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1.
Exp Oncol ; 37(2): 94-9, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26112934

RESUMEN

AIM: In this study, we evaluated the carcinostatic effects of combined ascorbic acid (AsA) and a capacitive-resistive electric transfer (CRet) hyperthermic apparatus-induced hyperthermic treatment on Ehrlich ascites tumor (EAT) cells. MATERIALS AND METHODS: EAT cells were exposed to various AsA (0-10 mM) concentrations for 1 h; they subsequently underwent CRet treatment for 15 min at 42 °C. Cell viability was assessed by the WST-8 assay 24 h after the combined treatment. Reactive oxygen species involvement was evaluated using catalase and tempol; caspase-3/7 activation was determined by their fluorescent substrates; cell proliferation were estimated by time-lapse observation. The effect on the cell cycle was analyzed by flow cytometry. RESULTS: Combined AsA and CRet treatment synergistically suppressed cell viability compared with either treatment alone, and these synergistically carcinostatic effects were evident even at noncytotoxic concentrations of AsA alone (≤ 2 mM). The carcinostatic effects of combined AsA and CRet treatment were attenuated in a dose-dependent manner by catalase addition, but not by the superoxide anion radical scavenger tempol. Time-lapse observation revealed that combined AsA and CRet treatment activated caspase-3/7 at 10-24 h after treatment, accompanied by significant cell growth suppression. Cell cycle analysis revealed that the rate of sub-G1-phase (apoptotic) cells was drastically increased at 12 h and 24 h, and that the G2/M-phase cells gradually increased at 6-24 h after treatment. CONCLUSION: These results indicate that combined AsA and CRet treatment synergistically inhibits EAT cell growth through G2/M arrest and apoptosis induction via H2O2 generation at lower AsA concentrations; this carcinostatic effect cannot be exerted by AsA alone.


Asunto(s)
Antineoplásicos/farmacología , Ácido Ascórbico/farmacología , Carcinoma de Ehrlich/terapia , Animales , Apoptosis , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Terapia Combinada , Ensayos de Selección de Medicamentos Antitumorales , Hipertermia Inducida , Especies Reactivas de Oxígeno/metabolismo
2.
Bone Marrow Transplant ; 49(7): 921-6, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24777192

RESUMEN

We retrospectively studied 108 marrow harvests from 105 pediatric sibling donors. The median age of donors was 8 years (range: 1-15) and the median body weight was 27 kg (range: 10-100). The volumes of aspirated marrow were 5.0-23.8 mL/kg donor body weight, and harvested bone marrow volume exceeded 15 mL/kg in 42% of the donors. A total of 100 autologous blood donations were performed, and eight donors had red cells salvaged from their harvests reinfused. The median Hb levels before and after harvests were 12.3 g/dL (range: 10.0-14.7) and 11.0 g/dL (range: 8.9-13.8), respectively. None of the donors received allogeneic blood transfusions or hematopoietic growth factors such as EPO and G-CSF before or after collection. Transplanted dose was 1.4-10.8 × 10(8) cells/kg recipient body weight without differences due to donor age. Higher concentrations of nucleated and CD34(+) cells were obtained from younger donors. All donors tolerated the procedures well, with no serious complications. Thus, children may safely donate marrow for allogeneic transplantation, and the yields of nucleated cells for engraftment are substantial.


Asunto(s)
Transfusión de Sangre Autóloga/métodos , Trasplante de Médula Ósea/métodos , Donantes de Tejidos , Adolescente , Niño , Preescolar , Estudios de Factibilidad , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Hermanos
3.
Oncogene ; 33(1): 74-84, 2014 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-23178499

RESUMEN

Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.


Asunto(s)
Adenocarcinoma/metabolismo , Receptores de Leptina/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/deficiencia , Adenocarcinoma/tratamiento farmacológico , Animales , Anticuerpos/administración & dosificación , Antineoplásicos/administración & dosificación , Carcinogénesis/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Mucosa Gástrica/metabolismo , Humanos , Inyecciones Intraperitoneales , Mucosa Intestinal/metabolismo , Leptina/antagonistas & inhibidores , Leptina/inmunología , Ratones , Ratones Transgénicos , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Proteínas Quinasas/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Estómago/patología , Neoplasias Gástricas/tratamiento farmacológico , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética
4.
Int J Tuberc Lung Dis ; 15(2): 169-73, i, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21219676

RESUMEN

SETTING: Japan's National Tuberculosis Programme (NTP). OBJECTIVES: To determine and assess the chronological change of chronic excretors. DESIGN: We compared two groups of chronic excretors (continuous excretion of TB bacilli in the last 2 years) classified by time of registration; the first group was registered from 1991 to 1997, and the second from 1998 to 2004. The epidemiological situation and the NTP were also compared. RESULT: There were 481 cases in the first group, comprising 0.17% of registered cases, and 159 cases in the second group, comprising 0.06%. Stratified analysis by treatment regimen and TB category confirmed a decrease in the ratio of chronic excretors in all sub-groups. Human factors such as non-adherence, no drug susceptibility testing (DST) on initiation of treatment and inadequate modification of treatment in new sputum smear-positive cases were more frequent in the first group than in the second (37.0% vs. 28.9%, 19.5% vs. 10.7%, 36.8% vs. 19.5%, P < 0.05). Other known risk factors, such as interruption due to side effects and complication of diabetes and/or alcoholism, were similarly distributed. CONCLUSION: The decline in chronic excretors has been associated with the DOTS strategy, baseline DST and appropriate modification of treatment regimen in new sputum smear-positive cases.


