RESUMEN
The present study was aimed to enhance the mitochondrial function in oxidative stress-induced diabetes. To achieve this, Ficus religiosa L. extract loaded solid lipid nanoparticles (ETNPs) were prepared and functionalized by using triphenylphosphonium. Developed nanoparticles demonstrated desired quality attributes with sustained release for up to 24 h and excellent storage stability for up to 180 days at 40 ± 2°C and 75 ± 5% relative humidity. In vitro cytotoxicity assessment showed no toxicity of ETNPs. Interestingly, oral administration of ETNPs to diabetic rats demonstrated improved mitochondrial function by normalizing the mitochondrial morphology, intracellular calcium ion concentration, complexes I, II, IV, and V activity, mitochondrial membrane potential, and antioxidant levels. Further, reduction in apoptotic markers viz. cytochrome-C, caspase-3, and caspase-9 was observed following the ETNP treatment. Moreover, significant reduction in blood glucose and glycosylated hemoglobin while significant improvement in plasma insulin was observed as compared to the diabetic group following the treatment with developed formulation. Furthermore, histopathology studies confirmed the safety of the developed formulation and thus, data in hand collectively suggest that proposed strategy can be effectively used to improve the mitochondrial function in oxidative stress-induced diabetes along with better control over blood glucose and glycosylated hemoglobin.
Asunto(s)
Antioxidantes/farmacología , Ficus/química , Nanopartículas , Compuestos Organofosforados/farmacología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Glucemia/metabolismo , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Citocromos c/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/aislamiento & purificación , Extractos Vegetales/administración & dosificación , Ratas , Ratas WistarRESUMEN
BACKGROUND: Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety. METHODS: A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments. RESULTS: The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57). CONCLUSIONS: Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Azetidinas/administración & dosificación , Azetidinas/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Dacarbazina/administración & dosificación , Dacarbazina/uso terapéutico , Humanos , Hidrazinas/administración & dosificación , Hidrazinas/uso terapéutico , Imidazoles/administración & dosificación , Imidazoles/uso terapéutico , Interleucina-2/administración & dosificación , Interleucina-2/uso terapéutico , Ipilimumab/administración & dosificación , Ipilimumab/uso terapéutico , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Melanoma/inmunología , Melanoma/patología , Metaanálisis en Red , Compuestos de Nitrosourea/administración & dosificación , Compuestos de Nitrosourea/uso terapéutico , Nivolumab/administración & dosificación , Nivolumab/uso terapéutico , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/uso terapéutico , Oximas/administración & dosificación , Oximas/uso terapéutico , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Piridonas/administración & dosificación , Piridonas/uso terapéutico , Pirimidinonas/administración & dosificación , Pirimidinonas/uso terapéutico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Sorafenib/administración & dosificación , Sorafenib/uso terapéutico , Tasa de Supervivencia , Temozolomida/administración & dosificación , Temozolomida/uso terapéutico , Resultado del TratamientoRESUMEN
Maternal smoking leads to glucose and lipid metabolic disorders and hepatic damage in the offspring, potentially due to mitochondrial oxidative stress. Mitoquinone mesylate (MitoQ) is a mitochondrial targeted antioxidant with high bioavailability. This study aimed to examine the impact of maternal cigarette smoke exposure (SE) on offspring's metabolic profile and hepatic damage, and whether maternal MitoQ supplementation during gestation can affect these changes. Female Balb/c mice (eight weeks) were either exposed to air or SE for six weeks prior to mating and throughout gestation and lactation. A subset of the SE dams were supplied with MitoQ in the drinking water (500 µmol/L) during gestation and lactation. Intraperitoneal glucose tolerance test was performed in the male offspring at 12 weeks and the livers and plasma were collected at 13 weeks. Maternal SE induced glucose intolerance, hepatic steatosis, mitochondrial oxidative stress and related damage in the adult offspring. Maternal MitoQ supplementation reduced hepatic mitochondrial oxidative stress and improved markers of mitophagy and mitochondrial biogenesis. This may restore hepatic mitochondrial health and was associated with an amelioration of glucose intolerance, hepatic steatosis and pathological changes induced by maternal SE. MitoQ supplementation may potentially prevent metabolic dysfunction and hepatic pathology induced by intrauterine SE.
