RESUMEN
Objective: To investigate the protective effect of intraperitoneal transplantation of human liver-derived stem cells at different times against concanavalin A (ConA)-induced acute liver injury in mice. Methods: A total of 88 male C57BL/6 mice were randomly divided into normal control group (group C), ConA model group (group M), and human liver-derived stem cells (HYX1)+ConA group (group E); according to the interval between phosphate buffer/HYX1 injection and ConA injection, Groups M and E were further divided into 3-hour groups (M1 and E1 groups), 6-hour groups (M2 and E2 groups), 12-hour groups (M3 and E3 groups), 24-hour groups (M4 and E4 groups), and 48-hour groups (M5 and E5 groups). The levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and total bilirubin (TBil) in peripheral blood were measured, liver tissue sections were used to observe pathological changes, and the Ishak score for liver inflammation was determined. The independent samples t-test was used for comparison between groups, and P < 0.05 was considered statistically significant. Results: The levels of ALT, AST, and TBil in group C were (36.25±1.16) U/L, (120.20±5.77) U/L, and (2.20±0.23) µmol/L, respectively; the levels of ALT, AST, and TBil and Ishak score were (8 721.23±837.39) U/L, (8 110.31±290.10) U/L, (8.41±0.10) µmol/L, and (13.32±1.30), respectively, in group M1, (8 334.31±666.50) U/L, (7 560.20±760.34) U/L, (10.40±0.80) µmol/L, and (12.67±0.81), respectively, in group M2, (8 960.75±551.93) U/L, (8 535.62±675.14) U/L, (10.95±1.43) µmol/L, and (14.57±0.65), respectively, in group M3, (8 618.57±886.40) U/L, (11 440.54 ± 1 327.86) U/L, (13.30±1.86) µmol/L, and (13.21±1.06), respectively, in group M4, and (10 170.13±1 112.37) U/L, (11 470.56±1 108.40) U/L, (12.75±1.55) µmol/L, and (15.07±1.58), respectively, in group M5. The levels of ALT, AST, and TBil and Ishak score were (1 016.35±163.47) U/L, (952.30±103.91) U/L, (7.77±0.62) µmol/L, and (3.50±0.21), respectively, in group E1, (42.10±6.20) U/L, (126.72±13.33) U/L, (3.41±0.53) µmol/L, and (2.01±0.40), respectively, in group E2, (44.21±4.30) U/L, (216.71±35.88) U/L, (3.47±0.44) µmol/L, and (2.13±0.25), respectively, in group E3, (2 909.69±212.14) U/L, (2 988.43±333.70) U/L, (7.03±0.93) µmol/L, and (4.70±0.50), respectively, in group E4, and (7 874.26±799.60) U/L, (10 940.54±947.35) U/L, (10.53±1.09) µmol/L, and (8.60±0.83), respectively, in group E5. Groups M1-M5 had significantly higher levels of ALT, AST, and TBil than group C (all P < 0.01), and groups M1-M4 had significantly higher levels of AST and ALT than groups E1-E4 (all P < 0.01), while there were no significant differences in the levels of AST and ALT between groups M5 and E5 (both P > 0.05). The pathological sections of liver tissue showed that compared with group M, group E had significant reductions in the degree of necrosis and Ishak score (both P < 0.05). Conclusion: Intraperitoneal transplantation of human liver-derived stem cells has a protective effect against ConA-induced acute liver injury in mice, and the injection at 6 and 12 hours in advance has the best protective effect.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Concanavalina A , Trasplante de Células Madre Mesenquimatosas , Mitógenos , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/cirugía , Concanavalina A/efectos adversos , Humanos , Hígado , Trasplante de Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Mitógenos/efectos adversosRESUMEN
Serum amyloid A is a proinflammatory molecule that induces leukocyte infiltration and promotes neutrophil adhesion to endothelial cells under inflammatory conditions. The aim of this study was to examine whether Saa1 aggravates T cell-mediated hepatitis by inducing chemokines in a liver-specific, Saa1-overexpressing, transgenic (TG) mouse model. We generated TG mice in which Saa1 was overexpressed specifically in liver tissue. The chemokines monocyte chemotactic protein 1 (MCP1), MIP1α, MIP1ß, interferon γ-induced protein 10 (IP-10), and eotaxin were induced in Saa1 TG mice. After concanavalin A treatment, Saa1 expression was higher in Saa1 TG mice than in WT mice. More severe liver injury, increased hepatocyte apoptosis, and higher levels of hepatic enzymes were observed in Saa1 TG mice than in WT mice. Liver infiltration of CD4(+) T cells and macrophages increased after inducing hepatitis. Activation of T cells was higher in Saa1 TG mice than in WT mice, and the populations of Th17 cells and regulatory T cells were altered by overexpressing Saa1 in TG mice. Secretion of various cytokines, such as interferon γ, tumor necrosis factor α, and interleukin 6, increased in Saa1 TG mice. Injecting a Toll-like receptor 2 (TLR2) antagonist in vivo inhibited chemokine expression and IκBα phosphorylation and showed that the induction of chemokines by Saa1 was dependent on TLR2. Hepatic Saa1 accelerated T cell-mediated hepatitis by inducing chemokine production and activating T cells by TLR2. Therefore, Saa1 might be a novel inflammatory factor that acts as a chemokine modulator in hepatitis.