Asunto(s)
Antituberculosos/uso terapéutico , Cumplimiento de la Medicación , Mycobacterium tuberculosis/aislamiento & purificación , Esputo/microbiología , Tuberculosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antituberculosos/efectos adversos , Terapia por Observación Directa , Encuestas de Atención de la Salud , Humanos , Japón/epidemiología , Persona de Mediana Edad , Programas Nacionales de Salud , Prevalencia , Evaluación de Programas y Proyectos de Salud , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Tuberculosis/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Adulto Joven
5.
Osteoporos Int ; 22(8): 2373-83, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20959962

RESUMEN

UNLABELLED: Improvements in total content of enzymatic cross-linking, the ratio of hydroxylysine-derived enzymatic cross-links, and non-enzymatic advanced glycation end product cross-link formation from once-weekly administration of hPTH(1-34) for 18 months in OVX cynomolgus monkeys contributed to the improvement of bone strength. INTRODUCTION: Parathyroid hormone (PTH) is used for the treatment of osteoporosis. To elucidate the contribution of material properties to bone strength after once-weekly treatment with hPTH(1-34) in an ovariectomized (OVX) primate model, the content of collagen and enzymatic immature, mature, and non-enzymatic cross-links, collagen maturity, trabecular architecture, and mineralization in vertebrae were simultaneously estimated. METHODS: Adult female cynomolgus monkeys were divided into four groups (n = 18-20 each) as follows: SHAM group, OVX group, and OVX monkeys given once-weekly subcutaneous injections of hPTH(1-34) either at 1.2 or 6.0 µg/kg (low- or high-PTH groups) for 18 months. The content of collagen, enzymatic and non-enzymatic cross-linking pentosidine, collagen maturity, trabecular architecture, mineralization, and cancellous bone strength of vertebrae were analyzed. RESULTS: Low-PTH and high-hPTH treatments increased the content of enzymatic immature and mature cross-links, bone volume (BV/TV), and trabecular thickness, and decreased pentosidine, compared with the OVX group. Stepwise logistic regression analysis revealed that BV/TV, the content of total enzymatic cross-links, and calcium content independently affected ultimate load (model R (2) = 0.748, p < 0.001) and breaking energy (model R (2) = 0.702, p < 0.001). BV/TV was the most powerful and enzymatic cross-link content was the second powerful determinant of both ultimate load and breaking energy. The most powerful determinant of stiffness was the enzymatic cross-link content (model R (2) = 0.270, p < 0.001). CONCLUSION: Once-weekly preventive administration of hPTH(1-34) increased the total contents of immature and mature enzymatic cross-links, which contributed significantly to vertebral cancellous bone strength.


Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Densidad Ósea/efectos de los fármacos , Colágeno/metabolismo , Osteoporosis/metabolismo , Teriparatido/farmacología , Animales , Arginina/análogos & derivados , Arginina/metabolismo , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/uso terapéutico , Calcio/metabolismo , Fuerza Compresiva/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Evaluación Preclínica de Medicamentos/métodos , Femenino , Productos Finales de Glicación Avanzada/metabolismo , Vértebras Lumbares/efectos de los fármacos , Vértebras Lumbares/metabolismo , Vértebras Lumbares/fisiología , Lisina/análogos & derivados , Lisina/metabolismo , Macaca fascicularis , Osteoporosis/fisiopatología , Osteoporosis/prevención & control , Ovariectomía , Fosfatos/metabolismo , Teriparatido/administración & dosificación , Teriparatido/uso terapéutico , Microtomografía por Rayos X/métodos
6.
Toxicol Ind Health ; 25(3): 197-203, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19482914

RESUMEN

Various water-soluble derivatives of fullerene-C60 (C60) have been developed as detoxifiers for reactive oxygen species (ROS), whereas C60 incorporated in liposome (Lpsm) has not been reported yet. We prepared the liposome-fullerene (0.2% aqueous phase, Lpsm-Flln) which was composed of hydrogenated lecithin, glycine soja (soybean) sterols, and C60 in the weight ratio of 89.7:10:0.3, then examined the photocytotoxicity and bacterial reverse mutagenicity, as comparing with the Lpsm containing no C60. Photocytoxicity of Lpsm-Flln or Lpsm was examined using Balb/3T3 fibroblastic cells at graded doses of 0.49-1000 microg/mL under the condition of UVA- or sham-irradiation. The cells were irradiated with UVA (5 J/cm2, 320-400 nm, lambda max = 360 nm) at room temperature for 50 min. The resultant cell viability (% of control) did not decrease dose-dependently to 50% or less regardless of the UVA-irradiation. These results show that Lpsm-Flln or Lpsm does not possess photocytotoxicity to Balb/3T3 fibroblasts, and Lpsm-Flln may not exert a UVA-catalytic ROS-increasing action. A possibility for the reverse mutation by Lpsm-Flln or Lpsm was examined on four histidine-demanding strains of Salmonella typhimurium and a tryptophan-demanding strain of Escherichia coli. As for the dosages of Lpsm-Flln or Lpsm (313-5000 microg/plate), the dose-dependency of the number of reverse mutation colonies of each strain did not show a twice or more difference versus the negative control regardless of the metabolic activation, and, in contrast, marked differences for five positive controls (sodium azide, N-ethyl-N'-nitro-N-nitrosoguanidine, 2-nitrofluorene, 9-aminoacridine, and 2-aminoanthracene). The growth inhibition of bacterial strains and the deposition of Lpsm-Flln or Lpsm were not found. As a result, the bacterial reverse mutagenicity of Lpsm-Flln or Lpsm was judged to be negative under the conditions of this test. Thus, Lpsm-Flln and Lpsm may not give any significant biological toxic effects, such as photocytotoxicity and bacterial reverse mutagenicity.


