RESUMEN
We describe a π-topological transformation-based synthetic method for the preparation of a new type of near-infrared (NIR)-emissive rhodamine dye called Polymethine-embedded Rhodamine Fluorophore (PeR Fluor). In contrast to conventional NIR-emissive dyes that require tedious synthetic steps and/or a high cost, linear fully π-conjugated PeR Fluor can be regioselectively prepared in one step by mixing different nucleophiles with ABPXs, a family of rhodamines with a cross-conjugated structure. PeR Fluor exhibits bright NIR fluorescence emission and high photostability owing to the cooperative π-electron system of rhodamines and polymethine scaffolds. Large bathochromic shifts of the absorption and fluorescence emission maxima can be achieved by modifying the N-substituted group to obtain NIR-absorbing/emitting PeR Fluor. We also demonstrate the stimulus-responsive functionality of PeR Fluor through the addition of chemicals (acid/base), which shows switchable NIR and visible fluorescence response. Our π-topological transformation-based synthetic method is a promising approach to produce new functionalized rhodamine dyes.
RESUMEN
The fluorescence spectral fingerprint, also known as the excitation-emission matrix (EEM), is used to assess and visualize therapeutic drug photodegradation in combination with chemometrics. Examination of EEM-parallel factor analysis (PARAFAC) data showed that an individual component was easily separated from a mixture of photogenerated products of a heterocyclic pharmacophore, in this case, phenothiazine drugs (PTZs). Detailed investigations of both structure-EEM relationships and kinetics revealed that the components extracted from EEM-PARAFAC could be quantitatively attributed to such photogenerated products as phenothiazine sulfoxide and carbazole derivatives. EEM in combination with principal component analysis (PCA) could be used as a mapping tool to visualize information of the photodegradation process of PTZs. We also assessed the photostability of various types of PTZs containing side chains by using validated EEM-PARAFAC methodology.
RESUMEN
Herein, a new NIR photoredox catalyst, bridged eosin Y (BEY), has been developed. Its detailed structure and NIR optical properties are clarified by using various spectroscopic methods, X-ray single-crystal structure analysis and DFT calculations. In addition, we demonstrate the photoreaction in colored reagents and high-concentration suspensions to show the advantage of NIR photoredox-catalyzed reactions.
Asunto(s)
Eosina Amarillenta-(YS) , CatálisisRESUMEN
BACKGROUND/AIM: Indoleamine 2,3-dioxygenase (IDO) is regarded as an important molecular target for cancer immune therapy. This study aimed to examine the IDO1 inhibitory activity of newly synthesized indomethacin derivatives to develop an IDO1 inhibitor. MATERIALS AND METHODS: The inhibitory effects of indole-containing compounds against recombinant human IDO1 (rhIDO1) were evaluated. RESULTS: While some drugs including those with an indole scaffold could inhibit rhIDO1, simple indole compounds were inactive. A total of 27 indomethacin derivatives, including 18 newly synthesized derivatives, were evaluated. Numerous derivatives showed enhanced IDO1 inhibitory activity. The functional group at the 3-position had a strong effect on IDO1 inhibitory activity. The IDO1 inhibitory activity was not directly correlated with tumor cell cytotoxicity. CONCLUSION: We report the finding of novel IDO1 inhibitors and the structure-activity relationship based on indomethacin derivatives. Our findings will be beneficial for the development of IDO1 inhibitors for cancer immune therapy.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indometacina/farmacología , Relación Estructura-Actividad , Biocatálisis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indometacina/química , Espectroscopía de Resonancia Magnética/métodos , Estructura MolecularRESUMEN
Most heteroaryl selenides and diselenides are biologically active, with some reported to act as antioxidants and show activities that are medicinally relevant; hence, the development of efficient methods for their synthesis is an important objective. Herein, a simple method for the synthesis of selenides and diselenides bearing imidazo[1,2-a]pyridine rings and their anticancer activity are described. The double C-H selenation of imidazo[1,2-a]pyridine with Se powder was catalyzed by CuI (10 mol %) ligated with 1,10-phenanthroline (10 mol %) at 130 °C under aerobic conditions. The selenides or diselenides were prepared almost selectively using selenium powder in an appropriate quantity under otherwise identical reaction conditions. The prepared selenides and diselenides bearing two imidazo[1,2-a]pyridine rings were all novel compounds. Among the prepared diselenides and selenides that exhibited cytotoxicity against cancer cells, bis[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl] diselenide showed an excellent anticancer activity and low cytotoxicity toward noncancer cells, suggesting that this diselenide is a potential lead compound for anticancer therapy.
