Gene/Protein Disease Symptom Drug Enzyme Compound
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A series of N-phenyl-2-aza-spiro[4.5]decane-1,3-diones [III-VIIII] structurally related to the previously described N-phenyl-3-arylpyrrolidine-2,5-dione (11) was synthesized and tested for their anticonvulsant activity in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc. MET) tests. The most potent of the series were N-(2-methylphenyl)-2-aza-spiro[4.5]decane-1,3-dione [III] and N-(3-methylphenyl)-2-aza-spiro [4.5]decane-1,3-dione [IV], which inhibited seizures in the MES and sc.MET tests. On the other hand, as a preliminary assay we synthesized and tested for the anticonvulsant activity a new N-substituted 8-phenyl-2-aza-spiro[4.5]decane-1,3-dione, containing either a benzyl or a cyclohexyl moiety [IX-XII] at the nitrogen atom. The obtained results showed that the presence and position of the methyl group in the aryl ring [III, IV], as well as an cyclohexane moiety [XI, XIII connected with the imide nitrogen atom, played the essential role for anticonvulsant activity.
Acta Pol Pharm
PMID:Synthesis and anticonvulsant properties of a series of N-substituted 2-aza-spiro[4.5]decane-1,3-diones and 8-phenyl-2-aza-spiro[4.5]decane-1,3-diones. 1579 40

Cells respond to a variety of extracellular and intracellular forms of stress by down-regulating rRNA synthesis. We have investigated the mechanism underlying stress-dependent inhibition of RNA polymerase I (Pol I) transcription and show that the Pol I-specific transcription factor TIF-IA is inactivated upon stress. Inactivation is due to phosphorylation of TIF-IA by c-Jun N-terminal kinase (JNK) at a single threonine residue (Thr 200). Phosphorylation at Thr 200 impairs the interaction of TIF-IA with Pol I and the TBP-containing factor TIF-IB/SL1, thereby abrogating initiation complex formation. Moreover, TIF-IA is translocated from the nucleolus into the nucleoplasm. Substitution of Thr 200 by valine as well as knock-out of Jnk2 prevent inactivation and translocation of TIF-IA, leading to stress-resistance of Pol I transcription. Our data identify TIF-IA as a downstream target of the JNK pathway and suggest a critical role of JNK2 to protect rRNA synthesis against the harmful consequences of cellular stress.
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PMID:The nucleolus as a stress sensor: JNK2 inactivates the transcription factor TIF-IA and down-regulates rRNA synthesis. 1580 66

Felodipine-loaded poly (epsilon-caprolactone) (PCL) microspheres were prepared by two methods, the conventional emulsion solvent evapouration method and the quenching method. The aim of this work was to investigate the effects of process parameters such as emulsion type, drug loading, molecular-weight of the polymer, types of emulsion stabilizer and dispersed phase solvents, as well as preparation methods. The results show that, when conventional emulsion solvent evapouration method was used, the o/w-method produced smaller mean size and higher encapsulation efficiency compared with the o/o-method. The encapsulation efficiencies increased with an increase in the molecular weight and a decrease in crystallinity of PCL. The size of microspheres varied with the type of emulsion stabilizer used, smaller microspheres with PVA and narrow size distribution with Pol 237. The water solubility of the dispersed phase solvent was one of the critical factors in controlling the encapsulation efficiency and microsphere mean size. When water-soluble solvents such as acetonitrile and ethyl formate were used, the encapsulation efficiencies decreased due to higher evapouration rate. When quenching methods were used, in contrast to the conventional emulsion solvent evapouration method, very narrowly size-distributed but bigger microspheres were obtained.
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PMID:Characteristics of felodipine-located poly(epsilon-caprolactone) microspheres. 1601 4

