state for the IgG response was robust and resisted repeated immunization. These observations provide an important proof-of-concept that adjunct therapies can synergize with anti-CD40L Abs to tolerize B cell responses independent of their effects on T cells. This model, which does not require mixed chimerism, provides a unique opportunity for investigating the mechanism of peripheral tolerance in a clinically relevant population of carbohydrate-specific B cells.

Acute Disease↗
PubMed1995

Human ferrochelatase: a novel mutation in patients with erythropoietic protoporphyria and an isoform caused by alternative splicing.

Erythropoietic protoporphyria (EPP), attributable to deficiency of ferrochelatase activity (FECH), is characterised mainly by cutaneous photosensitivity. To define the molecular defect in two EPP-affected siblings and their parents in a Swiss family, ferrochelatase cDNA was amplified by the polymerase chain reaction (PCR) and subjected to sequence analysis. A 5-bp deletion (T580-G584) was identified on one allele of the ferrochelatase gene in both patients and their mother. Screening of the mutation among family members of RsaI digestion of PCR-amplified genomic DNA revealed autosomal dominant inheritance associated with abnormal protoporphyrin concentration and enzyme activity. We also isolated ferrochelatase cDNAs containing a 18-bp insertion (part of the intron 2 sequence) between exons 2 and 3; this corresponded to six extra amino acids (YESNIR) inserted between Arg-65 and Lys-66 of the known ferrochelatase. This isoform was identified initially in mRNAs derived from both alleles of the ferrochelatase gene in one patient. Its existence was confirmed in six additional EPP patients, in five out of seven controls, and in four different cell lines (fibroblast, muscle, hepatoma and myelogenous leukaemia). This isoform, roughly 20% of the total ferrochelatase mRNA, was generated through splicing at a second donor site in intron 2 and its presence was not linked to EPP.

Adolescent↗
PubMed2005

Mismatched antigen prepares gamma delta T cells for suppression of airway hyperresponsiveness.

Gammadelta T cells suppress airway hyperresponsiveness (AHR) induced in allergen-challenged mice but it is not clear whether the suppression is allergen specific. The AHR-suppressive cells express TCR-Vgamma4. To test whether the suppressive function must be induced, we adoptively transferred purified Vgamma4(+) cells into gammadelta T cell-deficient and OVA-sensitized and -challenged recipients (B6.TCR-Vgamma4(-/-)/6(-/-)) and measured the effect on AHR. Vgamma4(+) gammadelta T cells isolated from naive donors were not AHR-suppressive, but Vgamma4(+) cells from OVA-stimulated donors suppressed AHR. Suppressive Vgamma4(+) cells could be isolated from lung and spleen. Their induction in the spleen required sensitization and challenge. In the lung, their function was induced by airway challenge alone. Induction of the suppressors was associated with their activation but it did not alter their ability to accumulate in the lung. Vgamma4(+) gammadelta T cells preferentially express Vdelta4 and -5 but their AHR-suppressive function was not dependent on these Vdeltas. Donor sensitization and challenge not only with OVA but also with two unrelated allergens (ragweed and BSA) induced Vgamma4(+) cells capable of suppressing AHR in the OVA-hyperresponsive recipients, but the process of sensitization and challenge alone (adjuvant and saline only) was not sufficient to induce suppressor function, and LPS as a component of the allergen was not essential. We conclude that AHR-suppressive Vgamma4(+) gammadelta T cells require induction. They are induced by allergen stimulation, but AHR suppression by these cells does not require their restimulation with the same allergen.

Adoptive Transfer↗
PubMed2004

A scaleless wings mutant associated with tracheal system developmental deficiency in wing discs in the silkworm, Bombyx mori.

