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(1) Background: The disease-modifying mechanisms of high-dose intravenous vitamin C (HDIVC) in sepsis induced acute respiratory distress syndrome (ARDS) is unclear. (2) Methods: We performed a post hoc study of plasma biomarkers from subjects enrolled in the randomized placebo-controlled trial CITRIS-ALI. We explored the effects of HDIVC on cell-free DNA (cfDNA) and syndecan-1, surrogates for neutrophil extracellular trap (NET) formation and degradation of the endothelial glycocalyx, respectively. (3) Results: In 167 study subjects, baseline cfDNA levels in HDIVC (84 subjects) and placebo (83 subjects) were 2.18 ng/µL (SD 4.20 ng/µL) and 2.65 ng/µL (SD 3.87 ng/µL), respectively, p = 0.45. At 48-h, the cfDNA reduction was 1.02 ng/µL greater in HDIVC than placebo, p = 0.05. Mean baseline syndecan-1 levels in HDIVC and placebo were 9.49 ng/mL (SD 5.57 ng/mL) and 10.83 ng/mL (SD 5.95 ng/mL), respectively, p = 0.14. At 48 h, placebo subjects exhibited a 1.53 ng/mL (95% CI, 0.96 to 2.11) increase in syndecan-1 vs. 0.75 ng/mL (95% CI, 0.21 to 1.29, p = 0.05), in HDIVC subjects. (4) Conclusions: HDIVC infusion attenuated cell-free DNA and syndecan-1, biomarkers associated with sepsis-induced ARDS. Improvement of these biomarkers suggests amelioration of NETosis and shedding of the vascular endothelial glycocalyx, respectively.
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Ácidos Nucleicos Libres de Células , Trampas Extracelulares , Síndrome de Dificultad Respiratoria , Sepsis , Humanos , Glicocálix , Sindecano-1/metabolismo , Sindecano-1/farmacología , Ácido Ascórbico/uso terapéutico , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/etiología , Vitaminas/uso terapéutico , BiomarcadoresRESUMEN
In utero hyperglycemia has consequences on future outcomes in the offsprings. We had earlier shown that in utero hyperglycemia impacts proteoglycans/glycosaminoglycans, one of the key molecules involved in brain development. Hypothalamic HSPGs such as syndecan-1 and syndecan-3 are well known for their involvement in feeding behavior. Therefore, studies were carried out to determine the effect of maternal hyperglycemia on the expression of HSPGs in the hypothalamus of offspring brain. Results revealed increased protein abundance of Syndecan-1 and -3 as well as glypican-1 in postnatal adults from hyperglycemic mothers. This was associated with increased hyperphagia and increased expression of Neuropeptide Y. These results indicate the likely consequences on offsprings exposed to in utero hyperglycemia on its growth.
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Hiperglucemia , Sindecano-1 , Adulto , Cinamatos , Femenino , Heparitina Sulfato/metabolismo , Humanos , Hiperfagia , Hipotálamo/metabolismo , Glicoproteínas de Membrana/metabolismo , Madres , Sindecano-1/metabolismo , TiadiazolesRESUMEN
INTRODUCTION: Lipids regulate a wide range of biological processes. The mechanisms by which fatty acids (FA) and its metabolites influence the hypothalamic regulation of energy homeostasis have been highly studied. However, the effect of ageing and food restriction (FR) on this process is unknown. METHODS: Herein, we analyzed the gene expression, protein and phosphorylation levels of hypothalamic enzymes and transcription factors related to lipid metabolism. Experiments were performed in male Wistar rats of 3-, 8- and 24-month-old Wistar rats fed ad libitum (AL), as ageing model. Besides, 5- and 21-month-old rats were subjected to a moderate FR protocol (equivalent to ≈ 80% of normal food intake) for three months before the sacrifice. RESULTS: Aged Wistar rats showed a situation of chronic lipid excess as a result of an increase in de novo FA synthesis and FA levels that reach the brain, contributing likely to the development of central leptin and insulin resistance. We observe a hypothalamic downregulation of AMP-activated protein kinase (AMPK) and stearoyl-CoA desaturase (SCD1) and an increase of carnitine palmitoyltransferase-1c (CPT1c) expression. DISCUSSION: Our results suggest an impairment in the physiological lipid sensing system of aged Wistar rats, which would alter the balance of the intracellular mobilization and trafficking of lipids between the mitochondria and the Endoplasmic Reticulum (ER) in the hypothalamus, leading probably to the development of neurolipotoxicity in aged rats. Lastly, FR can only partially restore this imbalance.Schematic representation of the fate of LCFA-CoA in the hypothalamus of young and old rats. Blood circulating LCFAs in young Wistar rats reach the hypothalamus, where they are esterified to LCFA-CoA. Into glial cells or neurons, LCFA-CoA are driven to mitochondria (CPT1a) or ER (CPT1c) where could be desaturated by SDC1 and, thereby, converted into structural and signaling unsaturated lipids as oleic acid, related with neuronal myelinization and differentiation. However, the excess of LCFA that reach to the hypothalamus in old animals, could generate an increase in LCFA-CoA, which together with an increase in CPT1c levels, could favor the capture of LCFA-CoA to the ER. The decrease in the levels of SCD1 in old rats would decrease FA unsaturation degree that could trigger lipotoxicity process and neurodegeneration, both related to the development of neurodegenerative diseases linked to age.