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Quimiocinas/biosíntesis , Mediadores de Inflamación/metabolismo , Proteína Amiloide A Sérica/biosíntesis , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Receptor Toll-Like 2/metabolismo , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Quimiocinas/genética , Concanavalina A/efectos adversos , Concanavalina A/farmacología , Hígado/metabolismo , Hígado/patología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/genética , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Transgénicos , Mitógenos/efectos adversos , Mitógenos/farmacología , Proteína Amiloide A Sérica/genética , Linfocitos T Reguladores/patología , Células Th17/patología , Receptor Toll-Like 2/antagonistas & inhibidores , Receptor Toll-Like 2/genéticaRESUMEN
STAT4, which is activated mainly by IL-12, promotes inflammatory responses by inducing Th1 and Th2 cytokines. Recent genome-wide association studies indicate that STAT4 gene variants are associated with risk of various types of liver diseases, but how STAT4 contributes to liver disease pathogenesis remains obscure. In this study, STAT4 activation was detected in liver immune cells from patients with viral hepatitis and autoimmune hepatitis, as well as in a mouse model of concanavalin A (Con A)-induced hepatitis. Such STAT4 activation was detected mainly in T cells, natural killer T cells, and macrophages and Kupffer cells, and was diminished in Il12a(-/-) and Il12b(-/-) mice. As expected, disruption of the Stat4 gene reduced production of Th1 and Th2 cytokines, but surprisingly exacerbated Con A-induced liver injury. Similarly, disruption of Il12a or Il12b also augmented Con A-induced hepatocellular damage. Further studies showed that hepatic natural killer T (NKT) cells from Con A-treated Stat4(-/-) mice had higher levels of FasL expression and increased cytotoxicity against hepatocytes than those from Con A-treated WT mice. In vitro, blocking FasL attenuated Stat4(-/-) NKT cytotoxicity against hepatocytes. In conclusion, despite up-regulation of proinflammatory cytokines, STAT4 protects against acute T-cell hepatitis, which is mediated by direct or indirect down-regulation of FasL expression on NKT cells.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Concanavalina A/efectos adversos , Hepatocitos/inmunología , Mitógenos/efectos adversos , Células T Asesinas Naturales/inmunología , Factor de Transcripción STAT4 , Enfermedad Aguda , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Concanavalina A/farmacología , Hepatocitos/patología , Subunidad p35 de la Interleucina-12/genética , Subunidad p35 de la Interleucina-12/inmunología , Ratones , Ratones Noqueados , Mitógenos/farmacología , Células T Asesinas Naturales/patologíaRESUMEN
Loss of tumor-suppressor PTEN is the most common alteration in endometrial carcinoma. However, the relationship between loss of PTEN, growth factors [eg, insulin/insulin-like growth factor (IGF)-1], epidermal growth factor (EGF), and hyperestrogenism in the development of endometrial carcinoma is still controversial. By using three-dimensional (3D) cultures of PTEN(+/+) and PTEN(+/-) endometrial epithelial cells, we investigated the effects of EGF, insulin/IGF, and estradiol in endometrial cell proliferation. We have previously demonstrated that 3D cultures of endometrial cells require EGF and insulin/IGF to proliferate. Herein, we demonstrate that, in the presence of EGF and insulin/IGF, long-term estradiol treatment directly induces proliferation of 3D cultures. Moreover, we show that the mitogenic effects of estradiol require the presence of insulin/IGF and EGF, because withdrawal of such factors completely abolishes estradiol-induced proliferation. In the presence of EGF and insulin/IGF, PTEN(+/-) and PTEN(+/+) spheroids display a similar rate of proliferation. However, the addition of estradiol causes an exaggerated proliferation of PTEN(+/-) cultures, leading to formation of complex structures, such as those observed in endometrial hyperplasia or carcinoma. In summary, we demonstrate that EGF and insulin/IGF prime endometrial epithelial cells to direct the mitogenic effects of estradiol. Furthermore, PTEN deficiency results in enhanced responsiveness to this combination, leading to the development of hyperplasia of endometrial cells in culture.