As part of our study, a series of N-phenyl- and N-benzyl-bicyclo [2.2.1] hept-5-ene-2,3-dicarboximides [III-XVI], structurally related to the previously described N-phenyl- or N-pirydyl-3-arylpyrrolidine-2,5-dione [I, II], were synthesized and tested for their anticonvulsant activity in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc. MET) tests. The most potent in the maximum electroshock seizure (MES) test were compounds with methyl [III] and chloro [XI] substituents at position -2 of the aromatic ring, whereas of all the synthesized compounds, only N-(2-methoxybenzyl)-bicyclo [2.2.1] hept-5-ene-2,3-dicarboximide [XII] was active in the sc. MET. Compounds with substituents at position -3 or -4 of the aromatic ring were found to be less active [V, VI, XIII and XIV], or devoid of activity [VII, IX, XV and XVI]. In contrast, the N-(4-chlorophenyl)-bicyclo [2.2.1] hept-5-ene-2,3-dicarboximide [VIII] at a dose of 100 mg/kg was active in the MES test.
Acta Pol Pharm
PMID:Synthesis and anticonvulsant activity of a series of N-substituted bicyclo [2.2.1] hept-5-ene-2,3-dicarboximides. 1619 14

Gene expression analyses with cDNA microarray technology identified distinct groups of breast cancers. Tumors with no ER expression could be divided into three subgroups: "basal-like" subtype, HER2-positive subtype, and "normal breast-like". "Basal-like" subtype was characterized by high expression of keratins 5 and 17, laminin and fatty acid binding protein 7. In the present study, we analyzed the usefulness of immunohistochemistry for separation of the distinct subtypes of the breast ductal carcinomas and provided further characterization of "basal-like subtype". A consecutive series of 195 primary operable invasive breast carcinomas was immunostained for HER2, ER, PGR, CK5/6 and CK17. CK5/6 or CK17 were expressed in 72 cases (36.9%), and 41 cases (21%) presented expression of CK5/6 or CK17 without ER/PGR or HER2. ER/PGR was present in 109 cases (55.9%), but in this group there were 8 cases with HER2 overexpression and 17 cases with basal-cytokeratin positivity. Similarly, in 17 out of 72 "basal-like" tumors there was ER/PGR positivity, and also in 17 of them there was HER2 overexpression. Three of these cases belonged to all three groups, representing expression of all markers. Tumor grade differed significantly (p < 0.001) between luminal and basal cytokeratin- or HER2-positive tumors. Differences for tumor size and lymph node status were not statistically significant. Our study showed that immunohistochemistry is useful for dividing breast cancers into separate subgroups, but further analyses for better characterization of cases presenting two or three markers should be performed.
Pol J Pathol 2005
PMID:Immunohistochemical identification of basal-type cytokeratins in invasive ductal breast carcinoma--relation with grade, stage, estrogen receptor and HER2. 1633 76