A mutant of Bombyx mori has wings with few scales and is named scaleless. We investigated the morphology of this mutant and found that it had many fewer wing scales than the corresponding wild type (WT) silkworm and that the remaining scales were smaller in shape with fewer furcations. Reciprocal transplantation of wing discs between scaleless and WT revealed that the WT wing disc could develop into a small wing with scales after transplantation into a scaleless larva; however, the scaleless wing disc developed into a small wing without scales in a WT larva. Upon dissection of WT and scaleless wing discs at different stages from the fifth instar larva to adulthood, no obvious differences were found before pupation. However, after pupation, tracheae produced from WT wing veins extended to the lacunae between the veins and formed a network on the second day after pupation, whereas this did not happen in scaleless. At the same time, no marked difference in adult body tracheal development was found between the mutant and wild type. Furthermore, if the surface of a wing disc was cut and its veins injured, the resulting wing also had fewer scales than the corresponding WT. Also, we found that higher partial pressure of O2 could rescue the loss of scales in scaleless. These data suggest that the factors affecting the growth of scales were not produced in the hemolymph, but in the wing disc itself. It is also implied that wing scale development is dependent on the correct organization of the tracheal system in the wing disc.

Animals↗
PubMed2006

Depression of MAD2 inhibits apoptosis of gastric cancer cells by upregulating Bcl-2 and interfering mitochondrion pathway.

Mitotic arrest deficient 2 (MAD2) is an essential component of the mitotic spindle checkpoint pathway. It was previously shown to be associated with drug resistance of tumor cells. To further explore the roles of MAD2 in responses of gastric cancer cells to chemotherapy drugs, we constructed the siRNA vectors of MAD2 and transfected them into gastric cancer SGC7901 cells to inhibit expression of MAD2. MTT assay showed that the downregulation of MAD2 increased the resistance of SGC7901 cells to spindle inhibitors and DNA damaging agents. The apoptosis rates of gastric cancer cells transfected with MAD2-siRNA were 10.7% and 10%, respectively, after treated by 1.0microg/ml VCR and cisplatin. In contrast, the apoptosis rates of SGC7901 and SGC7901/psilencer3.1 induced by VCR were 43.2%, 38.7%; and that induced by cispaltin were 34.1%, 31.4%. The ratio of Bcl-2 to Bax was much higher in the MAD2-siRNA transfectants compared with the SGC7901/psilencer. In SGC7901/psilencer, cytochrome c and cleaved caspase 3 protein levels increased along with the exposure time increased. However, these protein levels of SGC7901/MAD2-siRNA had no changes during the drug treatment. These results indicate that down regulation of MAD2 could promote the drug resistance of gastric cancer cells and inhibit anticancer drugs induced-apoptosis by upregulating Bcl-2 and interfering the mitochondrion apoptosis pathway.

Antineoplastic Agents↗
PubMed1997

Involvement of juvenile hormone in regulation of prothoracicotropic hormone transduction during the early last larval instar of Bombyx mori.

We previously reported that a deficiency in prothoracicotropic hormone (PTTH) transduction during the early last larval instar of Bombyx mori plays a role in leading to very low ecdysteroid levels in the hemolymph, inactivation of corpora allata, as well as larval-pupal transformation. In the present study, the role of juvenile hormone (JH) in the regulation of PTTH transduction was clarified. When JH analog (hydroprene) was applied to early last instar larvae, the development of larvae was greatly inhibited. It was found that it was not PTTH release, but prothoracic gland competency in both cAMP generation and ecdysteroidogenesis to the stimulation of PTTH which was developmentally inhibited by hydroprene application. Glands in hydroprene-treated larvae showed no response in ecdysteroidogenesis to either PTTH or 1-methyl-3-isobutylxanthine (MIX) until day 7, 4 days later than those of control larvae. JH-I application showed the same effects as those of hydroprene. By contrast, allatectomy on day 0 of the last instar accelerated development, and glands showed the activation response to either PTTH or MIX in both cAMP generation and ecdysteroidogenesis 1 day after allatectomy. From these results, we conclude that the absence of JH is a prerequisite for successful PTTH transduction and for acquisition of the cAMP generating system of gland cells.