Asunto(s)
Ácidos Carboxílicos/toxicidad , Fulerenos/toxicidad , Liposomas/toxicidad , Ácidos Carboxílicos/química , Ácidos Carboxílicos/efectos de la radiación , Supervivencia Celular , Fulerenos/química , Fulerenos/efectos de la radiación , Glicina/química , Lecitinas/química , Liposomas/química , Liposomas/efectos de la radiación , Pruebas de Mutagenicidad , Aceite de Soja/química , Esteroles/química , Rayos Ultravioleta
7.
J Gastrointest Surg ; 8(3): 346-57, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15019933

RESUMEN

The effects of heme oxygenase (HO) inhibitors, zinc-protoporphyrin-IX (ZnPP-IX), and tin protoporphyrin-IX (SnPP-IX) and their interactions with L-arginine/nitric oxide synthase (NOS) and cyclooxygenase (COX) pathways were investigated in postoperative ileus in rats. Intestinal transit was measured as Evans blue migration after skin incision, laparotomy or laparotomy plus gut evisceration and handling. Laparotomy and small intestinal manipulations increased blood plasma nitrites/nitrates level 1.88-fold. N(omega)-nitro-L-arginine methyl ester, indomethacin, a selective COX-1 blocker (resveratrol) and COX-2 antagonists (nimesulide, DuP-697, NS-398) reversed the additional inhibitory effects of gut manipulation subsequent to laparotomy. In contrast, N-(3-(aminomethyl)benzyl)acetamidine or S-methylisothiourea, highly selective inducible NOS blockers, remained ineffective. ZnPP-IX and SnPP-IX overturned the effects of laparotomy on dye propulsion, but were only partially effective after laparotomy and gut handling attenuating the additional inhibitory influences of gut manipulation, the intestinal transit reaching 89.21%, 92.87%, 53.46%, and 48.56% of respective controls transit. Salutary effects of L-NAME, ZnPP-IX, and SnPP-IX were dose-dependent, L-arginine or hemin (HO substrate) sensitive. Administration of indomethacin and resveratrol subsequent to SnPP-IX reversed the inhibitory effects of laparotomy and manipulation, amounting to 93.91% and 87.43% of controls. On the other hand, L-NAME injected after SnPP-IX abolished the salutary effects of the latter, study dye migration reached 25.18% of control rat. Therefore we demonstrated that nitric oxide, carbon monoxide, and prostanoids play a role in the pathogenesis of postoperative ileus albeit in different mechanisms. Laparotomy stimulated HO activity, whereas gut manipulation led to an excessive constitutive NOS stimulation accompanied by augmented prostanoid synthesis by COX-1. Unaffected synthesis of either NO or CO enables a return of gastrointestinal transit during postoperative period, whereas a pharmacological blockade of two complementary metabolic pathways provides a most effective measure against postoperative ileus development.


Asunto(s)
Monóxido de Carbono/farmacología , Ileus/etiología , Óxido Nítrico/farmacología , Complicaciones Posoperatorias/etiología , Prostaglandinas/farmacología , Animales , Arginina/farmacología , Ciclooxigenasa 2 , Inhibidores Enzimáticos/farmacología , Tránsito Gastrointestinal/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Indometacina/farmacología , Isoenzimas/metabolismo , Laparotomía , Masculino , Metaloporfirinas/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Prostaglandina-Endoperóxido Sintasas/metabolismo , Protoporfirinas/farmacología , Ratas , Ratas Wistar , Resveratrol , Estilbenos/farmacología
8.
Pharmacopsychiatry ; 37(2): 57-62, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15048612