Polycystic ovary syndrome (PCOS) is a common heterogenous endocrine disorder associated with amenorrhoea (or oligomenorrhoea), hyperandrogenism, hirsutism, obesity, insulin resistance, and an approximately 7-fold increased risk of type 2 diabetes mellitus (NIDDM - non-insulin dependent diabetes mellitus). It is a leading cause of female infertility. The prevalence of PCOS among reproductive-age women has been estimated at 4%-12%. Familial aggregation of this syndrome is well established. There are also ethnic and racial variations in the prevalence of the syndrome and its symptoms. Multiple biochemical pathways have been implicated in the pathogenesis of PCOS. Several genes from these pathways have been tested include genes involved in steroid hormone biosynthesis and metabolism (StAR, CYP11, CYP17, CYP19 HSD17B1-3, HSD3B1-2), gonadotropin and gonadal hormones action (ACTR1, ACTR2A-B, FS, INHA, INHBA-B, INHC, SHBG, LHCGR, FSHR, MADH4, AR), obesity and energy regulation (MC4R, OB, OBR, POMC, UCP2-3), insulin secretion and action (IGF1, IGF1R, IGFBPI1-3, INS VNTR, IR, INSL, IRS1-2, PPARG) and many others. Most women with PCOS, both obese and lean, have a degree of insulin resistance. The minisatellite of insulin gene (INS VNTR), especially class III alleles and III/III genotypes might not only determine the predisposition to anovulatory PCOS but also the concomitant risk for development of type 2 diabetes. The function of the insulin receptor (IR) is probably normal in woman with PCOS. However abnormal serine phosphorylation in the receptor may impair signal transduction accounting for a post-binding defect in insulin action. Serine phosphorylation is also involved in the postranslational regulation of 17,20-lyase activity (CYP17). There may be a common aetiology for both insulin resistance and hyperandrogenism. Polymorphic alleles of both IRS-1 and IRS-2 (insulin receptor substrate 1 - 2), alone or in combination, may have a functional impact on the insulin-resistant component of PCOS. There is no evidence to suggest that follistatin gene polymorphisms play a role in the pathogenesis of insulin resistance in PCOS women. PCOS appears to be associated with the absence of the four-repeat-units allele in a polymorphic region of pentanucleotide (TTTTA)n repeats within CYP11A gene, which encodes cytochrome P450scc. It has been hypothesized that up-regulation of this enzyme could lead to increased androgen production. There is no evidence of any association of alleles of CYP19 gene (encoding cytochrome P450arom) with PCOS. Association exists between androgen receptor gene (AR) polymorphisms an androgens action in PCOS. Increased hirustism and decreased CAG repeat length within AR gene has been also demonstrated in women with normal testosterone levels. Expression of estrogen receptor (ERs) as well as 5-alpha-reeducates (SRD5A1-2 genes) activity was analysed in granulosa (GC) and theca cells (TC). The results of this study demonstrate that there are significant alterations in the expression of ERalpha and ERbeta in PCOS that may be related to abnormal follicular development. On the other hand elevated SRD5A activity in polycystic ovaries supported the hypothesis that 5-alpha-reduced androgens may play a role in the pathogenesis of the syndrome. The genetic aetiology of PCOS remains unknown. There are a number of interlinking factors that affects expression of PCOS. Single cause of PCOS is unlikely. Other possible mechanisms in pathogenesis of PCOS are discussed.
Endokrynol Pol
PMID:[Genetic aspects of polycystic ovary syndrome]. 1635 Jul 21

Current views on the molecular aspects of familial parathyroid gland diseases have been presented (familial primary hyperparathyroidism, hypoparathyroidism and psuedohypoparathyroidism). Their inherited mode and genetic abnormalities have been described. Particularly, the following genes: HRPT2, MEN1, RET, CASR, GNAS have been shown. Localization, structure, expression and structural changes (mutations) found in patients with familial parathyroid gland diseases have been presented. Attention has been paid to clinical and histopathologic symptoms, which should indicate the need to undertake genetic studies.
Endokrynol Pol
PMID:[Molecular aspects of the etiopathogenesis of the parathyroid gland diseases]. 1635 Jul 27

According to classic theory of neogenesis, cancer arises from well-differentiated cell that in response to variety of factors de-differentiates, becomes able to proliferate without control and/or loses its ability to undergo apoptosis. According to another theory, cancers (at least cancers of some organs) originate from stem cells, which "by definition" are poorly differentiated and able to proliferate indefinitely. Therefore a lower number of abnormal events is necessary for these cells to escape proliferation-controlling mechanisms. With regard to papillary thyroid cancers it is still thought that it arises from well-differentiated thyreocyte. One of the characteristic features of cancer cell is chromosomal instability. Lowest number of such abnormalities is observed in well-differentiated thyroid cancers (including papillary cancer), intermediate - in poorly-differentiated cancers, while highest - in anaplastic cancers. Microarray analysis shows that despite of clinical heterogeneity, gene expression profiles of papillary cancers are very similar. Genetic anomalies predisposing to the development of papillary cancer most commonly regard proteins that possess kinase activity. Kinases phosphorylate other proteins, and play an extremely important role in signal transduction from outside the cell as well as inside the cell. Constitutive activation of some kinases may lead to the excessive and/or permanent activation of some transduction pathways specific for mitogens or growth factors. This results in excessive proliferation. The best known protein of such type which function is altered in papillary thyroid cancers is RET - a membrane-located growth factor-receptor with kinase activity. RET gene undergoes different rearrangements in this type of cancer. There are approximately 10 RET rearrangements known, with RET/PTC3 and RET/PTC1 being most common. In this anomaly kinase domain-encoding 3' end of RET gene is aberrantly bound to 5' end of another gene. Fusion protein synthesized on such hybrid template is not present in the cell membrane but in the cytoplasm, where it permanently activates transduction pathway specific for RET. NTRK1 gene encoding a member of family of neuronal growth factor receptors containing thyrosine kinase domain is also rearranged in papillary cancers. However, genes fused to its kinase domain-encoding sequence are different from the ones fused to RET. MET, a gene encoding another membrane protein with thyrosine kinase activity, which acts as a growth factor-receptor, is overexpressed in 70%-90% of papillary thyroid cancers. BRAF gene encoding another yet kinase transducing signals from RAS and RAF to the cell is mutated at position 1796 (T/A, amino acid substitution V599E) in 38-69% of papillary cancers. The presence of this activatory mutation is associated with higher degree of clinical advancement of the disease. In addition, in majority of papillary cancers tested, mutations of the genes encoding nuclear triiodothyronine receptors were found. Transgenic mice with both TRB allele replaced with dominant-negative TRB mutants develop aggressive thyroid cancers. Progression from papillary to anaplastic cancer is most possibly caused by the occurrence of additional anomalies within P53, RAS, NM23,b-catenin gene and other genes.
Endokrynol Pol
PMID:[Genetic factors predisposing to the development of papillary thyroid cancer]. 1635 Jul 29