Asunto(s)
Hiperplasia Endometrial/inducido químicamente , Endometrio/efectos de los fármacos , Factor de Crecimiento Epidérmico/metabolismo , Estradiol/efectos adversos , Insulina/metabolismo , Mitógenos/efectos adversos , Fosfohidrolasa PTEN/deficiencia , Animales , Biomarcadores/metabolismo , Western Blotting , Proliferación Celular/efectos de los fármacos , Hiperplasia Endometrial/metabolismo , Hiperplasia Endometrial/patología , Endometrio/metabolismo , Endometrio/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Estrógenos/efectos adversos , Femenino , Técnica del Anticuerpo Fluorescente , Factor I del Crecimiento Similar a la Insulina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esferoides CelularesRESUMEN
The immunobiology of FXR has attracted significant attention in immune regulation and innate immunity. We have studied the mechanism of action of FXR activation on two models of acute hepatitis, inflammation mediated by Con A and α-GalCer and focused on the interactions of FXR activation and expression of PIR-B, both in vivo and in vitro using luciferase reporter and CHIP assays. In addition, based upon our data, we studied the role of FXR activation on the immunobiology of myeloid-derived suppressor cells (MDSCs). Importantly, we report herein that FXR activation reduces the inflammatory insult induced by either α-GalCer or Con A; such treatment expands CD11b(+)Ly6C(+) MDSCs. The protective effect of FXR activation is dependent on expansion of MDSCs, particularly liver CD11b(+)Ly6C(high) cells. Indeed, FXR activation enhances the suppressor function of MDSCs through upregulation of PIR-B by binding the PIR-B promoter. FXR activation drives the accumulation of MDSCs to liver through upregulation of S100A8. FXR activation facilitates homing and function of MDSCs, which function as a critical negative feedback loop in immune-mediated liver injury. The novel mechanisms defined herein emphasize not only the importance of liver lymphoid subpopulations, but also the potential roles of modulating FXR in autoimmune liver disease.
Asunto(s)
Hepatitis Autoinmune/inmunología , Hígado/inmunología , Células Mieloides/inmunología , Receptores Citoplasmáticos y Nucleares/inmunología , Animales , Antígenos Ly/genética , Antígenos Ly/inmunología , Antígeno CD11b/genética , Antígeno CD11b/inmunología , Calgranulina A/genética , Calgranulina A/inmunología , Concanavalina A/efectos adversos , Concanavalina A/farmacología , Galactosilceramidas/toxicidad , Hepatitis Autoinmune/genética , Hepatitis Autoinmune/patología , Hígado/patología , Ratones , Ratones Transgénicos , Mitógenos/efectos adversos , Mitógenos/farmacología , Células Mieloides/patología , Regiones Promotoras Genéticas/inmunología , Receptores Citoplasmáticos y Nucleares/genética , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunologíaRESUMEN
We studied the effect of short-term activation of the maternal immune system with T-cell mitogen concanavalin A at the early terms of pregnancy on the postnatal development of the spleen in the offspring. It was found that single immunostimulatory exposure prior to the formation of the fetal immune system delays the postnatal development of the spleen until the beginning of puberty and impairs the formation of splenic lymphatic nodules with the predominant development of germinal centers as well as increases the number of mast cells in this organ.