RESUMEN

BACKGROUND: Serotonin (5-HT) syndrome is the most serious side effect of antidepressants. Although several drugs have been used for the treatment of 5-HT syndrome, a universal pharmacotherapy has not been established. NMDA receptor antagonists have been reported to have neuroprotective effects. In the present study, the efficacy of NMDA antagonists, including memantine and MK-801, and potent 5-HT (2A) antagonists, including risperidone and ketanserin, was evaluated in a 5-HT syndrome animal model. METHODS: 5-Hydroxy-l-tryptophan (100 mg/kg) and clorgyline (2 mg/kg) were administered intraperitoneally in rats to induce 5-HT syndrome. The rectal temperature of the rats was measured, and the noradrenaline (NA) and 5-HT levels in the anterior hypothalamus were measured using a microdialysis technique. RESULTS: In the group pretreated with saline, the rectal temperature increased to more than 40 degrees C, and all of the animals died within 90 min of the drug's administration. The NA and 5-HT levels in the anterior hypothalamus increased to about 15- and 1100-fold of the pre-administration levels, respectively. Pretreatment with risperidone (0.5 mg/kg) and ketanserin (5 mg/kg) prevented the development of hyperthermia and the increase in the NA level. Memantine (10 mg/kg) and MK-801 (0.5 mg/kg) also prevented the development of hyperthermia and the increase in the NA level. These results suggest that NMDA antagonists, as well as potent 5-HT (2A) antagonists, may be effective drugs for the treatment of 5-HT syndrome. CONCLUSIONS: Since memantine is clinically well tolerated, this drug is a particularly promising therapeutic drug for 5-HT syndrome treatment.


Asunto(s)
Antagonistas de Aminoácidos Excitadores/uso terapéutico , Fiebre/prevención & control , Memantina/uso terapéutico , 5-Hidroxitriptófano , Animales , Temperatura Corporal/efectos de los fármacos , Clorgilina , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Interacciones Farmacológicas , Fiebre/etiología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Ketamina/farmacología , Masculino , Microdiálisis/métodos , Norepinefrina/análisis , Ratas , Ratas Wistar , Risperidona/farmacología , Serotonina/análisis , Antagonistas de la Serotonina/farmacología , Síndrome de la Serotonina/inducido químicamente , Síndrome de la Serotonina/complicaciones , Factores de Tiempo
9.
Acta Neuropathol ; 106(5): 441-8, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12898156

RESUMEN

We performed a neuropathological analysis, including in situ nick end labeling (ISEL) and immunohistochemistry, of two cases of clinicogenetically confirmed infantile spinal muscular atrophy (SMA) type II. Both cases showed severe reduction of the motor neurons and gliosis in the spinal cord and brain stem, although the occurrences of central chromatolysis and ballooned neurons were not frequent. Clark's and lateral thalamic nuclei, which are usually altered in SMA type I, were spared, whereas Betz cells in the precentral gyrus and large myelinated fibers in the lateral funiculus were reduced in number. Regarding apoptosis, only the younger case demonstrated a few ISEL-positive nuclei in the dorsal horn, with reduced Bcl-x expression level in the Purkinje cells. Unlike SMA type I, the expression of neurofilaments was not disturbed and the reduction in synaptophysin expression level in the anterior horn was mild. An oxidative stress-related product was deposited in atrophic motor neurons in the spinal cord, and neurons with nuclei immunoreactive for 8-hydroxy-2'-deoxyguanosine were found in the lateral thalamus. In contrast, the expression of glial glutamate transporters was not altered. These data suggest that oxidative stress and, to a lesser extent, apoptotic cell death, but not disturbed neurofilament metabolism or excitotoxicity, may be involved in neurodegeneration in SMA type II.


Asunto(s)
Médula Espinal/patología , Atrofias Musculares Espinales de la Infancia/patología , Adulto , Sistema de Transporte de Aminoácidos X-AG/metabolismo , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Estudios de Casos y Controles , Núcleo Celular/metabolismo , Núcleo Celular/patología , Preescolar , Desoxiadenosinas/metabolismo , Transportador 2 de Aminoácidos Excitadores/metabolismo , Exones , Femenino , Gliosis , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ/métodos , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Fibras Nerviosas Mielínicas/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Médula Espinal/metabolismo , Atrofias Musculares Espinales de la Infancia/genética , Atrofias Musculares Espinales de la Infancia/metabolismo , Sinaptofisina/metabolismo , Tálamo/metabolismo , Tálamo/patología
10.
Br Poult Sci ; 43(1): 117-21, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12003327

RESUMEN

1. The effect of L-carnitine supplemented into experimental diets with varying dietary protein concentrations (50, 200 and 400 g/kg) on body weight gain and plasma insulin-like growth factor-I (IGF-I) concentration in chicks was examined. 2. Dietary L-carnitine supplementation provided 0, 200, 500 and 1000 mg/kg. Chicks were given the diet ad libitum for 10 d. 3. When L-carnitine was provided as 500 or 1000 mg/kg, body weight gain was significantly improved in birds receiving the 200 and 400 g protein/kg diets. 4. There was an interaction between dietary L-carnitine and protein content on plasma IGF-I concentration. L-carnitine supplementation had little influence on plasma IGF-I concentrations in birds receiving the low protein (50 g/kg) diet. When dietary L-carnitine concentrations were increased from 0 to 1000 mg/kg in the adequate protein (200 g/kg) diet, plasma IGF-I concentrations were also increased. However, when dietary L-carnitine content was more than 500 mg/kg in the 400 g/kg protein group, plasma IGF-I concentration decreased with increasing dietary L-carnitine content. 5. Body weight change correlated significantly with the alteration in plasma IGF-I concentrations in chicks given diets with adequate dietary protein. 6. In conclusion, the improvement in body weight gain caused by dietary L-carnitine supplementation was achieved when chicks were given their dietary protein requirement, which may be partially explained by an increase in plasma IGF-I concentration.