Animals↗
PubMed2003

Suppression of oxidative neuronal damage after transient middle cerebral artery occlusion in mice lacking interleukin-1.

Interleukin-1 (IL-1) contributes to ischemic neurodegeneration. However, the mechanisms regulating action of IL-1 are still poorly understood. In order to clear this central issue, mice that were gene deficient in IL-1alpha and beta (IL-1 KO) and wild-type mice were subjected to 1-h transient middle cerebral artery occlusion (tMCAO). Expression levels of IL-1beta and IL-1 receptor I (IL-1RI) were then examined. Generation of peroxynitrite and the expression of mRNAs for nitric oxide synthase (NOS) subtypes were also determined. Immunostaining for IL-1beta was increased from 6 h and peaked at 24 h after tMCAO in the microglia and macrophage. The immunoreactivities of IL-1RI were increased progressively in the microvasculature and neuron-like cells of the ipsilateral hemisphere. Infarct volumes were significantly lower in IL-1 KO mice compared with wild-type mice 48 h after tMCAO (P<0.01). The immunoreactivities of 3-nitro-L-tyrosine were determined in the neurons and microvasculature 24 h after tMCAO and were significantly decreased in the IL-1 KO mice compared to wild-type mice. In addition, expression levels of NOS mRNA in IL-1 KO mice were lower than that measured in wild-type mice. These results indicate that IL-1 is up-regulated and may play a role in neurodegeneration by peroxynitrite production during ischemia.

Animals↗
PubMed2006

Polymorphism of the DNA repair gene ERCC2 Lys751Gln and risk of lung cancer in a northeastern Chinese population.

The ERCC2 gene (excision repair cross-complementing rodent repair deficiency, complementation group 2 [xeroderma pigmentosum D]) (previously XPD), encoding a DNA repair protein, is involved in nucleotide excision repair and basal transcription. To test the effect of the polymorphism ERCC2 Lys751Gln on the risk of lung cancer in a northeastern Chinese population, a hospital-based case-control study was designed consisting of 147 newly diagnosed and previously untreated subjects with lung cancer and 145 cancer-free control subjects matched on age (+/-3 years), gender, and ethnicity. Among the controls, the allele frequency of the C-allele of ERCC2 Lys751Gln was 0.02. The C-allele of ERCC2 Lys751Gln was significantly overrepresented among lung cancer cases (C versus A: adjusted odds ratio OR(adj) = 2.61, 95% CI = 1.12-6.05, P = 0.03). The carriers of AC genotype were at 2.78-fold (OR(adj) = 2.78, 95% CI = 1.12-6.93) higher risk of lung cancer than carriers of the AA genotype. Subdivided by tumor type, carriers of AC genotype had a 4.65-fold higher risk of squamous cell carcinoma of lung compared with carriers of AA genotype (OR(adj) = 4.65, 95% CI = 1.67-12.98, P = 0.003); similar, but not statistically significant estimates were found for adenocarcinoma of lung. In conclusion, our results suggest that ERCC2 Lys751Gln(C) allele is a potential risk marker for lung cancer in this northeastern Chinese population.

Adult↗
PubMed2006

De novo mutation in the BTK gene of atypical X-linked agammaglobulinemia in a patient with recurrent pyoderma.

BACKGROUND: X-linked agammaglobulinemia (XLA), characterized by a profound deficiency of all immunoglobulins and the absence of mature B cells, is caused by mutations in the gene encoding Bruton tyrosine kinase (BTK). Most patients have recurrent sinopulmonary infection. Infections usually occur in multiple locations across time, but single infection may be limited to one anatomic location. OBJECTIVES: To report a case of atypical XLA with recurrent pyoderma and to observe the immunologic changes in the patient in 10 years. METHODS: Immunologic investigations, skin wound culture, and molecular study with DNA sequencing were performed. RESULTS: The patient was originally diagnosed as having common variable immunodeficiency disease because of the presence of circulating B cells (CD19+ B cells: 7%) at 11 years old. On further evaluation at the age of 20 years, flow cytometric analysis of lymphocytes showed only 0.4% B cells. The molecular study with DNA sequencing of the patient showed a point mutation in complementary DNA 1630 A>G(p.R544G) in the BTK gene, indicating that the patient has XLA. The mutation analysis of the BTK gene revealed a normal DNA sequence in the other family members. CONCLUSIONS: This case is an important example of a possible presentation of XLA with a predominant skin manifestation, and it demonstrates that maintaining a high level of clinical suspicion is essential for the diagnosis of XLA in a child with recurrent pyoderma.