Asunto(s)
Hígado Graso/inducido químicamente , Exposición Materna , Síndrome Metabólico/inducido químicamente , Compuestos Organofosforados/farmacología , Contaminación por Humo de Tabaco/efectos adversos , Ubiquinona/análogos & derivados , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Femenino , Lactancia , Lipidómica , Masculino , Ratones , Ratones Endogámicos BALB C , Mitocondrias Hepáticas/fisiología , Compuestos Organofosforados/administración & dosificación , Estrés Oxidativo , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ubiquinona/administración & dosificación , Ubiquinona/farmacologíaRESUMEN
BACKGROUND: Betanins have become excellent replacers for artificial red-purple food colourants. Red beet (Beta vulgaris L. spp. vulgaris) known as beetroot, is a rich source of betalains, which major forms are betanin (red to purple) and vulgaxanthin (yellow). Betalains and phenolic compounds are secondary metabolites, accumulation of which is often triggered by elicitors during plant stress responses. In the present study, pre-harvest applications of ethephon (an ethylene-releasing compound) and postharvest UV-B radiation were tested as elicitors of betalains and phenolic compounds in two beetroot cultivars. Their effects on quality parameters were investigated, and the expression of biosynthetic betalain genes in response to ethephon was determined. RESULTS: Ethephon was applied as foliar spray during the growth of beetroot, resulting in increased betanin (22.5%) and decreased soluble solids contents (9.4%), without detrimental effects on beetroot yield. The most rapid accumulation rate for betanin and soluble solids was observed between 3 and 6 weeks after sowing in both untreated and ethephon-treated beetroots. Overall, the expression of the betalain biosynthetic genes (CYP76AD1, CYP76AD5, CYP76AD6 and DODA1), determining the formation of both betanin and vulgaxanthin, increased in response to ethephon treatment, as did the expression of the betalain pathway activator BvMYB1. In the postharvest environment, the use of short-term UV-B radiation (1.23 kJ m- 2) followed by storages for 3 and 7 days at 15 °C resulted in increased betanin to vulgaxanthin ratio (51%) and phenolic content (15%). CONCLUSIONS: The results of this study provide novel strategies to improve key profitability traits in betalain production. High betanin concentration and high betanin to vulgaxanthin ratio increase the commercial value of the colourant product. In addition, lowering soluble solids levels facilitates higher concentration of beetroot colour during processing. Moreover, we show that enhanced betanin content in ethephon-treated beetroots is linked to increased expression of betalain biosynthetic genes.
Asunto(s)
Beta vulgaris/efectos de los fármacos , Compuestos Organofosforados/farmacología , Reguladores del Crecimiento de las Plantas/farmacología , Rayos Ultravioleta , Beta vulgaris/anatomía & histología , Beta vulgaris/fisiología , Betalaínas/metabolismo , Producción de Cultivos/métodos , Manipulación de Alimentos/métodos , Calidad de los Alimentos , Expresión Génica/efectos de los fármacos , Compuestos Organofosforados/administración & dosificación , Fenoles/metabolismoRESUMEN
OBJECTIVE: This prospective, randomized, controlled and open-label clinical trial sought to evaluate the tolerability and efficacy of the FTD regimen (fotemustine, teniposide and dexamethasone) compared to HD-MA therapy (high-dose methotrexate plus cytarabine) and to elucidate some biomarkers that influence outcomes in patients with newly diagnosed primary CNS lymphoma. METHODS: Participants were stratified by IELSG risk score (low versus intermediate versus high) and randomly assigned (1:1) to receive four cycles of FTD or HD-MA regimen. Both regimens were administered every 3 weeks and were followed by whole-brain radiotherapy. The primary endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Between June 2012, and June 2015, 52 patients were enrolled, of whom 49 patients were randomly assigned and analyzed. Of the 49 eligible patients, no significant difference was observed in terms of ORR between FTD (n = 24) and HD-MA (n = 25) groups (88% versus 84%, respectively, P = 0.628). Neither the 2-year PFS nor the 3-year OS rate differed significantly between FTD and HD-MA groups (37% versus 39% for 2-year PFS, P = 0.984; 51% versus 46% for 3-year OS, P = 0.509; respectively). The HD-MA group showed more serious neutropenia (P = 0.009) than the FTD group. High Bcl-6 expression correlated with longer OS (P = 0.038). CONCLUSIONS: FTD chemotherapy appeared to be safe and effective for PCNSL patients. High Bcl-6 expression correlated with longer survival.