Asunto(s)
Efectos Tardíos de la Exposición Prenatal/inmunología , Bazo/inmunología , Animales , Concanavalina A/efectos adversos , Femenino , Ganglios Linfáticos/inmunología , Masculino , Intercambio Materno-Fetal , Ratones Endogámicos C57BL , Mitógenos/efectos adversos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/patología , Bazo/crecimiento & desarrollo , Bazo/patologíaRESUMEN
Corynebacterium parvum (CP), a kind of immunomodulator, has been well documented in many diseases. Non-cell C. parvum product (NCPP) is a newly-found nano-preparation. To investigate the effect of NCPP on Con A-induced murine severe hepatitis, we pretreated mice with NCPP intraperitoneally. After 12 h, ConA (25 µg/g body wt) was injected intravenously to provoke severe hepatitis and the degree of liver injury was evaluated by serum transaminase analysis and heptatic tissue pathology. Results have shown that levels of serum transaminase and degree of liver injury in ConA/NCPP groups had significantly declined than those in ConA/PBS groups. Notably, results of flow cytometry have demonstrated that activation of CD4+T cells in ConA/NCPP groups has been down-regulated, compared with ConA/PBS groups. Further, levels of serum and KC-related nitric oxide (NO) was displayed significantly lower in ConA/NCPP groups than those in ConA/PBS groups. The results indicate that NCPP may alleviate ConA-induced hepatitis by reducing CD4+T activation and NO production.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Extractos Celulares/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Concanavalina A/efectos adversos , Activación de Linfocitos/efectos de los fármacos , Mitógenos/efectos adversos , Óxido Nítrico/biosíntesis , Propionibacterium acnes/química , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Extractos Celulares/química , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Concanavalina A/farmacología , Femenino , Ratones , Ratones Endogámicos BALB C , Mitógenos/farmacología , Óxido Nítrico/inmunologíaRESUMEN
The anti-inflammatory effects of noopept (dipeptide analog of piracetam) upon a single intraperitoneal (i.p.) administration at doses of 1, 5, and 10 mg/kg in comparison to the reference drug diclofenac (10 mg/kg, i.p.) have been studied on a model of acute exudative inflammation induced by carrageenan in outbred rats and concanavalin A (Con A) in CBA mice. The level of cytokines was studied on the lipopolysaccharide (LPS) model (single administration, 100 mg/kg, i.p.) with 5-day administration of noopept at a dose of 5 mg/kg (i.p., before endotoxin injection) in C57BL/6 mice. The administration of noopept led to a significant suppression of the inflammatory response to both carrageenan and Con A. The administration of Con A caused a 16-fold increase in the level of IL-6 interleukin in the blood serum of mice as compared to control. Noopept (5 mg/kg) reduced the level of IL-6 by a factor of 1.8 in the inflammatory response to Con A. The administration of LPS led to pronounced increase in the levels ofpro-inflammatory IL-6 and TNF-alpha in the blood serum of test mice as compared to intact animals. The course administration of noopept (5 mg/kg) significantly decreased the level of IL-6 and reduced by half the level of TNF-alpha.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Citocinas/sangre , Dipéptidos/farmacología , Animales , Carragenina/toxicidad , Concanavalina A/efectos adversos , Concanavalina A/farmacología , Diclofenaco/farmacocinética , Relación Dosis-Respuesta a Droga , Inflamación/sangre , Inflamación/inducido químicamente , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos CBA , Mitógenos/efectos adversos , Mitógenos/farmacología , RatasRESUMEN
The molecular safety of insulin analogues has received a great deal of attention over the last year. In particular, attention has been directed to the mitogenic properties of insulin analogues as compared with human insulin. Understanding the mechanisms implicated in mediating mitogenic effects of insulin is therefore of particular interest. In this review we detail the story of the rapid-acting insulin analogue known as X10, which was the first insulin analogue in clinical development, but ended up being discontinued at an early clinical development stage following findings of mammary tumours in female Sprague-Dawley rats. The molecular characteristics of insulin X10, along with its interaction at both the IGF-1 receptor and the insulin receptor, have provided us with important insights into mechanisms implicated in metabolic and mitogenic signalling of insulin analogues.
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Insulina de Acción Corta/uso terapéutico , Insulina/análogos & derivados , Mitógenos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Insulina de Acción Corta/efectos adversos , Insulina de Acción Corta/farmacología , Neoplasias Mamarias Experimentales/inducido químicamente , Mitógenos/efectos adversos , Mitógenos/farmacología , Ratas , Ratas Sprague-Dawley , Receptor IGF Tipo 1/efectos de los fármacos , Receptor de Insulina/efectos de los fármacosRESUMEN