Asunto(s)
Carnitina/farmacología , Pollos/metabolismo , Proteínas en la Dieta/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Albúminas/metabolismo , Animales , Glucemia/metabolismo , Proteínas Sanguíneas/metabolismo , Peso Corporal/fisiología , Carnitina/metabolismo , Pollos/sangre , Colesterol/sangre , Proteínas en la Dieta/metabolismo , Ácidos Grasos no Esterificados/sangre , Masculino , Triglicéridos/sangre
11.
J Neurochem ; 80(5): 763-70, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11948239

RESUMEN

The goldfish optic nerve can regenerate after injury. To understand the molecular mechanism of optic nerve regrowth, we identified genes whose expression is specifically up-regulated during the early stage of optic nerve regeneration. A cDNA library constructed from goldfish retina 5 days after transection was screened by differential hybridization with cDNA probes derived from axotomized or normal retina. Of six cDNA clones isolated, one clone was identified as the Na,K-ATPase catalytic subunit alpha3 isoform by high- sequence homology. In northern hybridization, the expression level of the mRNA was significantly increased at 2 days and peaked at 5-10 days, and then gradually decreased and returned to control level by 45 days after optic nerve transection. Both in situ hybridization and immunohistochemical staining have revealed the location of this transient retinal change after optic nerve transection. The increased expression was observed only in the ganglion cell layer and optic nerve fiber layer at 5-20 days after optic nerve transection. In an explant culture system, neurite outgrowth from the retina 7 days after optic nerve transection was spontaneously promoted. A low concentration of ouabain (50-100 nm ) completely blocked the spontaneous neurite outgrowth from the lesioned retina. Together, these data indicate that up-regulation of the Na,K-ATPase alpha3 subunit is involved in the regrowth of ganglion cell axons after axotomy.


Asunto(s)
Regeneración Nerviosa/fisiología , Nervio Óptico/fisiología , Retina/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Secuencia de Aminoácidos , Animales , Axotomía , Dominio Catalítico/fisiología , Células Cultivadas , ADN Complementario/genética , ADN Complementario/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Perfilación de la Expresión Génica , Carpa Dorada , Inmunohistoquímica , Hibridación in Situ , Datos de Secuencia Molecular , Neuritas/efectos de los fármacos , Neuritas/fisiología , Nervio Óptico/citología , Ouabaína/farmacología , Subunidades de Proteína , ARN Mensajero/metabolismo , Retina/citología , Retina/efectos de los fármacos , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Factores de Tiempo , Regulación hacia Arriba/fisiología
12.
J Bone Miner Res ; 16(11): 2057-65, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11697802

RESUMEN

Immune cells carry receptors for 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; vitamin D receptor (VDR)] and individuals with severe vitamin D deficiency have immune abnormalities. The aim of this study was to investigate the role of vitamin D in the immune system by studying VDR-knockout (VDR-KO) mice. VDR-KO mice had the same metabolic phenotype as rachitic animals with severe hypocalcemia. Leukocytosis, lymphocyte subset composition in different immune organs, and splenocyte proliferation to several stimuli were normal, except for a lower response to anti-CD3 stimulation (simulation index [SI] of 13 +/- 4 vs. 24 +/- 9 in wild-type mice; p < 0.01). Macrophage chemotaxis was impaired (41 +/- 19% vs. 60 +/- 18% in wild-type mice; p < 0.01) but phagocytosis and killing were normal. In vivo rejection of allogeneic (31 +/- 12 days vs. 45 +/- 26 days of survival in wild-type mice, NS) or xenogeneic (10 +/- 2 days vs. 16 +/- 9 days of survival in wild-type mice, NS) islet grafts was comparable with wild-type mice. Surprisingly, VDR-KO mice were protected from low-dose streptozotocin-induced diabetes mellitus (LDSDM; 5% vs. 65% in wild-type mice; p < 0.001). Correcting hypocalcemia by use of lactose-rich or polyunsaturated fat-rich diets fully restored the immune abnormalities in vitro and the sensitivity to diabetes in vivo. On the other hand, treatment with 1,25(OH)2D3 protected wild-type mice against diabetes but did not protect normocalcemic VDR-KO mice. We conclude that immune defects observed in VDR-KO mice are an indirect consequence of VDR disruption because they can be restored by calcium homeostasis normalization. This study proves that although 1,25(OH)2D3 is a pharmacologic and probably a physiological immunomodulator, its immune function is redundant. Moreover, we confirm the essential role of calcium in the immune system.


Asunto(s)
Receptores de Calcitriol/inmunología , Adyuvantes Inmunológicos/farmacología , Animales , Calcifediol/metabolismo , Calcitriol/metabolismo , Calcitriol/farmacología , Calcio/metabolismo , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/metabolismo , Humanos , Hipocalcemia/inmunología , Hipocalcemia/metabolismo , Técnicas In Vitro , Activación de Linfocitos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Receptores de Calcitriol/deficiencia , Receptores de Calcitriol/genética , Linfocitos T/inmunología
13.
J Gastroenterol Hepatol ; 16(10): 1112-9, 2001 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11686837