RESUMEN
Trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a-f) were synthesized by the Cu-catalyzed azide-alkyne cycloaddition of various ethynylstibanes (1) with benzylazide (2) in the presence of CuBr (5 mol%) under aerobic conditions. The reaction of 5-stibanotriazoles with HCl afforded C5-unsubstituted 1,2,3-triazoles (4a-f). The antitumor activity of trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a-f) and their 5-unsubstituted 1,2,3-triazoles (4a-f) were evaluated in several tumor cell lines. All 5-stibanotriazoles (3a-f) exerted an excellent antitumor activity. On the contrary, 5-unsubstituted 1,2,3-triazoles (4a-f) without a diphenylantimony group in the molecule exhibited very low antitumor activity compared with 5-stibanotriazoles (3a-f). In compounds of both the series, the substituted 4-butyl group appeared to decrease antitumor activity. However, results suggested that organometal (antimony) in the molecule was required for greater antitumor activity. In addition, all 5-stibanotriazoles (3a-f), but not all 5-unsubstituted 1,2,3-triazoles (4a-f), exhibited cytotoxicity in normal vascular endothelial cells derived from bovine aorta. Among the compounds (3b-e) that exhibited excellent antitumor activity, those with 4-methylphenyl (3b) and 1-cyclohexenyl (3e) showed relatively low cytotoxicity to vascular endothelial cells. Together, these results suggest that trisubstituted 5-organostibano-1H-1,2,3-triazoles, including compounds 3b and 3e, may serve as potential anticancer therapeutic drugs in the future.
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Antineoplásicos/farmacología , Triazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Bovinos , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales/efectos de los fármacos , Humanos , Estructura Molecular , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
To investigate the chemical structure-cytotoxicity relationship of methacrylate-based resin monomers, we studied their effects on anti-oxidant responsive element (ARE)-mediated transcription. HepG2 cells stably expressing an ARE-regulated luciferase reporter gene were cultured for 6 h with various concentrations of several resin monomers and subjected to a luciferase assay. The doseresponse curves observed for hydrophobic monomers with different hydrocarbon chains (MMA, EMA, PMA and BMA) began to rise at concentrations between 0.5 and 1 mM; the curves rose as the monomer concentrations increased up to 5 (BMA), 10 (PMA), or 30 mM (MMA and EMA). In contrast, hydrophilic monomers having a hydroxyl group (HEMA and HPMA) showed bell-shaped curves, and stimulated the reporter expression more strongly than the hydrophobic monomers in a low concentration range (0.5-5 mM). The results suggest that introduction of a hydroxyl group in a methacrylate-based resin monomer increases its intracellular electrophilic reactivity and cytotoxicity.