BACKGROUND AND OBJECTIVE: Feeding long-chain polyunsaturated fatty acids (LCP) influences immunity in adults; however, less is known about their effect during development. The aim of the study was to determine the effect of feeding LCP on immunity in healthy infants during the first 4 months of life. PATIENTS AND METHODS: Formula-fed infants were randomized at Asunto(s)
Proteínas en la Dieta/efectos adversos
, Ácidos Grasos Insaturados/farmacología
, Inmunidad Innata/efectos de los fármacos
, Leucocitos Mononucleares/efectos de los fármacos
, Mitógenos/efectos adversos
, Lectinas de Plantas/efectos adversos
, Proteínas de Soja/efectos adversos
, Antígenos/metabolismo
, Proliferación Celular/efectos de los fármacos
, Células Cultivadas
, Suplementos Dietéticos
, Ácidos Docosahexaenoicos/farmacología
, Femenino
, Hipersensibilidad a los Alimentos
, Humanos
, Lactante
, Fórmulas Infantiles
, Recién Nacido
, Interleucina-2/sangre
, Masculino
, Factor de Necrosis Tumoral alfa/sangre
, Ácido alfa-Linolénico/farmacología
RESUMEN
UNLABELLED: Concanavalin A (Con A)-induced injury is an established natural killer T (NKT) cell-mediated model of inflammation that has been used in studies of immune liver disease. Extracellular nucleotides, such as adenosine triphosphate, are released by Con A-stimulated cells and bind to specific purinergic type 2 receptors to modulate immune activation responses. Levels of extracellular nucleotides are in turn closely regulated by ectonucleotidases, such as CD39/NTPDase1. Effects of extracellular nucleotides and CD39 on NKT cell activation and upon hepatic inflammation have been largely unexplored to date. Here, we show that NKT cells express both CD39 and CD73/ecto-5'-nucleotidase and can therefore generate adenosine from extracellular nucleotides, whereas natural killer cells do not express CD73. In vivo, mice null for CD39 are protected from Con A-induced liver injury and show substantively lower serum levels of interleukin-4 and interferon-gamma when compared with matched wild-type mice. Numbers of hepatic NKT cells are significantly decreased in CD39 null mice after Con A administration. Hepatic NKT cells express most P2X and P2Y receptors; exceptions include P2X3 and P2Y11. Heightened levels of apoptosis of CD39 null NKT cells in vivo and in vitro appear to be driven by unimpeded activation of the P2X7 receptor. CONCLUSION: CD39 and CD73 are novel phenotypic markers of NKT cells. In turn, CD39 expression [corrected] modulates nucleotide-mediated cytokine production by, and limits apoptosis of, hepatic NKT cells. Deletion of CD39 is protective in [corrected] Con A-induced hepatitis. This study illustrates a [corrected] role for purinergic signaling in NKT-mediated mechanisms that result in liver immune injury.
Asunto(s)
Antígenos CD/metabolismo , Apirasa/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Concanavalina A/efectos adversos , Células Asesinas Naturales/metabolismo , Mitógenos/efectos adversos , Subgrupos de Linfocitos T/metabolismo , 5'-Nucleotidasa/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antígenos CD/genética , Apoptosis/fisiología , Apirasa/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Modelos Animales de Enfermedad , Células Asesinas Naturales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nucleótidos/metabolismo , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Subgrupos de Linfocitos T/patologíaRESUMEN
BACKGROUND: Autoimmune hepatitis (AIH) is an immune-mediated inflammation of the liver characterized by disorganized hepatic parenchyma and inflammatory cell infiltration. Although the increased incidence of AIH, the development of novel therapeutic strategies are impeded by the poor understanding of the accompanied detailed immunopathogenic changes. CD4+ T cells are key mediators of inflammatory cell infiltration in initial phases of liver injuries like AIH. The distribution of CD4+ cells and the histopathological changes accompanying Con A-induced AIH were investigated together with the postulated protective effect of Amygdalin (Amg.). MATERIALS AND METHODS: 30 adult male mice were divided into three groups; control, AIH and AIH-Amg. groups. AIH was induced by a single intravenous injection of Concanavalin A (Con A) (15 mg/kg). The AIH-Amg. group received Amg. 5 mg/kg intraperitoneally once a week for three weeks. Blood samples were examined for ALT and AST. MDA, SOD, and GSH were determined in hepatic homogenates. Liver section stained with hematoxylin and eosin, Masson trichrome and CD4+ immune stain were examined by light and electron microscopy. RESULTS: AIH group showed a significant increase in levels of ALT, AST and MDA and a significant decline in SOD and GSH compared to the controls. The liver tissue showed distorted hepatic architecture with intercellular hemorrhage, necrosis, and inflammatory cell infiltration. The area percent of CD4+ immune staining was significantly increased. Electron microscopic examination showed massive cellular degenerative changes. Amg. pretreatment in AIH-Amg. group significantly reversed these changes. CONCLUSION: AIH induced CD4+ cells infiltration in the liver with subsequent liver tissue damage. Amg. pretreatment inhibited CD4+ cell infiltration and protected the liver tissue. This finding suggests that Amg. could be a therapeutic agent in the management of AIH.