RESUMEN

BACKGROUND AND AIM: We evaluated the effect of rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid), a novel anti-ulcer drug, on indomethacin-induced small intestinal lesions in rats. METHODS: The animals were administered indomethacin (10 mg/kg, s.c.), and they were killed 24 h later. Rebamipide (30-300 mg/kg) was administered p.o. twice, 30 min before, and 6 h after indomethacin. RESULTS: Indomethacin caused hemorrhagic lesions in the rat small intestine, accompanied by an increase in enterobacterial translocation, inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO) activities, as well as thiobarbituric acid (TBA) reactants, and these changes were significantly prevented by the supplementation with 16,16-dimethyl prostaglandin E2 (dmPGE2; 10 microg/kg, i.v.) or the pretreatment of animals with the antibiotic ampicillin. Treatment of the animals with rebamipide dose-dependently prevented the development of intestinal lesions, and this effect was mimicked by i.v. administration of superoxide dismutase (SOD: 3000 U/kg) + catalase (CAT: 5000 U/kg). The protection by rebamipide was accompanied by a significant suppression of the increase in both MPO and iNOS activities, and a complete inhibition of the increase in TBA reactants, while SOD + CAT significantly inhibited the increase of MPO activity and TBA reactants, but not iNOS activity. The bacterial translocation following indomethacin was also significantly decreased by either rebamipide or SOD + CAT. CONCLUSION: These results confirmed the importance of enterobacteria and iNOS/NO in the pathogenesis of indomethacin-induced small intestinal lesions, and suggested that rebamipide prevents the development of these lesions, probably by its radical scavenging action.


Asunto(s)
Alanina/análogos & derivados , Alanina/farmacología , Antiulcerosos/farmacología , Inhibidores Enzimáticos/farmacología , Enfermedades Intestinales/prevención & control , Quinolonas/farmacología , Ampicilina/farmacología , Animales , Traslocación Bacteriana/efectos de los fármacos , Catalasa/farmacología , Relación Dosis-Respuesta a Droga , Enterobacteriaceae/efectos de los fármacos , Indometacina , Enfermedades Intestinales/inducido químicamente , Enfermedades Intestinales/enzimología , Peroxidación de Lípido , Masculino , Óxido Nítrico Sintasa/biosíntesis , Peroxidasa/biosíntesis , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/farmacología
14.
Endocrinology ; 142(12): 5332-41, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11713233

RESUMEN

VDR forms heterodimers with one of three RXRs, RXR alpha, RXR beta, and RXR gamma, and it is thought that RXR ligands can also modulate the trans-activation function of VDR/RXR heterodimers. In the present study we generated VDR/RXR gamma double null mutant mice to examine the convergent actions of vitamin D and vitamin A signaling and to explore the possibility of a functionally redundant VDR. Although RXR gamma(-/-) mice exhibited no overt abnormalities, VDR(-/-)/RXR gamma(-/-) mice appeared similar to VDR(-/-) mice, showing features typical of vitamin D-dependent rickets type II, including growth retardation, impaired bone formation, hypocalcemia, and alopecia. However, compared to VDR(-/-) mice, growth plate development in VDR(-/-)/RXR gamma(-/-) mutant mice was more severely impaired. Normalizing mineral ion homeostasis through dietary supplementation with high calcium and phosphorous effectively prevented rachitic abnormalities, except for disarranged growth plates in VDR(-/-)/RXR gamma(-/-) mutant mice, and alopecia in both VDR(-/-) and VDR(-/-)/RXR gamma(-/-) mutant mice. Histological analysis of VDR(-/-)/RXR gamma(-/-) growth plates revealed that development of the hypertrophic chondrocytes was selectively impaired. Thus, our findings indicated that the combined actions of VDR- and RXR gamma-mediated signals are essential for the normal development of growth plate chondrocytes, and raised the possibility that a functionally redundant VDR is present on chondrocytes as a heterodimer with RXR gamma.


Asunto(s)
Placa de Crecimiento/crecimiento & desarrollo , Receptores de Calcitriol/deficiencia , Receptores de Ácido Retinoico/deficiencia , Factores de Transcripción/deficiencia , Animales , Apoptosis/fisiología , Huesos/patología , Huesos/fisiopatología , Condrocitos/patología , Dieta , Placa de Crecimiento/patología , Homeostasis , Hipertrofia , Ratones , Ratones Noqueados/genética , Minerales/administración & dosificación , Minerales/metabolismo , Osteoclastos/fisiología , Fenotipo , Receptores de Calcitriol/genética , Receptores de Ácido Retinoico/genética , Receptores X Retinoide , Factores de Transcripción/genética
15.
J Altern Complement Med ; 7(4): 355-9, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11558778

RESUMEN

OBJECTIVE: To evaluate the effects of Hachimi-jio-gan, a traditional Japanese Kampo medication composed of eight medicinal herbs used for treating older people. SUBJECTS: Sixteen laboratory-bred Fischer 344 rats DESIGN: The rats were divided into two groups. One was the control group and the other was given chow containing 7% Hachimi-jio-gan powder for a period 110-120 weeks. OUTCOME MEASURES: The rats were assessed for wheel running and an inclined screen test from weeks 119-120; then laboratory and histologic examinations were performed. RESULTS: The group receiving Hachimi-jio-gan was more active in spontaneous mobility during wheel running; they maintained a significantly higher angle of retaining posture than the control group on the inclined screen; there was no significant difference in laboratory and histologic findings. CONCLUSIONS: Aged rats that received Hachimi-jio-gan were more active and stronger than the control group rats. The findings suggest that Hachimi-jio-gan is a safe and effective Kampo prescription for aging rats.