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Genes Reporteros , Metacrilatos/toxicidad , Resinas Sintéticas , Fibroblastos , Humanos , Luciferasas , OxidantesRESUMEN
Sapacitabine (CS-682 or CYC682; 1-[2-C-cyano-2-deoxy-ß-D-arabino-pentfuranosyl]N4-palmitoyl cytosine), a novel antitumor 2'-deoxycytidine analogue, shows a marked reduction in the water solubility because of the fatty acid side chain on the N4 group of the cytosine moiety. Poor water solubility is one of the important reasons why sapacitabine does not exert maximum antitumor activity. Therefore, we attempted to improve the water solubility of sapacitabine using a novel surfactant, Soluplus®, which consisted of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In this study, we examined whether Soluplus® increased the water solubility and an antitumor activity of sapacitabine. The cytotoxicity of Soluplus® alone was lower than that of Tween 80 and Kolliphor® D-α-tocopherylpolyethylene glycol 1000 succinate (TPGS). The water solubility and the chemosensitivity of sapacitabine against several tumor cell lines to sapacitabine markedly increased upon using Soluplus®. In addition, the potential of Soluplus® including sapacitabine in increasing the antitumor activity was compared with sapacitabine alone in vivo. Although the total dose in the experimental period was considerably lower than the effective dose of sapacitabine alone, the life span of mice treated with sapacitabine containing 40 mg/mL Soluplus® increased by 150%. If Soluplus® was used as the solubilizing agent in clinical trials of sapacitabine, a low administration dose was appeared to require, and thus side effects might be prevented.
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Antineoplásicos/química , Antineoplásicos/farmacología , Arabinonucleósidos/química , Arabinonucleósidos/farmacología , Citosina/análogos & derivados , Polietilenglicoles/farmacología , Polivinilos/farmacología , Tensoactivos/farmacología , Animales , Línea Celular Tumoral , Citosina/química , Citosina/farmacología , Relación Dosis-Respuesta a Droga , Ratones , Polietilenglicoles/química , Polisorbatos/química , Polisorbatos/farmacología , Polivinilos/química , Solubilidad/efectos de los fármacos , Tensoactivos/química , Análisis de Supervivencia , Vitamina E/análogos & derivados , Vitamina E/química , Vitamina E/farmacologíaRESUMEN
We designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug resistance indicated that NSAIDS modulation of multidrug-resistant P-glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Diseño de Fármacos , Indometacina/síntesis química , Indometacina/farmacología , Antiinflamatorios no Esteroideos/química , Línea Celular Tumoral , Técnicas de Química Sintética , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Humanos , Indometacina/análogos & derivados , Indometacina/química , Modelos Moleculares , Conformación Molecular , Prostaglandina-Endoperóxido Sintasas/metabolismoRESUMEN
Conformationally restricted indomethacin analogues were designed and prepared from the corresponding 2-substituted indoles, which were synthesized by a one-pot isomerization/enamide-ene metathesis as the key reaction. Conformational analysis by calculations, NMR studies, and X-ray crystallography suggested that these analogues were conformationally restricted in the s-cis or the s-trans form due to the 2-substituent as expected. Their biological activities on cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, and modulation of MRP-1-mediated multidrug resistance (MDR) are described. Some of these indomethacin analogues enhanced doxorubicin cytotoxicity, although they do not have any COX inhibitory activity, which suggests that the MDR-modulating effect of an NSAID can be unassociated with its COX-inhibitory activity. This may be an entry into the combination chemotherapy of doxorubicin with a MDR modulator.
RESUMEN
Antitumor 2'-deoxycytidine (dCyd) analogs such as gemcitabine (dFdC), cytarabine (Ara-C), and 2'-C-cyano-2'-deoxy-1-ß-d-arabinofuranosylcytosine (CNDAC) are activated by dCyd kinase, whereas cytidine deaminase (CDA) inactivates them by conversion to their uracil forms. To elucidate the relationship between the chemosensitivity to antitumor dCyd nucleosides and CDA expression, we established a stable line of human gastric carcinoma TMK-1 cells constitutively overexpressing CDA (TMK-1/CDA) and examined its chemosensitivity to antitumor dCyd analogs in vitro and in vivo. We observed comparable reactivity for dFdC and Ara-C, and the substrate reactivity of CNDAC to recombinant human CDA was more than 10 times less efficient than those of Ara-C and dFdC. Next, we examined the in vitro chemosensitivity of TMK-1/CDA and observed a marked decrease in the sensitivity of TMK-1/CDA to Ara-C, dFdC, and CNDAC compared with mock-transfected cells. In addition, we transplanted TMK-1/CDA cells into a nude mouse xenograft model and examined their in vivo chemosensitivity to CNDAC. The in vivo antitumor effect of CNDAC on TMK-1/CDA cells was substantially reduced compared with that of mice transplanted with mock-transfected cells. These results indicate that CDA could play an important role in regulating susceptibility to antitumor dCyd analogs in vitro and in vivo. In addition, the expression level of CDA was found to affect the antitumor activity of CNDAC, even though the substrate reactivity of CNDAC to CDA is relatively low.