Adolescent↗
PubMed1998

Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP; MIM 177000) is an inherited disorder caused by partial deficiency of ferrochelatase (FECH), the last enzyme in the heme biosynthetic pathway. In EPP patients, the FECH deficiency causes accumulation of free protoporphyrin in the erythron, associated with a painful skin photosensitivity. In rare cases, the massive accumulation of protoporphyrin in hepatocytes may lead to a rapidly progressive liver failure. The mode of inheritance in EPP is complex and can be either autosomal dominant with low clinical penetrance, as it is in most cases, or autosomal recessive. To acquire an in-depth knowledge of the genetic basis of EPP, we conducted a systematic mutation analysis of the FECH gene, following a procedure that combines the exon-by-exon denaturing-gradient-gel-electrophoresis screening of the FECH genomic DNA and direct sequencing. Twenty different mutations, 15 of which are newly described here, have been characterized in 26 of 29 EPP patients of Swiss and French origin. All the EPP patients, including those with liver complications, were heterozygous for the mutations identified in the FECH gene. The deleterious effect of all missense mutations has been assessed by bacterial expression of the respective FECH cDNAs generated by site-directed mutagenesis. Mutations leading to a null allele were a common feature among three EPP pedigrees with liver complications. Our systematic molecular study has resulted in a significant enlargement of the mutation repertoire in the FECH gene and has shed new light on the hereditary behavior of EPP.

Adolescent↗
PubMed2006

Differential effects of chronic amphetamine and baclofen administration on cAMP levels and phosphorylation of CREB in distinct brain regions of wild type and monoamine oxidase B-deficient mice.

Roles of GABA(B) transmission were explored in the action of amphetamine (Amph) on the brain. Adult male wild type (WT) and monoamine oxidase B-knocked out (MAOBKO) mice received i.p. injections of saline, d-Amph (5 mg/kg), plus baclofen (GABA(B) receptor agonist, 10 mg/kg), or baclofen and Amph, twice daily for 3 days and single treatments on day 4, followed by immuno-cyclic-AMP (cAMP) and immunoblotting assays on the brain tissue. The WT mice responded with higher levels of behavioral responses than the KO to the daily Amph injection; however, baclofen blocked the Amph-induced behavioral hyperactivity of both WT and KO mice. After the last treatment, levels of cAMP and phosphorylated (p) cyclic-AMP response element binding protein (CREB) were up-regulated in the striatum and somatosensory cortex of Amph-treated WT mice, while similar to the saline-controls in the baclofen+Amph-treated group, indicating the blockade by baclofen to Amph. Baclofen similarly suppressed the Amph-induced increases in pCREB levels of WT hippocampus and amygdala, and decreases of olfactory bulb and thalamus. For MAOBKO mice, baclofen hindered the Amph-generated increases in motor cortical cAMP and pCREB, and amygdaloid pCREB, and the decrease in olfactory bulb pCREB, whereas did not affect the Amph-raised hippocampal pCREB. Furthermore, the levels of CREB were variably modified in distinct regions by the drug exposures. The data reveal that the GABA(B)-mediated intracellular signaling differentially participates in mechanisms underlying Amph perturbation to various regions, and may thereby contribute explanations to the behavioral consequences. Moreover, MAOB is region-dependently involved in responses of the brain to Amph and baclofen, supporting interactions between GABA and monoamines.

Amphetamine↗