Asunto(s)
Envejecimiento/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicina Kampo , Actividad Motora/efectos de los fármacos , Animales , Masculino , Postura , Distribución Aleatoria , Ratas , Ratas Endogámicas F344 , Resultado del Tratamiento
16.
Chemosphere ; 44(1): 23-9, 2001 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-11419755

RESUMEN

A bench-top study of phosphorus-recovering technology from ash associated with incinerated wastewater (sewage) treatment sludge was conducted by adding sulfuric acid to ashes for the elution of phosphorus. With the exception of lead, which is insoluble in sulfuric acid, when the pH of the ash fell below 2.0, phosphorus and various heavy metals in the ash were extracted. The study found that, when alkalis were added to adjust the pH of the ash extract to 4.0, phosphorus was subsequently recovered via filtration. Furthermore, when alkalis were added to adjust the pH to 10, the recovery of various heavy metals was observed. In addition, disposal of the remaining solution (wastewater), which consists of a relatively low concentration of salts, is not considered to be a significant issue since it is within wastewater discharge standards and has been found to be useful as an acid-treating substance.


Asunto(s)
Conservación de los Recursos Naturales , Fósforo/análisis , Aguas del Alcantarillado , Eliminación de Residuos Líquidos/métodos , Concentración de Iones de Hidrógeno , Incineración , Metales Pesados/análisis , Ácidos Sulfúricos/química
17.
Digestion ; 63(3): 171-9, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11351144

RESUMEN

BACKGROUND/AIM: We examined the healing process of chronic gastric ulcers in adjuvant-induced arthritic rats and investigated the mechanism for delayed ulcer healing in arthritic rats, in relation to acid secretion and basic fibroblast growth factor (bFGF). METHODS: Arthritis was induced in male dark Agouti rats by a single injection of Freund's complete adjuvant (FCA), while gastric ulcers were induced by thermal cauterization (70 degrees C for 30 s) 7 days after FCA injection. RESULTS: Injection of FCA induced severe arthritis in all animals with a marked acid hypersecretion. The healing of gastric ulcers was significantly delayed in arthritic rats as compared with normal rats. Daily administration of indomethacin delayed ulcer healing in both normal and arthritic rats, but this effect was more pronounced in the latter. In contrast, the healing of gastric ulcers was significantly promoted in both normal and arthritic rats by omeprazole at a dose that inhibited acid secretion completely. The delayed healing of gastric ulcers was not influenced by twice daily administration of N(G)-nitro-L-arginine methyl ester, aminoguanidine or FR167653 (IL-1/TNF-alpha synthesis inhibitor), but was significantly accelerated by CS-23 (recombinant human bFGF) in a dose-dependent manner, without effect on the acid secretion. The expression of bFGF was markedly increased after ulceration, but this response was decreased in arthritic rats. CONCLUSION: The healing of gastric ulcers was delayed in arthritic rats, and this mechanism may be partly attributable to both acid hypersecretion and less expression of bFGF.


Asunto(s)
Artritis Reumatoide/complicaciones , Factores de Crecimiento de Fibroblastos/análisis , Ácido Gástrico/metabolismo , Omeprazol/administración & dosificación , Úlcera Gástrica/complicaciones , Úlcera Gástrica/patología , Úlcera Gástrica/fisiopatología , Animales , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/fisiopatología , Western Blotting , Modelos Animales de Enfermedad , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Indometacina/farmacología , Masculino , Ratas , Ratas Endogámicas , Úlcera Gástrica/tratamiento farmacológico , Factores de Tiempo , Resultado del Tratamiento
18.
Med Sci Monit ; 7(1): 20-5, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11208487

RESUMEN

Polaprezinc, N-(3-aminopropionyl)-L-histidinatozinc, has been shown to stimulate the production of insulin-like growth factor-1 (IGF-1) in mesenchymal cells, the polypeptide playing a role in the gastric epithelial wound repair. The present study was performed to examine the effect of polaprezinc on the impaired healing of chronic gastric ulcers in adjuvant-induced arthritic rats, in relation to IGF-1. Arthritis was induced in male Dark Agouti (DA) rats by a single injection of Freund's complete adjuvant (FCA), and the gastric ulcers were induced by thermal cauterization (70 degrees C for 30 sec) 7 days after FCA injection. Omeprazole (30 mg/kg) was administered p.o. once daily, while recombinant human IGF-1 (rhIGF-1) (30 micrograms/kg, s.c.) or polaprezinc (3-10 mg/kg, p.o.) was administered twice daily, starting from 3 days after ulceration for 14 days. The healing of gastric ulcers was significantly delayed in arthritic rats as compared to normal rats on day 10 and 17 following ulceration. The expression of IGF-1 mRNA was markedly increased in the ulcerated mucosa, but this response was apparently attenuated in arthritic rats. Repeated administration of polaprezinc accelerated the healing of gastric ulcers in both normal and arthritic rats, in a dose-dependent manner, and this effect was more pronounced in arthritic rats. Likewise, treatment with omeprazole also significantly promoted the healing of gastric ulcers in both normal and arthritic rats. On the other hand, rhIGF-1 significantly promoted the gastric ulcer healing in arthritic rats without any effect on that in normal rats. These results suggest that the impaired healing of chronic gastric ulcers in arthritic rats is, at least partly, accounted for by less expression of IGF-1, and the polaprezinc improves the delayed healing of gastric ulcers in arthritic rats, probably through an increase in IGF-1 production.