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Antineoplásicos/farmacocinética , Citidina Desaminasa/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Animales , Antineoplásicos/uso terapéutico , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citidina Desaminasa/genética , Desoxicitidina/uso terapéutico , Femenino , Humanos , Ratones , Ratones Desnudos , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/enzimología , Neoplasias Experimentales/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidad por Sustrato , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The first asymmetric synthesis of (S)- and (R)-5-hydroxythalidomides, one of thalidomide's major metabolites, was achieved using HMDS/ZnBr(2)-induced imidation as a key reaction. 5-Hydroxythalidomide was found to be configurationally more stable than thalidomide at physiological pH. Stereochemical biological effects of thalidomide and 5-hydroxythalidomide on anti-angiogenesis and antitumor activities were also investigated using racemic and pure enantiomers.
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Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Talidomida/análogos & derivados , Talidomida/química , Inhibidores de la Angiogénesis/química , Antineoplásicos/química , Línea Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración de Iones de Hidrógeno , Estereoisomerismo , Talidomida/síntesis química , Talidomida/metabolismo , Talidomida/farmacologíaRESUMEN
3'-ethynyladenosine (EAdo) was an adenosine analog with potent antitumor activity against various human tumor cells in vitro. However, EAdo was enzymatically inactivated by adenosine deaminase (ADA) in vitro and in vivo. Therefore, we synthesized two ADA-resistant EAdo derivatives (2-F-EAdo and EAdo-5'-monophosphate, EAMP) and examined their antitumor activities.
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Adenosina/análogos & derivados , Adenosina/síntesis química , Antineoplásicos/síntesis química , Adenosina/química , Adenosina/farmacología , Adenosina Desaminasa/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desaminación/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , HumanosRESUMEN
Nucleoside transporters play an important role in the disposition of nucleosides and their analogs. To elucidate the relationship between chemosensitivity to antitumor nucleosides and the functional expression of equilibrative nucleoside transporters (ENT), we established stable cell lines of human fibrosarcoma HT-1080 and gastric carcinoma TMK-1 that constitutively overexpressed green fluorescent protein-tagged hENT1, hENT2, hENT3 and hENT4. Both hENT1 and hENT2 were predictably localized to the plasma membrane, whereas hENT3 and hENT4 were localized to the intracellular organelles. The chemosensitivity of TMK-1 cells expressing hENT1 and hENT2 to cytarabine and 1-(3-C-ethynyl-beta-D-ribopentofuranosyl) cytosine increased markedly in comparison to that of mock cells. However, no remarkable changes in sensitivity to antitumor nucleosides were observed in cell lines that expressed both hENT3 and hENT4. These data suggest that hENT3 and hENT4, which are mainly located in the intracellular organelles, are not prominent nucleoside transporters like hENT1 and hENT2, which are responsible for antitumor nucleoside uptake.