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores de Tumor/metabolismo , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/mortalidad , Citarabina/administración & dosificación , Citarabina/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Femenino , Humanos , Linfoma/metabolismo , Linfoma/mortalidad , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Compuestos de Nitrosourea/administración & dosificación , Compuestos de Nitrosourea/efectos adversos , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/efectos adversos , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Tenipósido/administración & dosificación , Tenipósido/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Toll-like receptors (TLRs) are transmembrane proteins expressed on the surface of ovarian cancer (OC) and immune cells. Identifying the specific roles of the TLR-mediated signaling pathways in OC cells is important to guide new treatments. Because immunotherapies have emerged as the adjuvant treatment for patients with OC, we investigated the effect of a promising immunotherapeutic strategy based on protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) combined with cisplatin (CIS) on the TLR2 and TLR4 signaling pathways via myeloid differentiation factor 88 (MyD88) and TLR-associated activator of interferon (TRIF) in an in vivo model of OC. METHODS: Tumors were chemically induced by a single injection of 100 µg of 7,12-dimethylbenz(a)anthracene (DMBA) directly under the left ovarian bursa in Fischer 344 rats. After the rats developed serous papillary OC, they were given P-MAPA, CIS or the combination P-MAPA+CIS as therapies. To understand the effects of the treatments, we assessed the tumor size, histopathology, and the TLR2- and TLR4-mediated inflammatory responses. RESULTS: Although CIS therapy was more effective than P-MAPA in reducing the tumor size, P-MAPA immunotherapy significantly increased the expressions of TLR2 and TLR4. More importantly, the combination of P-MAPA with CIS showed a greater survival rate compared to CIS alone, and exhibited a significant reduction in tumor volume compared to P-MAPA alone. The combination therapy also promoted the increase in the levels of the following OC-related proteins: TLR4, MyD88, TRIF, inhibitor of phosphorylated NF-kB alpha (p-IkBα), and nuclear factor kappa B (NF-kB p65) in both cytoplasmic and nuclear sites. While P-MAPA had no apparent effect on tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6, it seems to increase interferon-γ (IFN-γ), which may induce the Thelper (Th1)-mediated immune response. CONCLUSION: Collectively, our results suggest that P-MAPA immunotherapy combined with cisplatin could be considered an important therapeutic strategy against OC cells based on signaling pathways activated by TLR4.
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Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Línea Celular Tumoral , Cisplatino/administración & dosificación , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunohistoquímica , Ácidos Linoleicos/administración & dosificación , FN-kappa B , Clasificación del Tumor , Compuestos Organofosforados/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/inmunología , Ratas , Receptor Toll-Like 2/metabolismo , Carga Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A novel ß-D-2'-deoxy-2'-α-fluoro-2'-ß-C-(fluoromethyl)uridine phosphoramidate prodrug (1) has been synthesized. This compound exhibits submicromolar-level antiviral activity in vitro against HCV genotypes 1b, 1a, 2a, and S282T replicons (EC50 = 0.18-1.13 µM) with low cytotoxicity (CC50 > 1000 µM). Administered orally, prodrug 1 is well tolerated at doses of up to 4 g/kg in mice, and produces a high level of the corresponding triphosphate in rat liver.
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Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Compuestos Organofosforados/farmacología , Profármacos/farmacología , Uridina/análogos & derivados , Administración Oral , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hepacivirus/genética , Humanos , Hígado/efectos de los fármacos , Hígado/virología , Ratones , Ratones Endogámicos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/química , Profármacos/administración & dosificación , Profármacos/síntesis química , Profármacos/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Uridina/administración & dosificación , Uridina/química , Uridina/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
The use of phosphonate ligands to modify the nanoparticle (NPs) surface has attracted a strong interest in the last years for the design of highly functional hybrid materials. Here, we applied a methodology to synthesize bisphosphonates having functionalized PEG side chains with a specific length in order to design a novel class of hybrid nanomaterials composed by tetraphosphonate-complex-gold COOH-terminated PEG-coated NPs (Bis-PO-PEG-AuNPs). The synthetic approach consist in three steps: (1) Complexation between new phosphonate ligands (Bis PO) and tetrachloroauric acid (HAuCl4) to form gold clusters; (2) adsorption of COOH-terminated PEG molecules (PEG) onto Bis PO-Au complex; (3) reduction of metal ions in that vicinity, growth of gold particles and colloidal stabilization. The obtained snow-shape-like hybrid nanoparticles, have been characterized by ultra-violet/visible, Raman spectroscopies, and electron microscopy imaging, involving their optical properties and photothermal activity in pancreatic adenocarcinoma cancer cells (PDAC).