Asunto(s)
Amigdalina/administración & dosificación , Linfocitos T CD4-Positivos/efectos de los fármacos , Hepatitis Autoinmune/tratamiento farmacológico , Hígado/inmunología , Hígado/patología , Alanina Transaminasa/sangre , Análisis de Varianza , Animales , Aspartato Aminotransferasas/sangre , Concanavalina A/efectos adversos , Glutatión/metabolismo , Hepatitis Autoinmune/etiología , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/prevención & control , Inmunohistoquímica , Hígado/efectos de los fármacos , Hígado/ultraestructura , Masculino , Malondialdehído/metabolismo , Ratones , Mitógenos/efectos adversos , Estrés Oxidativo , Superóxido Dismutasa/metabolismoRESUMEN
BACKGROUND: Vitiligo is a relatively common, acquired pigmentary disorder characterized by areas of depigmented skin resulting from loss of melanocytes in the epidermis. Although several hypotheses have been proposed for the aetiology and pathogenesis of vitiligo, the cause of vitiligo remains unclear. OBJECTIVE: To evaluate spontaneous micronucleus (MN) frequency using the cytokinesis block MN assay to determine damages at the DNA or chromosome level in phytohaemagglutinin (PHA)-stimulated blood cells of patients with vitiligo and healthy control subjects. METHODS: Peripheral blood samples were obtained and cultured from 21 patients with vitiligo (mean age: 21.48 +/- 9.78 years) and 21 age- and sex-matched healthy control subjects (mean age: 21.52 +/- 9.80 years). MN values were scored in binucleated cells obtained from whole-blood cultures of patients and control subjects. RESULTS: MN frequencies (mean +/- SD) in PHA-stimulated blood cells of patients with vitiligo and control subjects were 0.94 +/- 0.58 and 0.58 +/- 0.32, respectively. Compared with control subjects, MN frequencies of patients with vitiligo were found significantly higher than those of the control subjects (P = 0.012). CONCLUSION: Our results indicate unexpectedly some chromosomal/DNA damage in whole-blood cultures of patients with vitiligo. We do not know, however, if these chromosome/DNA instabilities observed in the cells of vitiligo patients resulted from the cause or from the consequences of the disorder.
Asunto(s)
Células Sanguíneas/patología , Daño del ADN , Micronúcleos con Defecto Cromosómico/inducido químicamente , Vitíligo/genética , Vitíligo/patología , Adolescente , Adulto , Células Sanguíneas/efectos de los fármacos , Estudios de Casos y Controles , Células Cultivadas , Niño , Femenino , Humanos , Masculino , Pruebas de Micronúcleos , Mitógenos/efectos adversos , Mitógenos/farmacología , Fitohemaglutininas/efectos adversos , Fitohemaglutininas/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/patologíaRESUMEN
Maintenance of the red blood cell volume is a fundamental aspect of ensuring oxygen supply to the tissue. Recombinant human erythropoietin (rHuEPO) was approved for marketing in Japan in 1990 for the treatment of anemia in patients on dialysis. Recombinant human erythropoietin caused a significant increase in hemoglobin (Hb) levels in patients on dialysis. However, not all have a good response to rHuEPO therapy; the causes of rHuEPO failure include iron deficiency, infection, uremia, and interaction of some drugs. Juzen-taiho-to (TJ-48), a mixture of extracts from 10 medicinal herbs, has been used traditionally to treat patients with anemia, anorexia, or fatigue. To clarify the effect of TJ-48 on erythropoietin-resistant anemia, we studied the effect of TJ-48 in patients on hemodialysis with erythropoietin-resistant anemia. We divided 42 end-stage renal disease patients on hemodialysis with erythropoietin-resistant anemia (Hb<10.0 g/dL with rHuEPO 9000 U/wk or 15 U/kg/wk treatment) into 2 groups as follows: a TJ-48-treated group (TJ-48 group, 7.5 g/d, n=22) and a TJ-48 nontreated (control group, n=20). At the beginning of this study, there was no significant difference between the groups in age, sex, serum creatinine, blood urea nitrogen, serum iron, and ferritin. After 12 weeks of treatment, the Hb level had significantly increased from 8.4 +/- 1.1 to 9.5 +/- 1.3 g/dL (P=0.0272) in the TJ-48 group. C-reactive protein (CRP) had significantly decreased from 1.4 +/- 1.7 to 0.6 +/- 0.8 mg/dL (P=0.0438). There was a significant negative correlation between Hb and CRP in the TJ-48 group (r(2)=0.121, P=0.0066). In contrast, in the control group, Hb and CRP showed no significant changes throughout this study. Nor was there a significant correlation between Hb and CRP in the control group. In conclusion, TJ-48 was effective in improving erythropoietin-resistant anemia in end-stage renal disease patients. This effect was, at least in part, due to the anti-inflammatory effect of TJ-48 in patients on hemodialysis.