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Antimetabolitos Antineoplásicos/farmacología , Membrana Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Citarabina/farmacología , Citidina/análogos & derivados , Proteínas de Transporte de Nucleósidos/metabolismo , Transporte Biológico , Citidina/farmacología , Proteínas de Transporte de Nucleósido Equilibrativas/genética , Proteínas de Transporte de Nucleósido Equilibrativas/metabolismo , Tranportador Equilibrativo 1 de Nucleósido/genética , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Transportador Equilibrativo 2 de Nucleósido/genética , Transportador Equilibrativo 2 de Nucleósido/metabolismo , Fibrosarcoma/tratamiento farmacológico , Fibrosarcoma/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Proteínas de Transporte de Nucleósidos/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Peritoneal dissemination is the most common cause of metastasis from malignancies in the abdominal cavity. There are no standard treatments for peritoneal dissemination and the results are poor. The reasons for this are as follows: (1) no effective chemotherapeutic agents have been identified or developed; (2) surgical cytoreduction has little effect on survival improvement; and (3) the molecular mechanisms of peritoneal dissemination have not been clarified and no therapy against the target molecules has been developed. However, studies on the molecular mechanisms of peritoneal dissemination have elucidated some of the target molecules and the development of new multimodal therapies has also improved survival. Early postoperative intraperitoneal chemotherapy, hyperthermic intraperitoneal perfusion chemotherapy and neoadjuvant intraperitoneal-systemic chemotherapy have been newly developed, and a novel surgical therapy named peritonectomy has been proposed to perform complete cytoreduction of peritoneal dissemination. At present, these approaches appear to be effective therapeutic modalities for peritoneal dissemination. However, TS-1 and capecitabine have shown worthwhile results in recent clinical trials for patients with advanced gastric cancer. We recently found that newly developed antitumor cytosine nucleoside analogs show a survival advantage in peritoneal dissemination models using human cancer cells. These non-fluoropyrimidine nucleosides may potentially help to improve the poor prognosis observed in patients with advanced cancers involving peritoneal dissemination.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Gastrointestinales/patología , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/secundario , Animales , Humanos , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/metabolismoRESUMEN
Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are critical enzymes in nucleic acid metabolism. Proliferating cell nuclear antigen (PCNA) is a specific protein that is correlated with proliferative activity of cells. The TS gene has a variable number of tandem repeats (VNTR) in its 5'-untranslated region and a single nucleotide polymorphism (SNP) in the VNTR area. We examined the association of in vitro sensitivity to anticancer drugs with TS polymorphism, TS, DPD, and PCNA mRNA expression using human lung cancer tissues. Seventy-eight surgically resected lung cancer tissues were tested for in vitro sensitivity to 5-fluorouracil, cisplatin (CDDP), carboplatin (CBDCA), irinotecan, docetaxel, and gemcitabine by histoculture and MTT assay. The TS polymorphisms were analyzed by PCR and PCR-RFLP. TS, DPD, and PCNA mRNA expression levels were quantified by real-time RT-PCR and normalized relative to beta-actin mRNA expression. The inhibition rates (IRs) of CDDP and CBDCA were significantly correlated with TS/PCNA, the ratio of TS/actin and PCNA/actin, and DPD/PCNA, the ratio of DPD/actin and PCNA/actin. This correlation was further explored by subgroup analyses according to TS VNTR or TS functional type, in which 2R/3G, 3C/3G, or 3G/3G were classified into H-type group and 2R/2R, 2R/3C, or 3C/3C into L-type group. The associations of TS/PCNA and DPD/PCNA with the IRs of CDDP, CBDCA remained significant in the 3R/3R group and H-type group. These results suggest that in vitro sensitivity to platinum-derived drugs, CDDP and CBDCA, is associated with PCNA-normalized mRNA expression of TS and DPD in human lung cancer tissues, as affected by the TS polymorphism. The clinical significance of these pharmacogenomic markers for chemotherapy regimens with platinum-derived drugs should be investigated further for personalized treatment of lung cancer.