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Carcinoma Ductal Pancreático/terapia , Nanopartículas del Metal/administración & dosificación , Compuestos Organofosforados/administración & dosificación , Neoplasias Pancreáticas/terapia , Fototerapia , Polietilenglicoles/química , Oro/química , Humanos , Ligandos , Nanopartículas del Metal/química , Compuestos Organofosforados/química , Células Tumorales CultivadasRESUMEN
Oxidative stress contributes to the pathogenesis of propionic acidemia (PA), a life threatening disease caused by the deficiency of propionyl CoA-carboxylase, in the catabolic pathway of branched-chain amino acids, odd-number chain fatty acids and cholesterol. Patients develop multisystemic complications including seizures, extrapyramidal symptoms, basal ganglia deterioration, pancreatitis and cardiomyopathy. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species and oxidative damage, all of which have been documented in patients' samples and in a hypomorphic mouse model. Here we set out to investigate whether treatment with a mitochondria-targeted antioxidant, MitoQ, or with the natural polyphenol resveratrol, which is reported to have antioxidant and mitochondrial activation properties, could ameliorate the altered redox status and its functional consequences in the PA mouse model. The results show that oral treatment with MitoQ or resveratrol decreases lipid peroxidation and the expression levels of DNA repair enzyme OGG1 in PA mouse liver, as well as inducing tissue-specific changes in the expression of antioxidant enzymes. Notably, treatment decreased the cardiac hypertrophy marker BNP that is found upregulated in the PA mouse heart. Overall, the results provide in vivo evidence to justify more in depth investigations of antioxidants as adjuvant therapy in PA.
Asunto(s)
Antioxidantes/uso terapéutico , Compuestos Organofosforados/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Acidemia Propiónica/tratamiento farmacológico , Estilbenos/uso terapéutico , Ubiquinona/análogos & derivados , Administración Oral , Aminoácidos de Cadena Ramificada , Animales , Antioxidantes/administración & dosificación , Modelos Animales de Enfermedad , Corazón/efectos de los fármacos , Humanos , Peroxidación de Lípido/efectos de los fármacos , Ratones , Compuestos Organofosforados/administración & dosificación , Acidemia Propiónica/fisiopatología , Resveratrol , Estilbenos/administración & dosificación , Ubiquinona/administración & dosificación , Ubiquinona/uso terapéuticoRESUMEN
Photoimmunotherapy (PIT) is an emerging low side effect cancer therapy based on a monoclonal antibody (mAb) conjugated with a near-infrared (NIR) phthalocyanine dye IRDye 700DX. IR700 is fluorescent, can be used as an imaging agent, and also is phototoxic. It induces rapid cell death after exposure to NIR light. PIT induces highly selective cancer cell death, while leaving most of tumor blood vessels unharmed, leading to an effect called super-enhanced permeability and retention (SUPR). SUPR significantly improves the effectiveness of the anticancer drug. Currently, the therapeutic effects of PIT are monitored using the IR700 fluorescent signal based on macroscopic fluorescence reflectance imagery. This technique, however, lacks the resolution and depth information to reveal the intratumor heterogeneity of mAb-IR700 distribution. We applied a minimally invasive two-channel fluorescence fiber imaging system by combining the traditional fluorescence imaging microscope with two imaging fiber bundles (~0.85mm). This method monitored mAb-IR700 distribution and therapeutic effects during PIT at different intratumor locations (e.g., tumor surface vs. deep tumor) in situ and in real time simultaneously. This enabled evaluation of the therapeutic effects in vivo and treatment regimens. The average IR700 fluorescence intensity recovery after PIT to the tumor surface is 91.50%, while it is 100.63% in deep tumors. To verify the results, two-photon microscopy combined with a microprism was also used to record the mAb-IR700 distribution and fluorescence intensity of green fluorescent protein (GFP) at different tumor depths during PIT. After PIT treatment, there was significantly higher IR700 fluorescence recovery in deep tumor than in the tumor surface. This phenomenon can be explained by increased vascular permeability immediately after NIR-PIT. Fluorescence intensity of GFP at the tumor surface decreased significantly more compared to that of deep tumor and in controls (no PIT).