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Ácidos Grasos , Hipotálamo , Envejecimiento , Animales , Coenzima A/metabolismo , Ácidos Grasos/metabolismo , Hipotálamo/metabolismo , Masculino , Ratas , Ratas Wistar , Sindecano-1/metabolismoRESUMEN
Salvianolic acid B (Sal B) is one of the main watersoluble components of Salvia miltiorrhiza Bge. Numerous reports have demonstrated that it could exert significant renalprotective effects, but the underlying mechanism remains unclear. The present study demonstrated that Sal B could alleviate renal injury by regulating the heparanase/syndecan1 (HPSE/SDC1) axis. In vivo, the serum creatinine, blood urea nitrogen, transforming growth factorß1 (TGFß1) and fibroblast growth factor2 (FGF2) levels, and the histopathological changes of mice kidneys were examined. Sal B could notably reduce the renal injury caused by left ureteral ligation. In vitro, Sal B downregulated the expression levels of HPSE/FGF2/TGFß1/αsmooth muscle actin and upregulated the expression levels of SDC1/Ecadherin in angiotensin IIstimulated HK2 cells in a dosedependent manner. In summary, to the best of the authors' knowledge, the present study provided evidence for the first time that Sal B could exert renalprotective effects via the inhibition of the HPSE/SDC1 axis, and these results suggest that the administration of Sal B may be a novel therapeutic strategy in treating renal interstitial fibrosis.
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Benzofuranos/uso terapéutico , Fibrosis/tratamiento farmacológico , Glucuronidasa/metabolismo , Riñón/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Sindecano-1/metabolismo , Animales , Línea Celular , Humanos , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Sustancias Protectoras/uso terapéuticoRESUMEN
It is well established that dendritic cells and macrophages play a role in antigen presentation to B and T cells and in shaping B and T cell responses via cytokines they produce. We have previously reported that depletion of neutrophils improves the production of mucosal IgA after sublingual immunization with Bacillus anthracis edema toxin as adjuvant. These past studies also demonstrated that an inverse correlation exists between the number of neutrophils and production of IgA by B cells. Using specific inhibitors of elastase, we addressed whether the elastase activity of neutrophil could be the factor that interferes with production of IgA and possibly other immunoglobulin isotypes. We found that murine splenocytes and mesenteric lymph node cells cultured for 5 days in the presence of neutrophil elastase inhibitors secreted higher levels of IgG and IgA than cells cultured in the absence of inhibitors. The effect of the inhibitors was dose-dependent and was consistent with increased frequency of CD138+ cells expressing IgG or IgA. Finally, neutrophil elastase inhibitors increased transcription of mRNA for AID, IL-10, BAFF and APRIL, factors involved in B cell differentiation. These findings identify inhibitors of elastase as potential adjuvants for increasing production of antibodies.