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Dihidrouracilo Deshidrogenasa (NADP)/biosíntesis , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Compuestos de Platino/farmacología , Timidilato Sintasa/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Dihidrouracilo Deshidrogenasa (NADP)/genética , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Repeticiones de Minisatélite , Polimorfismo de Nucleótido Simple , Antígeno Nuclear de Célula en Proliferación/biosíntesis , Antígeno Nuclear de Célula en Proliferación/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Timidilato Sintasa/genética , Timidilato Sintasa/metabolismoRESUMEN
To investigate the relationship between insulin resistance, postprandial hyperglycemia, postprandial hyperlipidemia, and oxidative stress in type 2 diabetes, changes in postprandial glucose, triglyceride, and nitrotyrosine levels vs baseline after diet loading were examined in type 2 diabetic patients given pioglitazone (PG) or glibenclamide (GB). Twenty-four outpatients with type 2 diabetes treated with oral PG for 6 mo (BMI, 26.3 +/- 0.9; HbA1c, 8.2 +/- 0.2%) and 10 type 2 diabetic patients treated with GB (BMI, 27.4 +/- 1.6; HbA1c, 8.1 +/- 0.2%) at our institutions were compared. These patients were given meal tolerance tests (MTT; each consisting of energy 400 kcal, protein 8.7 g, fat 22.4 g, carbohydrate 41 g) before and 6 mo after administration of either agent. PG produced a significant decrease in FPG, HbA1c, HOMA-R, and TG levels in the subjects compared to baseline. In contrast, GB significantly decreased FPG and HbA1c levels, while not affecting HOMA-R and TG values. While PG produced a significant increase in LPL, HDL-cholesterol, and adiponectin levels, GB did not affect these values. At MTT 6 mo after PG administration, insulin levels before and 4 h after MTT, free fatty acid (FFA) levels 1, 2, and 4 h after MTT, glucose, TG, and RLP-TG levels before and 1, 2, 4, and 6 h after MTT were significantly decreased compared to baseline. At MTT 6 mo after GB administration, while a significant decrease in fasting and 2 h, postprandial glucose values compared to baseline MTT levels was observed, fasting and postprandial TG and RLP-TG levels remained unchanged compared to baseline. After 6 mo of PG and GB administration, serum nitrotyrosine levels before and after MTT were significantly decreased compared to baseline in both groups, while the decrease in nitrotyrosine levels before and after MTT was more marked in the subjects given PG. Our study results suggest that PG suppresses increases in postprandial glucose and TG levels, and improves insulin resistance; and, in addition, that PG may have a favorable impact on oxidative stress in type 2 diabetic patients.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/fisiopatología , Gliburida/uso terapéutico , Hiperglucemia/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Estrés Oxidativo/fisiología , Tiazolidinedionas/uso terapéutico , Anciano , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Ácidos Grasos no Esterificados/sangre , Femenino , Gliburida/farmacología , Hemoglobina Glucada/efectos de los fármacos , Humanos , Hipoglucemiantes/farmacología , Insulina/sangre , Resistencia a la Insulina/fisiología , Lipoproteína Lipasa/sangre , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Pioglitazona , Periodo Posprandial , Tiazolidinedionas/farmacología , Factores de Tiempo , Triglicéridos/sangre , Tirosina/análogos & derivados , Tirosina/sangreRESUMEN
Amino acid-starved yeast activates the eIF2alpha kinase Gcn2p to suppress general translation and to selectively derepress the transcription factor Gcn4p, which induces various biosynthetic genes to elicit general amino acid control (GAAC). Well-fed yeast activates the target of rapamycin (TOR) to stimulate translation via the eIF4F complex. A crosstalk was demonstrated between the pathways for GAAC and TOR signaling: the TOR-specific inhibitor rapamycin activates Gcn2p. Here we demonstrate that, upon TOR-inactivation, the putative TOR-regulated eIF4E-associated protein Eap1p likely functions downstream of Gcn2p to attenuate GCN4 translation via a mechanism independent of eIF4E-binding, thereby constituting another interface between the two pathways.