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Carbocianinas/administración & dosificación , Colorantes Fluorescentes/administración & dosificación , Inmunoterapia , Neoplasias/terapia , Compuestos Organofosforados/administración & dosificación , Fototerapia , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/farmacocinética , Carbocianinas/química , Carbocianinas/farmacocinética , Línea Celular Tumoral , Femenino , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacocinética , Proteínas Fluorescentes Verdes , Inmunoglobulina G/inmunología , Rayos Infrarrojos , Ratones Desnudos , Neoplasias/metabolismo , Neoplasias/patología , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Panitumumab , Carga TumoralRESUMEN
Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon. Local administration of 2-PMPA in a hypotonic enema vehicle resulted in increased colorectal tissue absorption at 30min compared to 2-PMPA administered in an isotonic enema vehicle. Furthermore, local delivery of 2-PMPA in hypotonic enema vehicle resulted in prolonged drug concentrations for at least 24h with minimal systemic exposure. Finally, daily treatment with the hypotonic 2-PMPA enema ameliorated macroscopic and microscopic symptoms of IBD in the TNBS-induced colitis mouse model, indicating the potential of FOLH1/GCPII inhibitors for the local treatment of IBD.
Asunto(s)
Colitis/tratamiento farmacológico , Enema , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Compuestos Organofosforados/administración & dosificación , Animales , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Glutamato Carboxipeptidasa II/metabolismo , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Ratones Endogámicos BALB C , Compuestos Organofosforados/sangre , Compuestos Organofosforados/farmacocinética , Compuestos Organofosforados/uso terapéutico , Ácido TrinitrobencenosulfónicoRESUMEN
BACKGROUND: Senescence is a major factor that increases oxidative stress in mitochondria, which contributes toward the pathogenesis of heart disease. However, the effect of antioxidant therapy on cardiac mitochondria in aged-cardiac performance remains elusive. OBJECTIVES: We postulated that the mitochondrial targeting of superoxide scavenging would have benefits in the aged heart. METHODS AND RESULTS: Generation of superoxide in the mitochondria and nicotinamide adenine dinucleotide phosphate oxidase activity increased in the heart of old mice compared with that in young mice. In old mice treated with a mitochondria-targeted antioxidant MitoTEMPO (180 µg/kg/day, 28 days) co-infusion using a subcutaneously implanted minipump, levels of superoxide in the mitochondria and nicotinamide adenine dinucleotide phosphate oxidase activity as well as hydrogen peroxide decreased markedly in cardiomyocytes. Treatment with MitoTEMPO in old mice improved the systolic and diastolic function assessed by echocardiography. Endothelium-dependent vasodilation in isolated coronary arteries and endothelial nitric-oxide synthase phosphorylation were impaired in old mice compared with that in young mice and were improved by MitoTEMPO treatment. Mitochondria from the old mice myocardium showed lower rates of complex I-dependent and II-dependent respiration compared with that from young mice. Supplementation of MitoTEMPO in old mice improved the respiration rates and efficiency of ATP generation in mitochondria to a level similar to that of young mice. CONCLUSION: Resolution of oxidative stress in mitochondria by MitoTEMPO in old mice restored cardiac function and the capacity of coronary vasodilation to the same magnitude observed in young mice. An antioxidant strategy targeting mitochondria could have a therapeutic benefit in heart disease with senescence.