The paper is focused on guidelines of practice in inherited medullary thyroid cancer, diagnosed on the basis of DNA analysis. Identification of RET mutation implies further steps of diagnostic procedure, some of them - USG, FNAB and calcitonin level tests - are common for all types of mutation, other are related to ascertained type of mutation. In asymptomatic RET mutation carriers, prophylactic thyroidectomy is indicated. In MEN2B inherited cancer reveals its symptoms quickly and shows dynamic progress. In MEN2A/FMTC the clinical picture is diversified - in some patients the course of disease is mild, however in some other cases the progression of disease and even death occur regardless of the proper treatment. Unfortunately, there are no molecular prognostic markers in medullary thyroid carcinoma. Recent papers and also our own unpublished results show that gene expression profile, is similar in MEN2A and sporadic cancer. This group differs from MEN2B by its expression profile. In conclusion it is to be emphasized that although inherited medullary thyroid carcinoma is a rare disease, the diagnostic algorithm is well established and maximizes the chance for early diagnosis. Moreover, it needs to be stressed that DNA analysis results inform us not only about the necessity of further therapy, but also suggest different ways of proceeding in particular type of mutation.
Endokrynol Pol
PMID:[Medullary thyroid carcinoma: from molecular studies to clinical decision]. 1635 Jul 33

Mutations of genes coding effectors of signaling pathway RET/PTC-RAS-RAF-MEK-ERK, involved in cell growth and proliferation, are important in papillary thyroid cancer development. To earlier discovered mutations of RAS and RET/PTC genes, BRAF gene mutation has been recently added. Mutation of BRAF gene appears in various types of carcinomas, but most frequently in malignant melanomas (66%) and papillary thyroid cancer (average 44%). The BRAF gene protein product belongs to the serine-threonine kinase family and to the RAF proteins subfamily, among which it is the strongest activator of MAP kinases cascade. The most frequently mutation of BRAF gene is thymine to adenine transversion at nucleotide position 1796 (T1796A). This point mutation causes valine to glutamic acid substitution at residue 599 (V599E), that results in constitutive and oncogenic activation of BRAF kinase. The relation between mutations of BRAF, RAS and RET/PTC genes has not been found, although they together exist in two thirds of papillary thyroid cancers. BRAF(TI796A) oncogene appears in papillary thyroid cancer, whereas it has not been found in follicular thyroid cancer and benign thyroid adenomas. For this reason mutated BRAF gene could be specific molecular marker, with relatively high sensitivity in diagnostics of papillary thyroid cancer. In addition, BRAF gene has been demonstrated as a novel prognostic biomarker, which correlates with unfavorable clinicopathological factors, such as extrathyroidal invasion and distant metastasis.
Pol Merkur Lekarski 2006 Feb
PMID:[BRAF gene mutation in thyroid cancer]. 1670 43


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