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Regulación Fúngica de la Expresión Génica , Factores de Iniciación de Péptidos/metabolismo , Biosíntesis de Proteínas , Proteínas Quinasas/metabolismo , Proteínas de Saccharomyces cerevisiae/antagonistas & inhibidores , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Secuencia de Aminoácidos , Proteínas de Unión al ADN/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Eliminación de Gen , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Humanos , Datos de Secuencia Molecular , Mutación/genética , Factores de Iniciación de Péptidos/química , Factores de Iniciación de Péptidos/genética , Fosforilación , Unión Proteica , Biosíntesis de Proteínas/efectos de los fármacos , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Alineación de Secuencia , Sirolimus/farmacologíaRESUMEN
UNLABELLED: No standard treatment exists for peritoneal dissemination from gastric cancer. We reviewed our experience using a novel treatment consisting of peritonectomy and intraoperative chemo-hyperthermic peritoneal perfusion (CHPP). Records of all patients who underwent CHPP and cytoreductive surgery from 1992 to 2001 were reviewed. RESULTS: Data from 107 patients (average age, 52 years) were available. P3 dissemination was found in 72 patients, and 8 and 27 patients showed P1 or P2 dissemination, respectively. Peritoneal metastasis was synchronous in 75 and metachronous in 32 patients. All patients received CHPP after cytoreductive surgery. Peritonectomy was performed in 42 patients. Complete cytoreduction (CC-0) was achieved in 47 patients (44%). Peritonectomy, resulted in CC-0 in 69% (29/42), but CC-0 was achieved in 18 of 65 (28%) patients by ordinary surgical techniques. There were 23 postoperative complications (21%) after operation. The overall operative mortality was 2.8% (3/107). Median follow-up for the entire study group was 46 months. Seventeen patients (15%) were disease-free, and 90 patients were dead at the time of analysis. Eighty-seven deaths were related to progression of disease. The median survival of all patients was 16.2 months, with an actual 5-year survival of 6%. Median survival of CHPP plus ordinary cyoreduction was 12.0 months and that after CHPP and peritonectomy was 22.8 months. Completeness of cytoreduction and peritonectomy were significant prognostic factors on univariate analysis and 5-year survival rate was 27%. Lymph node status, grade of peritoneal dissemination (P1-2 vs P3), age (>60 years vs <60 years), tumor volume of dissemination (>2.5 cm vs <2.5 cm in diameter), and histologic type (differentiated vs. poorly differentiated type) did not affect survival. The cox proportional model demonstrated that completeness of cytoreduction was the strongest prognostic factor. Patients who had an incomplete resection had 2.8-fold higher risk of dying from disease than patients who underwent complete cytoreduction. The 5-year survival after complete cytoreduction was 12%, compared with 2% for incomplete resection. Four patients lived more than 5 years. Cytoreduction was incomplete in one 5-year survivor who showed complete response to CHPP. CONCLUSION: Complete cytoreduction using peritonectomy and CHPP may improve survival of patients with peritoneal dissemination from gastric cancer. This procedure is most appropriate for highly motivated patients who are committed to survive as long as possible.
Asunto(s)
Siembra Neoplásica , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/secundario , Neoplasias Gástricas/patología , Análisis de Varianza , Femenino , Humanos , Infusiones Parenterales , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/cirugía , Peritoneo/cirugía , Complicaciones Posoperatorias , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
This paper deals with the synthesis of a stable biotin-phosmidosine conjugate molecule 3 that is required for isolation of biomolecules that bind to phosmidosine (1). It was found that introduction of a biotin residue into the 6-N position of phosmidosine could be carried out by reaction of an N7-Boc-7,8-dihydro-8-oxoadenosine derivative 13 with phenyl chloroformate followed by displacement with a diamine derivative 6 along with the simultaneous removal of the Boc group and one of the two phenoxycarbonyl groups and the successive condensation with an N-tritylated biotin derivative 5. The condensation of an N-prolylphosphorodiamidite derivative 4 with an appropriately protected 7,8-dihydro-8-oxoadenosine derivative 17 having the biotin residue gave the coupling product 18, which was deprotected to give the biotin-phosmidosine (O-ethyl ester) conjugate 3.