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Envejecimiento/metabolismo , Antioxidantes/farmacología , Vasos Coronarios/efectos de los fármacos , Mitocondrias Cardíacas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Compuestos Organofosforados/farmacología , Estrés Oxidativo/efectos de los fármacos , Piperidinas/farmacología , Adenosina Trifosfato/metabolismo , Factores de Edad , Animales , Antioxidantes/administración & dosificación , Respiración de la Célula/efectos de los fármacos , Vasos Coronarios/metabolismo , Peróxido de Hidrógeno/metabolismo , Infusiones Subcutáneas , Masculino , Ratones Endogámicos C57BL , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Compuestos Organofosforados/administración & dosificación , Fosforilación , Piperidinas/administración & dosificación , Superóxidos/metabolismo , Vasodilatación/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
This study evaluated the effects of AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl) phenoxy)decyl) triphenyl phosphonium bromide], a mitochondrially targeted donor of hydrogen sulfide (H2S) in an in vitro model of hypoxia/oxidative stress injury in NRK-49F rat kidney epithelial cells (NRK cells) and in a rat model of renal ischemia-reperfusion injury. Renal oxidative stress was induced by the addition of glucose oxidase, which generates hydrogen peroxide in the culture medium at a constant rate. Glucose oxidase (GOx)-induced oxidative stress led to mitochondrial dysfunction, decreased intracellular ATP content, and, at higher concentrations, increased intracellular oxidant formation (estimated by the fluorescent probe 2, 7-dichlorofluorescein, DCF) and promoted necrosis (estimated by the measurement of lactate dehydrogenase release into the medium) of the NRK cells in vitro. Pretreatment with AP39 (30-300ânM) exerted a concentration-dependent protective effect against all of the above effects of GOx. Most of the effects of AP39 followed a bell-shaped concentration-response curve; at the highest concentration of GOx tested, AP39 was no longer able to afford cytoprotective effects. Rats subjected to renal ischemia/reperfusion responded with a marked increase (over four-fold over sham control baseline) blood urea nitrogen and creatinine levels in blood, indicative of significant renal damage. This was associated with increased neutrophil infiltration into the kidneys (assessed by the myeloperoxidase assay in kidney homogenates), increased oxidative stress (assessed by the malondialdehyde assay in kidney homogenates), and an increase in plasma levels of IL-12. Pretreatment with AP39 (0.1, 0.2, and 0.3âmg/kg) provided a dose-dependent protection against these pathophysiological alterations; the most pronounced protective effect was observed at the 0.3âmg/kg dose of the H2S donor; nevertheless, AP39 failed to achieve a complete normalization of any of the injury markers measured. The partial protective effects of AP39 correlated with a partial improvement of kidney histological scores and reduced TUNEL staining (an indicator of DNA damage and apoptosis). In summary, the mitochondria-targeted H2S donor AP39 exerted dose-dependent protective effects against renal epithelial cell injury in vitro and renal ischemia-reperfusion injury in vivo. We hypothesize that the beneficial actions of AP39 are related to the reduction of cellular oxidative stress, and subsequent attenuation of various positive feed-forward cycles of inflammatory and oxidative processes.
Asunto(s)
Lesión Renal Aguda/prevención & control , Citoprotección/fisiología , Sulfuro de Hidrógeno/metabolismo , Compuestos Organofosforados/farmacología , Estrés Oxidativo/efectos de los fármacos , Tionas/farmacología , Animales , Hipoxia de la Célula/efectos de los fármacos , Hipoxia de la Célula/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Células Epiteliales/efectos de los fármacos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/uso terapéutico , Ratas Sprague-Dawley , Tionas/administración & dosificación , Tionas/uso terapéuticoRESUMEN
BACKGROUND: The health implications of dietary phosphorus intake and the role of kidney function in managing serum phosphorus homeostasis are well studied. However, examining the source of dietary phosphorus intake and its impact on serum phosphorus has not been characterized in population studies. OBJECTIVE: This study aimed to distinguish the association of food sources of organic phosphorus and inorganic phosphate additives with serum phosphorus concentration. DESIGN: A cross-sectional analysis of 24-h food recall data from 7895 adult participants in the National Health and Nutrition Examination Survey 2003-2006 was performed. Phosphorus content of foods was categorized as organic or inorganic. Correlations of serum phosphorus to clinical and dietary intake variables were achieved by using multiple regression analysis. RESULTS: After controlling for estimated glomerular filtration rate (eGFR), body mass index (BMI; in kg/m²), and albumin-to-creatinine ratio, a significant increase in serum phosphorus occurred with dairy foods with inorganic phosphates [parameter estimate (PE) ± SE: 0.07 ± 0.02 mg/dL, P < 0.01] or without inorganic phosphates (PE: 0.02 ± 0.01, P < 0.001) and cereals/grains with inorganic phosphates (PE: 0.005 ± 0.002, P < 0.01). Significantly higher serum phosphorus occurred when eGRF was <30 (PE: 0.24 ± 0.08, P < 0.0001), but eGFR 30-44 (PE: -0.11 ± 0.04, P < 0.01) and 45-60 (PE: -0.10 ± 0.04, P < 0.01) were associated with lower serum phosphorus; higher serum phosphorus was associated with BMI <18.5 (PE: 0.18 ± 0.05, P = 0.0009) but lower with BMI ≥35-39 (PE: -0.09 ± 0.03, P = 0.0013) or ≥40 (PE: -0.10 ± 0.03, P = 0.014). CONCLUSIONS: This analysis shows that dairy products and cereals/grains having inorganic phosphate additives significantly increase serum phosphorus concentration, despite being consumed less frequently than foods without phosphate additives. It seems prudent for the Nutrient Facts Label to include phosphorus but also for food manufacturers to consider alternatives to phosphate additives.