Asunto(s)
Anemia/tratamiento farmacológico , Medicamentos Herbarios Chinos/administración & dosificación , Eritropoyetina/administración & dosificación , Fallo Renal Crónico/complicaciones , Mitógenos/administración & dosificación , Diálisis Renal , Administración Oral , Anciano , Anemia/etiología , Resistencia a Medicamentos/efectos de los fármacos , Quimioterapia Combinada , Medicamentos Herbarios Chinos/efectos adversos , Eritropoyetina/efectos adversos , Femenino , Hemoglobinas , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Mitógenos/efectos adversos , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
Insulin-like growth factor I (IGF-1) is a peptide synthesized in response to growth hormone stimulation. While most of the circulating IGF-1 comes from the liver, it can also be produced in other tissues and both its expression and processing undergo tissue-specific regulation. The predominant form, IGF-1Ea is a circulating factor while two others, IGF-1Eb and IGF-1Ec (MGF), are mostly expressed in different tissues or in response to various stimuli and show some preferences with respect to the signal transduction pathways they activate. In skeletal muscle specific forms of IGF-1 play a role in development and growth and in addition to these physiological roles IGF-1 functions in the damaged muscle. IGF-1 is also important for the developing and adult brain and can reduce neuronal death caused by different types of injuries. Like many other peptide hormones IGF-1 originates from a precursor pro-hormone that undergoes extensive post-translational modifications. Processing liberates the mature peptide, which acts via the specific IGF-1 receptor but additional short peptides can arise from both N- and C-termini of various IGF-1 isoforms. These derivatives function as autonomous biologically active peptides and extremely potent neuroprotective agents. Their biological effects are independent of the activation of the IGF-1 receptor. Unfortunately, little is known about their mechanism(s) of action. Likewise, the existence of the endogenous production and wider biological effects of these short peptides are uncertain. However, considering the difference in the modes of action it might be possible to dissociate the unwanted and potentially dangerous mitogenic activity of the full-length IGF-1 exerted via its receptor from the neuroprotective effects of short derivatives mediated through different pathways. Such small molecules show good penetration through the blood brain barrier, can be inexpensively manufactured and modified to increase their stability. Therefore, they are good candidates for development into a neuroprotective therapeutic modality.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/análogos & derivados , Factor I del Crecimiento Similar a la Insulina/farmacología , Fármacos Neuroprotectores/farmacología , Péptidos/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Encefalopatías/tratamiento farmacológico , Humanos , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Mitógenos/efectos adversos , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/uso terapéutico , Péptidos/farmacocinética , Péptidos/uso terapéutico , Estructura Terciaria de Proteína/efectos de los fármacos , Estructura Terciaria de Proteína/fisiología , Receptor IGF Tipo 1/agonistas , Receptor IGF Tipo 1/metabolismoRESUMEN
Sjögren's syndrome is an autoimmune disease characterized by sialoadenitis and elevated titers of autoantibodies. To assess whether it is possible to induce inflammatory changes in salivary gland tissues, a series of immunizations in Balb/c mice have been undertaken, using salivary gland extract, modified or not, added to several adjuvants. Mice's humoral immune response to salivary gland antigens was monitored by ELISA. Inflammatory cells infiltrating gland tissue were seen 3 months after immunization with salivary gland extract modified with pepsin (AgGp) and metaperiodate (AgGMp). Although pathological progression was not observed, the histopathological picture was similar to the initial phase of Sjögren's syndrome. In addition, a monoclonal antibody reactive with 3 gland polypeptides and anhydrase carbonic II was rescued among B cells from immunized mice. Thus, immunizations with modified autoantigens were able to initiate pathological damage to glandular tissue and stimulate the proliferation of auto-reactive B cells.
Asunto(s)
Glándulas Salivales/inmunología , Sialadenitis/inmunología , Vacunación , Animales , Autoantígenos/efectos adversos , Bovinos , Femenino , Hibridomas/inmunología , Ratones , Ratones Endogámicos BALB C , Mitógenos/efectos adversos , Ácido Peryódico/efectos adversos , Glándulas Salivales/patología , Sialadenitis/patología , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/patologíaAsunto(s)
Hipoglucemiantes/efectos adversos , Insulina/análogos & derivados , Neoplasias , Práctica Clínica Basada en la Evidencia , Humanos , Insulina/efectos adversos , Insulina Glargina , Insulina de Acción Prolongada , Mitógenos/efectos adversos , Neoplasias/inducido químicamente , Neoplasias/epidemiología , Revisión de la Investigación por Pares , Proyectos de Investigación , Factores de RiesgoRESUMEN
Some genes are expressed differently in earlier and later generations of most cell lines. Many diseases become clinically expressed only later in life, and show clustering of the age at onset in the affected siblings, which may be related to the changing expression with age of the genes involved. Because insulin and its receptor are extremely ancient and well preserved structures with almost universal mitogenic effects, insulin may serve a paradigm of this process. It is suggested that by stimulating cell proliferation, hyperinsulinemia speeds up the appearance of later generations of cells with different expression of the genes. Insulin resistance, accompanying any hyperinsulinemia and considered to be a pathogenetic factor of some common later-age diseases, involves only some biochemical, but not mitogenic effects of the hormone. In humans, high levels of insulin in blood are encountered both physiologically after meals and in many pathological conditions: insulin therapy inevitably causes peripheral hyperinsulinemia; in type 2 diabetes hyperinsulinemia precedes hyperglycemia by many years; hyperinsulinemia is an independent risk factor of atherosclerosis, of type 2 diabetes itself, of some forms of dementia and other diseases; obesity is an obligatory hyperinsulinemic condition. The opposite of hyperalimentation, i.e. calorie restriction (at least, in rodents) may exert its life-prolonging effects through decreasing insulinemia and therefore the rate of cell proliferation. Insulin is only one example, and different mitogens regulate proliferation of different cells. It is likely that growth factors in general accelerating the replication of cells, play a role in speeding up the appearance of later-age diseases involving these cells.