Asunto(s)
Antiulcerosos/uso terapéutico , Artritis Experimental/fisiopatología , Carnosina/análogos & derivados , Carnosina/uso terapéutico , Mucosa Gástrica/fisiopatología , Factor I del Crecimiento Similar a la Insulina/fisiología , Omeprazol/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/fisiopatología , Cicatrización de Heridas/efectos de los fármacos , Animales , Artritis Experimental/complicaciones , Peso Corporal/efectos de los fármacos , Cauterización , Edema/fisiopatología , Adyuvante de Freund , Mucosa Gástrica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Masculino , ARN Mensajero/genética , Ratas , Ratas Endogámicas , Proteínas Recombinantes/farmacología , Úlcera Gástrica/complicaciones , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Compuestos de Zinc
19.
Endocrinology ; 142(1): 494-7, 2001 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11145614

RESUMEN

Deficiency of vitamin D, which is required for calcium homeostasis, causes rickets with hypocalcemia and hypophosphatemia, resulting in growth retardation and impaired bone formation. Mice lacking the vitamin D receptor (VDR) develop the typical features of rickets, establishing that VDR plays a role in controlling the actions of vitamin D. Normalization of impaired mineral homeostasis in VDR KO mice fed a diet supplemented with high concentrations of calcium (2%) and phosphorus (1.25%) is reported to reverse the malformation of bone and the growth retardation as well. However, the relationship between mobilization of phosphorus and calcium and nuclear control of vitamin D actions remains unclear. The present study was undertaken to determine the effect of dietary phosphorus on mineral mobilization and bone mineralization. We report here that feeding a diet supplemented with a restricted amount of phosphorus (0.25%) and a normal amount of calcium (0.5%) for 4 weeks reverses the growth retardation and the impaired mineralization in VDR KO mice, as does a high-calcium and high-phosphorus diet (Ca: 2%; P: 1.25%). Thus, the present study suggests that mobilization of calcium and mobilization of phosphorus are differentially regulated through vitamin D-dependent and -independent systems, and that intake of calcium and phosphorus in the proper ratio is important for mineral homeostasis and bone mineralization.


Asunto(s)
Calcificación Fisiológica/fisiología , Fósforo Dietético , Fósforo/deficiencia , Receptores de Calcitriol/fisiología , Animales , Calcificación Fisiológica/genética , Cruzamientos Genéticos , Femenino , Fémur , Homeostasis , Masculino , Ratones , Ratones Noqueados , Receptores de Calcitriol/deficiencia , Receptores de Calcitriol/genética , Raquitismo/genética
20.
J Gastroenterol Hepatol ; 16(11): 1260-6, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11903745

RESUMEN

BACKGROUND AND AIM: We have reported that gut ischemia/reperfusion (I/R) causes hepatic microvascular dysfunction. Nitric oxide (NO) has been found to be a modulator of the adhesive interactions between leukocytes, platelets, and endothelial cells. Sho-saiko-to (TJ-9), a Japanese herbal medicine, is reported to have protective effects against liver injury and to regulate NO production. The objective of this study was to determine whether TJ-9 affects hepatic microvascular dysfunction elicited by gut I/R, and to investigate the role of NO. METHODS: Male Wistar rats were exposed to 30 min of gut ischemia followed by 60 min of reperfusion. Intravital microscopy was used to monitor leukocyte recruitment and the number of non-perfused sinusoids (NPS). Plasma tumor necrosis factor (TNF)-alpha and alanine aminotransferase (ALT) activities were measured. In another set of experiments, TJ-9 (1 g/kg per day intragastrically) was administered to rats for 7 days. In some experiments, dexamethasone (ST) (2 mg/kg per day intravenously) was administered. RESULTS: In control rats, gut I/R elicited increases in the number of stationary leukocytes, NPS, and plasma TNF-alpha and ALT activities, and these changes were mitigated by the pretreatment with TJ-9. Pretreatment with an NO synthase inhibitor diminished the protective effects of TJ-9 on the increase in leukostasis in the pericentral region, NPS, and plasma TNF-alpha levels, but not its effect on the increase in leukostasis in the midzonal region, total number of stationary leukocytes, or plasma ALT activities. Pretreatment with TJ-9 increased plasma nitrite/nitrate levels. The responses caused by gut I/R were attenuated by the pretreatment with ST. Pretreatment with an NO synthase inhibitor did not affect the effect of ST. CONCLUSIONS: These results suggest that TJ-9 attenuates the gut I/R-induced hepatic microvascular dysfunction and inflammatory responses such as TNF-alpha production in the early phase via enhancement of NO production, and sequential hepatocellular damage via its anti-inflammatory effect like corticosteroid effect.


Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Hepatopatías/prevención & control , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Hepatopatías/etiología , Masculino , Ratas , Ratas Wistar , Daño por Reperfusión/complicaciones
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