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Dieta , Suplementos Dietéticos , Aditivos Alimentarios/administración & dosificación , Riñón/fisiología , Compuestos Organofosforados/administración & dosificación , Fosfatos/administración & dosificación , Fósforo/sangre , Adulto , Anciano , Índice de Masa Corporal , Estudios de Cohortes , Contraindicaciones , Estudios Transversales , Productos Lácteos/efectos adversos , Productos Lácteos/análisis , Dieta/efectos adversos , Suplementos Dietéticos/efectos adversos , Suplementos Dietéticos/análisis , Grano Comestible/efectos adversos , Grano Comestible/química , Femenino , Aditivos Alimentarios/efectos adversos , Aditivos Alimentarios/metabolismo , Etiquetado de Alimentos , Tasa de Filtración Glomerular , Humanos , Riñón/fisiopatología , Masculino , Encuestas Nutricionales , Obesidad Mórbida/sangre , Obesidad Mórbida/etiología , Obesidad Mórbida/metabolismo , Obesidad Mórbida/fisiopatología , Compuestos Organofosforados/efectos adversos , Compuestos Organofosforados/metabolismo , Fosfatos/efectos adversos , Fosfatos/metabolismo , Fósforo/metabolismo , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Estados UnidosRESUMEN
BACKGROUND: In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination. PATIENTS AND METHODS: This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+) or CD45RA(+) T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status. RESULTS: Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in 'memory' but not in 'naïve' T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points. BRAF status did not correlate with clinical outcome. CONCLUSIONS: Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab. EUDRACT NUMBER: 2010-019356-50. CINICALTRIALSGOV: NCT01654692.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Biológica/mortalidad , Neoplasias Encefálicas/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Femenino , Estudios de Seguimiento , Humanos , Ipilimumab , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos de Nitrosourea/administración & dosificación , Compuestos Organofosforados/administración & dosificación , Pronóstico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Tasa de SupervivenciaRESUMEN
Chlorpyrifos (CPF) is an organophosphate compound that is slowly delivered in the organism after subcutaneous injection, keeping acetylcholinesterase (AChE) activity mildly inhibited for weeks. We have previously reported reduced voluntary ethanol drinking 8 weeks post-CPF administration in Wistar rats when AChE activity was almost completely recovered. Additionally, the OPs disrupt the functioning of certain neurochemical systems and modify the formation and/or degradation of some neuropeptides with a known role in regulating voluntary consumption of alcohol. Moreover, chronic ethanol intake significantly alters the regional expression of some of these neurochemical systems. Thus, the present study explored whether a previous history with ethanol consumption modify the disturbance in the voluntary ethanol consumption induced by CPF administration. For this aim, we measured ethanol consumption in increasing concentrations (8%, 15% and 20% w/v) from 4 days to 8 weeks following a single dose of CPF. Two experiments were carried out; experiment 1 was conducted in ethanol-naïve rats and experiment 2, in animals with a previous history of ethanol drinking before CPF administration. Additionally, food and body weight measures were collected. We report here a significant increase in ethanol consumption and preference at high ethanol concentrations (15% and 20%) in CPF-treated animals with a previous history of ethanol consumption (experiment 1) and a long-lasting increase in food intake both in ethanol-exposed (experiment 1) and ethanol-naïve CPF-treated rats (experiment 2). Present data are discussed under the interesting idea that CPF targets neurobiological pathways critically involved with ethanol consumption. Additionally, we conclude that CPF effects on voluntary ethanol consumption are ethanol-experience dependent.