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Linfocitos B/inmunología , Inmunoglobulina A/biosíntesis , Inmunoglobulina G/biosíntesis , Neutrófilos/inmunología , Elastasa Pancreática/antagonistas & inhibidores , Animales , Factor Activador de Células B/genética , Diferenciación Celular/inmunología , Células Cultivadas , Glicina/análogos & derivados , Glicina/farmacología , Interleucina-10/genética , Ganglios Linfáticos/citología , Ganglios Linfáticos/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/biosíntesis , Inhibidores de Serina Proteinasa/farmacología , Bazo/citología , Bazo/metabolismo , Sulfonamidas/farmacología , Sindecano-1/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genéticaRESUMEN
High-dose chemotherapies to treat multiple myeloma (MM) can be life-threatening due to toxicities to normal cells and there is a need to target only tumor cells and/or lower standard drug dosage without losing efficacy. We show that pharmacologically-dosed ascorbic acid (PAA), in the presence of iron, leads to the formation of highly reactive oxygen species (ROS) resulting in cell death. PAA selectively kills CD138+ MM tumor cells derived from MM and smoldering MM (SMM) but not from monoclonal gammopathy undetermined significance (MGUS) patients. PAA alone or in combination with melphalan inhibits tumor formation in MM xenograft mice. This study shows PAA efficacy on primary cancer cells and cell lines in vitro and in vivo.
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Apoptosis/efectos de los fármacos , Ácido Ascórbico/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ácido Ascórbico/química , Ácido Ascórbico/uso terapéutico , Proteínas de Unión al Calcio , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Quimioterapia Combinada , Humanos , Hierro/química , Melfalán/uso terapéutico , Ratones , Ratones Endogámicos NOD , Proteínas de Microfilamentos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Especies Reactivas de Oxígeno/metabolismo , Sindecano-1/metabolismo , Trasplante HeterólogoRESUMEN
Indatuximab ravtansine is a monoclonal antibody-linked cytotoxic agent that specifically targets CD138-expressing cells. Monotherapy has been shown to significantly inhibit multiple myeloma tumour growth in vivo and improve host survival. Here, we show that in most cell lines tested, indatuximab ravtansine acts additively or even synergistically with clinically approved therapies for treatment of multiple myeloma. In addition, in vivo mouse xenograft models confirmed the activity of indatuximab ravtansine in combination with lenalidamide and lenalidomide/dexamethasone. Indatuximab ravtansine may therefore be a suitable combination partner for multiple myeloma, and a clinical study is ongoing.
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Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoconjugados/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Animales , Dexametasona/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos , Lenalidomida , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Ratones , Sindecano-1/antagonistas & inhibidores , Sindecano-1/inmunología , Talidomida/análogos & derivados , Talidomida/uso terapéuticoRESUMEN
Heparanase is an endo-ß-D-glucuronidase capable of cleaving heparan sulfate side chains contributing to breakdown of the extracellular matrix. Increased expression of heparanase has been observed in numerous malignancies and is associated with a poor prognosis. It has generated significant interest as a potential antineoplastic target because of the multiple roles it plays in tumor growth and metastasis. The protumorigenic effects of heparanase are enhanced by the release of heparan sulfate side chains, with subsequent increase in bioactive fragments and cytokine levels that promote tumor invasion, angiogenesis, and metastasis. Preclinical experiments have found heparanase inhibitors to substantially reduce tumor growth and metastasis, leading to clinical trials with heparan sulfate mimetics. In this review, we examine the role of heparanase in tumor biology and its interaction with heparan surface proteoglycans, specifically syndecan-1, as well as the mechanism of action for heparanase inhibitors developed as antineoplastic therapeutics.
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Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Glucuronidasa/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Animales , Vacunas contra el Cáncer , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Matriz Extracelular/metabolismo , Expresión Génica , Glucuronidasa/genética , Glucuronidasa/metabolismo , Heparitina Sulfato/metabolismo , Humanos , Terapia Molecular Dirigida , Neoplasias/genética , Neoplasias/mortalidad , Pronóstico , Sindecano-1/genética , Sindecano-1/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Allergen exposure and air pollution are two risk factors for asthma development and airway inflammation that have been examined extensively in isolation. The impact of combined allergen and diesel exhaust exposure has received considerably less attention. Diesel exhaust (DE) is a major contributor to ambient particulate matter (PM) air pollution, which can act as an adjuvant to immune responses and augment allergic inflammation. We aimed to clarify whether DE increases allergen-induced inflammation and cellular immune response in the airways of atopic human subjects. METHODS: Twelve atopic subjects were exposed to DE 300 µg.m(-3) or filtered air for 2 h in a blinded crossover study design with a four-week washout period between arms. One hour following either filtered air or DE exposure, subjects were exposed to allergen or saline (vehicle control) via segmental challenge. Forty-eight hours post-allergen or control exposure, bronchial biopsies were collected. The study design generated 4 different conditions: filtered air + saline (FAS), DE + saline (DES), filtered air + allergen (FAA) and DE + allergen (DEA). Biopsies sections were immunostained for tryptase, eosinophil cationic protein (ECP), neutrophil elastase (NE), CD138, CD4 and interleukin (IL)-4. The percent positivity of positive cells were quantified in the bronchial submucosa. RESULTS: The percent positivity for tryptase expression and ECP expression remained unchanged in the bronchial submucosa in all conditions. CD4 % positive staining in DEA (0.311 ± 0.060) was elevated relative to FAS (0.087 ± 0.018; p = 0.035). IL-4% positive staining in DEA (0.548 ± 0.143) was elevated relative to FAS (0.127 ± 0.062; p = 0.034). CD138 % positive staining in DEA (0.120 ± 0.031) was elevated relative to FAS (0.017 ± 0.006; p = 0.015), DES (0.044 ± 0.024; p = 0.040), and FAA (0.044 ± 0.008; p = 0.037). CD138% positive staining in FAA (0.044 ± 0.008) was elevated relative to FAS (0.017 ± 0.006; p = 0.049). NE percent positive staining in DEA (0.224 ± 0.047) was elevated relative to FAS (0.045 ± 0.014; p = 0.031). CONCLUSIONS: In vivo allergen and DE co-exposure results in elevated CD4, IL-4, CD138 and NE in the respiratory submucosa of atopic subjects, while eosinophils and mast cells are not changed. TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01792232.
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Contaminantes Atmosféricos/efectos adversos , Alérgenos , Bronquios/efectos de los fármacos , Hipersensibilidad Inmediata/inmunología , Material Particulado/efectos adversos , Neumonía/inmunología , Hipersensibilidad Respiratoria/inmunología , Emisiones de Vehículos , Adulto , Contaminantes Atmosféricos/inmunología , Animales , Betula/inmunología , Biomarcadores/metabolismo , Biopsia , Bronquios/inmunología , Bronquios/metabolismo , Bronquios/patología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Hipersensibilidad Inmediata/diagnóstico , Hipersensibilidad Inmediata/metabolismo , Inmunohistoquímica , Mediadores de Inflamación/metabolismo , Interleucina-4/metabolismo , Elastasa de Leucocito/metabolismo , Masculino , Persona de Mediana Edad , Material Particulado/inmunología , Neumonía/inducido químicamente , Neumonía/diagnóstico , Neumonía/metabolismo , Poaceae/inmunología , Polen/inmunología , Pyroglyphidae/inmunología , Hipersensibilidad Respiratoria/diagnóstico , Hipersensibilidad Respiratoria/metabolismo , Sindecano-1/metabolismo , Factores de Tiempo , Adulto JovenRESUMEN
Predicated on evidence that diving-related microparticle generation is an oxidative stress response, this study investigated the role that oxygen plays in augmenting production of annexin V-positive microparticles associated with open-water SCUBA diving and whether elevations can be abrogated by ascorbic acid. Following a cross-over study design, 14 male subjects ingested placebo and 2-3 wk later ascorbic acid (2 g) daily for 6 days prior to performing either a 47-min dive to 18 m of sea water while breathing air (â¼222 kPa N2/59 kPa O2) or breathing a mixture of 60% O2/balance N2 from a tight-fitting face mask at atmospheric pressure for 47 min (â¼40 kPa N2/59 kPa O2). Within 30 min after the 18-m dive in the placebo group, neutrophil activation, and platelet-neutrophil interactions occurred, and the total number of microparticles, as well as subgroups bearing CD66b, CD41, CD31, CD142 proteins or nitrotyrosine, increased approximately twofold. No significant elevations occurred among divers after ingesting ascorbic acid, nor were elevations identified in either group after breathing 60% O2. Ascorbic acid had no significant effect on post-dive intravascular bubble production quantified by transthoracic echocardiography. We conclude that high-pressure nitrogen plays a key role in neutrophil and microparticle-associated changes with diving and that responses can be abrogated by dietary ascorbic acid supplementation.
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Ácido Ascórbico/administración & dosificación , Micropartículas Derivadas de Células/efectos de los fármacos , Enfermedad de Descompresión/prevención & control , Suplementos Dietéticos , Buceo/efectos adversos , Activación Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Biomarcadores/sangre , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Micropartículas Derivadas de Células/inmunología , Micropartículas Derivadas de Células/metabolismo , Estudios Cruzados , Enfermedad de Descompresión/sangre , Enfermedad de Descompresión/etiología , Enfermedad de Descompresión/inmunología , Embolia Aérea/diagnóstico por imagen , Embolia Aérea/etiología , Humanos , Masculino , Neutrófilos/inmunología , Neutrófilos/metabolismo , Sindecano-1/sangre , Factores de Tiempo , Resultado del Tratamiento , Tirosina/análogos & derivados , Tirosina/sangre , UltrasonografíaRESUMEN
OBJECTIVE: Epigallocatechin-gallate (EGCG) claims a plethora of health benefits including protection against neoplastic diseases. Meanwhile, heparan-sulfate proteoglycans (HSPGs) have defensive role against tumour cell invasion. Therefore, the chemopreventive and hepatoprotective effects of EGCG were studied in hepatocellular carcinoma (HCC) in vivo and in vitro and compared with strong water soluble antioxidant, sodium ascorbate. METHODS: HCC was induced in SD rats by thioacetamide (200 mg/Kg). Some rats were treated with EGCG (20 mg/Kg) or sodium ascorbate (100 mg/Kg). Liver impairment was assessed by measuring serum α-fetoprotein and investigating liver sections stained with H/E. Hepatic HSPGs, syndecan-1 and matrix metalloproteinase-9 (MMP-9) were measured by ELISA. Gene expression of fibroblast growth factor (FGF)-2 was measured. Cell death was assessed by caspase-3 activity. In addition, all markers were measured in human hepatocellular carcinoma cell line (HepG2). KEY FINDINGS: EGCG increased the animal survival and decreased both α-fetoprotein and HepG2 viability. In addition, EGCG ameliorated fibrosis and massive hepatic tissue breakdown. EGCG restored HSPGs and reduced expression of MMP-9, syndecan-1 and FGF-2 in-vivo and in-vitro. Sodium ascorbate showed significantly lower results than EGCG. CONCLUSIONS: Besides antioxidant activity, other mechanisms are involved in the chemopreventive and hepatoprotective effects of EGCG including restoration of HSPGs receptors and inhibition of vascular invasion.
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Antioxidantes/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Catequina/análogos & derivados , Proteoglicanos de Heparán Sulfato/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Hígado/efectos de los fármacos , Fitoterapia , Animales , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Antioxidantes/farmacología , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Camellia sinensis/química , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/metabolismo , Catequina/farmacología , Catequina/uso terapéutico , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Expresión Génica , Células Hep G2 , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica/prevención & control , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas Sprague-Dawley , Sindecano-1/metabolismo , Tioacetamida , alfa-Fetoproteínas/metabolismoRESUMEN
Despite considerable advances, multiple myeloma (MM) remains incurable and the development of novel therapies targeting the interplay between plasma cells (PCs) and their bone marrow (BM) microenvironment remains essential. We investigated the effect of various agents in vitro on the proliferation, phenotype, morphology, actin polymerization and migration of MM cells and, in vivo, the tumour growth of L363-bearing non-obese diabetic severe combined immunodeficient mice with a deficient interleukin-2 receptor gamma chain (NSG). In vitro, we observed a dose-dependent cytotoxicity with bortezomib and sorafenib. Using RPMI8226 cells co-expressing histone 2B-mCherry and cytochrome c-GFP, bortezomib- and sorafenib-induced apoptosis was confirmed, and both agents combined showed synergism. Sorafenib induced CD138-downregulation and abolished CXCL12-induced actin polymerization. L363 cells expressed CCR4 and CCR5 and migrated to their common ligand CCL5. Chemotaxis to BM stroma cells was notable and significantly reduced by sorafenib. Downregulation of phospho-ERK appeared relevant for the inhibition of actin polymerization and chemotaxis. Sorafenib alone, and combined with bortezomib, showed substantial antitumour activity in L363-bearing NSG. Correspondingly, sorafenib induced clinical responses in MM-/AL-amyloidosis patients. We conclude that, in addition to the cytotoxic and anti-angiogenic effects of sorafenib, blocking of MM cell migration and homing represent promising mechanisms to interrupt the interplay between PCs and their supportive microenvironment.
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Actinas/metabolismo , Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Sindecano-1/biosíntesis , Anciano , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Ácidos Borónicos/uso terapéutico , Bortezomib , Quimiocina CXCL12/antagonistas & inhibidores , Quimiocina CXCL12/farmacología , Quimiotaxis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteínas de Neoplasias/biosíntesis , Niacinamida/administración & dosificación , Niacinamida/farmacología , Niacinamida/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/farmacología , Fosforilación/efectos de los fármacos , Polimerizacion/efectos de los fármacos , Pirazinas/uso terapéutico , Sorafenib , Células Tumorales Cultivadas , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Multiple myeloma (MM) is an incurable B cell neoplasm causing significant morbidity and mortality. Despite recent advances in the MM-treatment, the disease still remains incurable; necessitating a search for new therapeutic agents. Therefore, Strychnos nux-vomica L. root extract (SN) was screened using the human MM-cell line, U266B1. SN-extract demonstrated anti-proliferative effect in a time- and dose-dependent manner. Morphological studies, cell cycle analysis by FACS indicate apoptosis. Furthermore, assessment of signaling molecules like IL-6 (interleukin-6) and CD-138 (Sydencan-1) confirmed apoptosis. The anti-proliferative activity of SN-extract is associated with apoptosis, which is likely due to the presence of alkaloids, strychnine and brucine, which have been identified by MALDI-TOF-MS and RP-HPLC analysis.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Mieloma Múltiple/patología , Extractos Vegetales/farmacología , Raíces de Plantas/química , Strychnos nux-vomica/química , Antineoplásicos/análisis , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Extractos Vegetales/análisis , Sindecano-1/metabolismoRESUMEN
CD138 expression is a hallmark of plasma cells and multiple myeloma cells. However, decreased expression of CD138 is frequently observed in plasma cells of myeloma patients, although the clinical significance of this is unclear. To evaluate the significance of low expression of CD138 in MM, we examined the phenotypes of MM cells expressing low levels of CD138. Flow cytometric analysis of primary MM cells revealed a significant decrease in CD138 expression in patients with relapsed/progressive disease compared with untreated MM patients. Patients with low levels of CD138 had a worse overall survival compared with patients with high levels of CD138, in newly diagnosed patients and patients receiving high-dose chemotherapy followed by autologous stem-cell transplantation. Two MM cell lines, KYMM-1 (CD138- low) and KYMM-2 (CD138- high), were established from a single MM patient with decreased CD138 expression. High expression of BCL6 and PAX5, and downregulation of IRF4, PRDM1 and XBP1 was observed in KYMM-1 compared with KYMM-2 cells, indicative of the immature phenotype of KYMM-1. KYMM-1 was less sensitive to lenalidomide than KYMM-2, while no difference in sensitivity to bortezomib was observed. KYMM-2 cells were further divided in CD138+ and CD138- fractions using anti-CD138-coated magnetic beads. CD138- cells sorted from the KYMM-2 cell line also showed high BCL6, low IRF4 expression and decreased sensitivity to lenalidomide compared with CD138+ cells. Our observations suggest that low CD138 expression relates to i) poor prognosis, ii) immature phenotype and iii) low sensitivity to lenalidomide. The observed distinct characteristics of CD138 low MM cells, suggest this should be recognized as a new clinical entity. Establishment of a treatment strategy for MM cells expressing low levels of CD138 is needed to improve their poor outcome.
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Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Sindecano-1/metabolismo , Talidomida/análogos & derivados , Anciano , Apoptosis , Biomarcadores de Tumor , Ácidos Borónicos/farmacología , Bortezomib , Línea Celular Tumoral , Metilación de ADN , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos , Femenino , Citometría de Flujo , Humanos , Factores Reguladores del Interferón/metabolismo , Lenalidomida , Factor de Transcripción PAX5/metabolismo , Fenotipo , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-6 , Pirazinas/farmacología , Factores de Transcripción del Factor Regulador X , Proteínas Represoras/metabolismo , Talidomida/farmacología , Factores de Transcripción/metabolismo , Proteína 1 de Unión a la X-BoxRESUMEN
Syndecan 1 is the predominant heparan sulfate proteoglycan found on the surface of epithelial cells and, like glutamine, is essential in maintaining the intestinal epithelial barrier. We therefore hypothesized that loss of epithelial syndecan 1 would abrogate the gut-protective effects of enteral glutamine. Both an in vitro and in vivo model of gut ischemia-reperfusion (IR) was utilized. In vitro, intestinal epithelial cells underwent hypoxia-reoxygenation to mimic gut IR with 2 mM (physiologic) or 10 mM glutamine supplementation. Permeability, caspase activity, cell growth, and cell surface and shed syndecan 1 were assessed. In vivo, wild-type and syndecan 1 knockout (KO) mice received ± enteral glutamine followed by gut IR. Intestinal injury was assessed by fluorescent dye clearance and histopathology, permeability as mucosal-to-serosal clearance ex vivo in everted sacs, and inflammation by myeloperoxidase (MPO) activity. In an in vitro model of gut IR, glutamine supplementation reduced epithelial cell permeability and apoptosis and enhanced cell growth. Shed syndecan 1 was reduced by glutamine without an increase in syndecan 1 mRNA. In vivo, intestinal permeability, inflammation, and injury were increased after gut IR in wild-type mice and further increased in syndecan 1 KO mice. Glutamine's attenuation of IR-induced intestinal hyperpermeability, inflammation, and injury was abolished in syndecan 1 KO mice. These results suggest that syndecan 1 plays a novel role in the protective effects of enteral glutamine in the postischemic gut.
Asunto(s)
Glutamina/uso terapéutico , Enfermedades Intestinales/prevención & control , Daño por Reperfusión/prevención & control , Sindecano-1/fisiología , Animales , Caspasas/metabolismo , División Celular/efectos de los fármacos , División Celular/fisiología , Hipoxia de la Célula/fisiología , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Glutamina/farmacología , Enfermedades Intestinales/patología , Enfermedades Intestinales/fisiopatología , Mucosa Intestinal/citología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Intestinos/irrigación sanguínea , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Permeabilidad/efectos de los fármacos , Ratas , Daño por Reperfusión/patología , Daño por Reperfusión/fisiopatología , Sindecano-1/deficiencia , Sindecano-1/metabolismoRESUMEN
BACKGROUND: We evaluated the predictive significance of 14 reported markers using immunohistochemical study in nasopharyngeal carcinoma. METHODS: Immunohistochemical stainings were done in 38 patients for Met, cyclooxygenase-2 (COX-2), nm23-H1, epidermal growth factor receptor (EGFR), p63, early growth response factor 1 (Egr1), chromosome segregation 1-like (CSE1L), cathepsin-D (aspartyl protease), C-erbB2, p53, signal transducers and activators of transcription (STAT3/STAT5), CD138 (Syndecan-1), and LIN28 with the usual methods. RESULTS: The median follow-up time was 30 months (11-83 months). High Met and CD138 expression were statistically significant negative prognostic factors on survival. The expression of Egr1 had a positive prognostic effect on survival. The combined score of these 3 markers, Met plus CD138 minus Egr1, was a strong prognostic factor. The median survival curve was distinctly separated in accord with this combined score. No prognostic value was revealed in COX-2, nm23-H1, EGFR, p63, CSE1L, cathepsin-D, C-erbB2, p53, STAT3, STAT5, and LIN28. CONCLUSIONS: The combined score of these markers could be used to stratify biomolecular risk groups.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/mortalidad , Adulto , Anciano , Carcinoma/metabolismo , Carcinoma/mortalidad , Carcinoma/terapia , Catepsina D/metabolismo , Proteína de Susceptibilidad a Apoptosis Celular/metabolismo , Quimioterapia Adyuvante , Ciclooxigenasa 2/metabolismo , Supervivencia sin Enfermedad , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Receptores ErbB/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Nucleósido Difosfato Quinasas NM23/metabolismo , Neoplasias Nasofaríngeas/terapia , Pronóstico , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas de Unión al ARN/metabolismo , Radioterapia de Intensidad Modulada , Receptor ErbB-2/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/metabolismo , Sindecano-1/metabolismo , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Human epidemiological studies have shown that diets enriched in n-3 polyunsaturated fatty acids (n-3 PUFA) are associated with a lower incidence of cancers including breast cancer. Our previous studies showed that the n-3 PUFA, docosahexaenoic acid (DHA), upregulated syndecan-1 (SDC-1) expression to induce apoptosis in the human breast cancer cell line MCF-7. We now present evidence of a signaling pathway that is impacted by SDC-1 in these cells and in mouse mammary tissues to result in apoptosis. In MCF-7 cells and SK-BR-3 cells, DHA and a SDC-1 ectodomain impaired signaling of the p44/42 mitogen-activated protein kinase (MAPK) pathway by inhibiting the phosphorylation of MAPK/Erk (MEK)/extracellular signal-regulated kinase (Erk) and Bad to induce apoptosis. SDC-1 siRNA significantly enhanced phosphorylation of these signal molecules and blocked the inhibitory effects of DHA on their phosphorylation. SDC-1 siRNA diminished apoptosis of MCF-7 cells, an effect that was markedly blocked by MEK inhibitor, PD98059. In vivo studies used (i) Fat-1 mice, a genetic model able to convert n-6 to n-3 PUFA to result in higher SDC-1 levels in Fat-1 mammary tissue compared with that of wild-type (wt) mice. Phosphorylation of MEK, Erk and Bad was lower in the Fat-1 versus wt tissue and (ii) SDC-1(-/-) mice that demonstrated markedly higher levels of phosphorylated MEK, Erk and Bad in mammary gland tissue compared with those of SDC(+/+) mice. These data elucidate a pathway whereby SDC-1, upregulated by DHA, induces apoptosis in breast cancer cells through inhibition of MEK/Erk/Bad signaling.
Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Ácidos Docosahexaenoicos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Glándulas Mamarias Animales/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Sindecano-1/fisiología , Animales , Western Blotting , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Cadherinas/fisiología , Femenino , Humanos , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sindecano-1/antagonistas & inhibidores , Células Tumorales Cultivadas , Proteína Letal Asociada a bcl/metabolismoRESUMEN
Primary central nervous system lymphoma (PCNSL) remains a devastating disease with poor prognosis, despite the improvement offered by methotrexate (MTX)-based chemotherapy. Several studies have attempted to identify biomarkers predictive of prognosis, which are expected to be both clinically useful and biologically important for understanding PCNSL. The present study attempts to classify human immunodeficiency virus (HIV)-unrelated PCNSL patients treated with radiation combined with rapid high-dose MTX chemotherapy according to B-cell differentiation status, and retrospectively examines the prognostic impact. Initial response to MTX was a strong predictor of favorable prognosis in terms of both progression-free survival (PFS) and overall survival (OS). Thirteen out of 29 cases were CD10(-)/BCL-6(+)/MUM-1(+), being more frequent compared with systemic peripheral nodal lymphoma. Although post-germinal-center B-cell-originating PCNSLs (CD10(-)/BCL-6(-)/MUM-1(+)) showed a trend towards better response to MTX and progression-free survival than did germinal-center-related B-cell-originating PCNSLs (CD10(+) OR CD10(-)/BCL-6(+)/MUM-1(+)), the difference was only marginal (P = 0.04 Gehan-Breslow-Wilcoxon, P = 0.17 log-rank). Our results imply that different B-cell stages in PCNSL have significant relevance in terms of biological behavior. However, clinical use as a prognostic marker requires further investigation.
Asunto(s)
Linfocitos B/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Neoplasias del Sistema Nervioso Central/patología , Inmunosupresores/farmacología , Linfoma/patología , Metotrexato/farmacología , Adulto , Anciano , Antígenos CD79/metabolismo , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Proteínas de Unión al ADN/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunosupresores/uso terapéutico , Factores Reguladores del Interferón/metabolismo , Linfoma/tratamiento farmacológico , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Neprilisina/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6 , Estudios Retrospectivos , Sindecano-1/metabolismoRESUMEN
Despite recent advances in the treatment of multiple myeloma, new agents are still needed to improve the outcome for patients. The established success of monoclonal antibodies in the treatment of some cancers has promoted interest in developing antibody-based therapies for multiple myeloma. Efforts have included the development of antibodies conjugated to potent cytotoxic moieties that combine the specificity of anti-myeloma-targeting antibodies with highly active anti-tumor compounds. Two such immunoconjugates currently in clinical development are composed of antibodies that target cell surface proteins found on multiple myeloma cells, and are coupled to cytotoxic maytansinoids. IMGN901 targets the neural cell adhesion molecule, CD56, which is expressed on the majority of myeloma cells, as well as on other cancers, while BT062 targets CD138, a primary diagnostic marker for multiple myeloma. In this review, we discuss the preclinical and early clinical data for these two promising new antibody-based anti-myeloma agents.