Asunto(s)
Envejecimiento/patología , Enfermedad/etiología , Mitógenos/efectos adversos , Factores de Edad , Envejecimiento/genética , División Celular/efectos de los fármacos , División Celular/genética , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Genes , Humanos , Hipoglucemiantes/efectos adversos , Insulina/efectos adversosRESUMEN
OBJECTIVE: To determine the effect of the adjuvant administration of interferon gamma on monocyte HLA-DR antigen expression and mitogen-stimulated interferon gamma production following injury. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: University Hospital, Newark, NJ, a level I trauma center. PATIENTS: Persons older than 16 years with an Injury Severity Score greater than 20 and documented bacterial contamination at the time of injury (N = 98). INTERVENTIONS: Recombinant human interferon gamma (n = 46; 0.1 mg subcutaneously) or placebo (n = 52) was given for 10 days following injury. OUTCOMES: Incidence of major infection, monocyte and lymphocyte cell surface antigen expression, and interferon gamma production at multiple time points following injury. RESULTS: Peripheral monocyte HLA-DR was measured as percent of cells staining positive and as mean channel fluorescence. Both values were significantly increased in the interferon gamma group compared with the placebo group on days 3, 5, 8, and 11. The incidence of major infection was unaffected by interferon gamma administration. Infection decreased percent of HLA-DR-positive monocytes and mean channel fluorescence as compared with noninfected patients on postinjury days 8 and 11 in the placebo group but not in the interferon gamma group. Interferon gamma production improved from 3 +/- 3 U/mL on day 1 to 15 +/- 10 U/mL by day 30 but was always significantly lower than normal (25 +/- 3 [mean +/- SD] U/mL). Interferon gamma production was unaffected by either infection or interferon gamma administration. CONCLUSIONS: Interferon gamma administration after injury stimulated monocyte HLA-DR antigen expression and density but failed to improve interferon gamma production, a T-cell-mediated function. The incidence of infection was not decreased by the administration of interferon gamma for 10 days. Improvement in monocyte HLA-DR antigen expression did not correlate with a global restoration of immune function, and other interventions will be necessary to decrease infection after injury.
Asunto(s)
Infecciones Bacterianas/prevención & control , Antígenos HLA-DR/análisis , Interferón gamma/biosíntesis , Interferón gamma/uso terapéutico , Monocitos/inmunología , Heridas y Lesiones/inmunología , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Células Cultivadas , Método Doble Ciego , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Antígenos HLA-DR/genética , Humanos , Interferón gamma/administración & dosificación , Recuento de Leucocitos , Lipopolisacáridos/efectos adversos , Linfocitos/inmunología , Masculino , Mitógenos/efectos adversos , Placebos , Estudios Prospectivos , Proteínas RecombinantesRESUMEN
Human non-small cell lung cancer (N-SCLC), a common malignancy generally unmanageable by conventional cytotoxic chemotherapy, represents a major world health burden. Suramin, a polyanionic drug which appears to interfere with growth-factor/receptor interaction, has recently been shown to be cytostatic for small cell lung cancer cells; it may also be effective for N-SCLC. As insulin-like growth factor I (IGF-I) is a known progression agent for N-SCLC, we have examined the effects of suramin on the 'IGF-I system' in a panel of human N-SCLC cell lines. Colorimetric and thymidine incorporation assays were used to assess cell chemosensitivity whereas a radio-receptor assay was employed to evaluate IGF-I/receptor binding. Suramin reversibly reduced, in a concentration- and time-dependent manner, the growth of each N-SCLC cell line examined either cultured in serum-containing or serum-free medium. Furthermore, suramin caused a concentration-related inhibition of labeled IGF-I peptide specific binding on all cell lines studied. Suramin caused a significant reduction in the Bmax values with only weak variations in the affinity constants (Kd). We hypothesize that suramin interference with IGF-I mitogenic activity is a pathway by which this drug produces its effect in vitro. These data indicate further studies on the mechanism of action and pharmacology of suramin in vivo are warranted.