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Consumo de Bebidas Alcohólicas , Alcoholismo/psicología , Cloropirifos/toxicidad , Ingestión de Alimentos/efectos de los fármacos , Compuestos Organofosforados/toxicidad , Plaguicidas/toxicidad , Acetilcolinesterasa/metabolismo , Animales , Encéfalo/enzimología , Cloropirifos/administración & dosificación , Inyecciones , Masculino , Neuropéptidos/metabolismo , Compuestos Organofosforados/administración & dosificación , Ratas , Ratas WistarAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neoplasias de la Úvea/tratamiento farmacológico , Anciano , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Metástasis Linfática , Masculino , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Estadificación de Neoplasias , Niacinamida/administración & dosificación , Niacinamida/análogos & derivados , Compuestos de Nitrosourea/administración & dosificación , Compuestos Organofosforados/administración & dosificación , Compuestos de Fenilurea/administración & dosificación , Estudios Retrospectivos , Sorafenib , Tasa de Supervivencia , Neoplasias de la Úvea/mortalidad , Neoplasias de la Úvea/patologíaRESUMEN
The aim of this study was to determine the effect of butaphosphan and cyanocobalamin (BTPC) supplementation on plasma metabolites and milk production in postpartum dairy cows. A total of fifty-two Holstein cows were randomly assigned to receive either: (1) 10 ml of saline (NaCl 0.9%, control group); (2) 1000 mg of butaphosphan and 0.5 mg of cyanocobalamin (BTPC1 group); and (3) 2000 mg of butaphosphan and 1.0 mg of cyanocobalamin (BTPC2 group). All cows received injections every 5 days from calving to 20 days in milk (DIM). Blood samples were collected every 15 days from calving until 75 DIM to determine serum concentration of glucose, non-esterified fatty acids (NEFA), ß-hydroxybutyrate (BHB), cholesterol, urea, calcium (Ca), phosphorus (P), magnesium (Mg), aminotransferase aspartate (AST) and γ-glutamyltransferase (GGT). The body condition score (BCS) and milk production were evaluated from calving until 90 DIM. Increasing doses of BTPC caused a linear reduction in plasma concentrations of NEFA and cholesterol. Supplementation of BTPC also reduced concentrations of BHB but it did not differ between the two treatment doses. Milk yield and milk protein had a linear increase with increasing doses of BTPC. A quadratic effect was detected for milk fat and total milk solids according to treatment dose, and BTPC1 had the lowest mean values. Concentrations of glucose, urea, P, Mg, AST, GGT, milk lactose and BCS were not affected by treatment. These results indicate that injections of BTPC during the early postpartum period can reduce NEFA and BHB concentrations and increase milk production in Holstein cows.
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Bovinos/metabolismo , Micronutrientes/farmacología , Leche/efectos de los fármacos , Leche/metabolismo , Compuestos Organofosforados/farmacología , Periodo Posparto/efectos de los fármacos , Animales , Análisis Químico de la Sangre/veterinaria , Composición Corporal/efectos de los fármacos , Brasil , Suplementos Dietéticos/análisis , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Inyecciones Intramusculares/veterinaria , Lactancia , Micronutrientes/administración & dosificación , Leche/química , Compuestos Organofosforados/administración & dosificación , Vitamina B 12/administración & dosificación , Vitamina B 12/farmacologíaRESUMEN
Since multiple myeloma (MM) is still not-curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B-MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80-100 mg/m² i.v.) on day 1. The original 21-day schedule was early amended for extra-hematological toxicity and a 35-day schedule was adopted (Bortezomib 1.3 mg/m² i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty-four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m². The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression-free survival (PFS) was 19.1 months. B-MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib-naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B-MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase.