Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy.

Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin+ BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemoresistance in vivo. Unlike bulk stroma, nestin+ BMSC numbers are not reduced in AML, but their function changes to support AML cells, at the expense of non-mutated hematopoietic stem cells (HSCs). Nestin+ cell depletion delays leukemogenesis in primary AML mice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin+ BMSCs support survival and chemotherapy relapse of AML through increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy.

Analgesic Effect of Botulinum Toxin A in Myofascial Pain Syndrome Patients Previously Treated with Local Infiltration of Anesthetic and Steroids.

The purpose of this study was to evaluate the analgesic effect of botulinum toxin A (BoNTA) injections in patients with myofascial pain syndrome (MPS) who were previously treated with the local infiltration of anesthetic and steroids (LIAS). The study included a retrospective phase and a longitudinal open-label prospective phase, which were conducted on consecutive patients with MPS previously treated with the local infiltration of anesthetic (levobupivacaíne 0.25%) and steroids (triamcinolone 40 mg). Eligible patients were treated with a single intramuscular injection of BoNTA (Botox; Allergan, Inc., Irvine, CA). The treatment efficacy was determined according to the degree of pain relief obtained. Eighty-two patients met the inclusion/exclusion criteria and were included in the study. Successful results were obtained for 32 (39.0%) and 30 (36.6%) patients, during treatment with BoNTA and LIAS, respectively. The mean (standard deviation) length of the analgesic effect was significantly longer with BoNTA (29.6 [SD = 17.7] weeks) than with LIAS (8.5 [SD = 6.4] weeks), P <.0001. As regards the side effects, 19 (23.2%) patients reported transient soreness at the injection site for 2 to 3 days with BoNTA. The MPS patients previously treated with a local infiltration of anesthetic and steroids who then received a single injection of BoNTA experienced significantly reduced pain for a relatively long time.

Effects of dietary supplementation with lemon verbena extracts on serum inflammatory markers of multiple sclerosis patients / Efecto de la suplementación dietética con extractos de hierbaluisa en los marcadores de inflamación en suero de personas con esclerosis múltiple

Introduction: Inflammation is one of the main contributory factors to the etiopathogenesis of multiple sclerosis (MS). Dietary interventions with Lipia citriadora (lemon verbena) extracts have been proved to be effective in the prevention of inflammatory diseases. Objectives: The aim of this study is to evaluate the effect of lemon verbena supplementation in pro- and anti- inflammatory serum biomarkers of patients with different clinical subtypes of multiple sclerosis. Methods: The effect of lemon verbena supplementation (10% w/w verbascoside) was evaluated in a randomized, double-blinded placebo-controlled study with 30 participants classified in relapsing-remitting (n=10), primary progressive (n=5) and secondary progressive (n=15) MS presentations. Serum cytokine and C reactive protein levels were assessed in intervention and control groups for each MS clinical subtype after 28 days of dietary supplementation. Results: Serum levels of C reactive protein and 8 cytokines/ inflammatory (IFN-γ, IL-12, IL-23, IL-6, TNF-α, TGF-β, IL-4 and IL-10) markers were studied. Secondary progressive MS- supplemented patients showed C reactive protein concentrations significantly lower compared to the placebo group (p<0.005). IFN-γ levels decreased for all MS-treated groups whereas IL-12 diminished levels were observed for relapsing-remitting type (p<0.05). Anti-inflammatory cytokine concentrations of IL-4 (difference 2.98 ± 2.99 pg/mL) and IL-10 (difference 1.78 ± 5.54 pg/mL) increased in secondary progressive MS patients (p<0.05). Conclusion: The variation of several pro- and anti-inflammatory markers after supplementation suggests that lemon verbena extracts may affect cytokine profiles in multiple sclerosis. Further investigation on dietary components with antioxidant and anti-inflammatory properties may contribute to understand MS pathogenesis and ameliorate MS symptoms (AU)

Introducción: La inflamación es uno de los principales factores que contribuyen en la etiopatogénesis de la esclerosis múltiple (EM). Se ha demostrado que las intervenciones en la dieta con extractos de Lipia citriadora (hierbaluisa) son efectivas en la prevención de las enfermedades inflamatorias. Objectivos: El objetivo de este estudio es evaluar el efecto de la suplementación con extractos de hierbaluisa en los biomarcadores de inflamación en suero de pacientes con diferentes subtipos clínicos de esclerosis múltiple. Métodos: El efecto de la suplementación con hierbaluisa (10 % p/p verbascósido) se evaluó mediante un estudio aleatorizado de doble ciego controlado con grupo placebo, constituido por 30 participantes clasificados según la forma de presentación de EM en: remitentes-recaídas (n=10), primaria progresiva (n=5) y secundaria progresiva (n=15). Los niveles de citoquinas y proteína C reactiva en suero se valoraron en los grupos intervención y control de cada uno de los subtipos clínicos de EM después de 28 días de suplementación en la dieta. Resultados: Se estudiaron los niveles en suero de proteína C reactiva y de 8 citoquinas como biomarcadores deinflamación (IFN-γ, IL-12, IL-23, IL-6, TNF-α, TGF-β, IL-4 e IL-10). Los pacientes del grupo de intervención con EM secundaria progresiva presentaron concentraciones de proteína C reactiva significativamente más bajos comparados con el grupo placebo (p<0.005). Los niveles de IFN-γ disminuyeron en todos los grupos tratados a la vez que se detectaron niveles inferiores de IL-12 en las formas secundaria progresiva y remitente-recaídas (p<0.05). Las concentraciones de las citoquinas anti-inflamatorias: IL-4 (diferencia 2,98 ± 2,99 pg/mL) y IL-10 (diferencia 1,78 ± 5,54 pg/mL) aumentaron en los pacientes con EM secundaria progresiva (p<0.05). Conclusión: La variación en la concentración de varias citoquinas pro- y anti-inflamatorias después de la suplementación con los extractos de hierbaluisa puede afectar al perfil de las citoquinas en la esclerosis múltiple. La investigación futura de los componentes de la dieta con propiedades anti-inflamatorias y antioxidantes puede contribuir a entender la patógenesis de la esclerosis múltiple así como a disminuir sus síntomas (AU)

Effects of dietary supplementation with lemon verbena extracts on serum inflammatory markers of multiple sclerosis patients.

INTRODUCTION: Inflammation is one of the main contributory factors to the etiopathogenesis of multiple sclerosis (MS). Dietary interventions with Lipia citriadora (lemon verbena) extracts have been proved to be effective in the prevention of inflammatory diseases. OBJECTIVES: The aim of this study is to evaluate the effect of lemon verbena supplementation in pro- and anti- inflammatory serum biomarkers of patients with different clinical subtypes of multiple sclerosis. METHODS: The effect of lemon verbena supplementation (10% w/w verbascoside) was evaluated in a randomized, double-blinded placebo-controlled study with 30 participants classified in relapsing-remitting (n=10), primary progressive (n=5) and secondary progressive (n=15) MS presentations. Serum cytokine and C reactive protein levels were assessed in intervention and control groups for each MS clinical subtype after 28 days of dietary supplementation. RESULTS: Serum levels of C reactive protein and 8 cytokines/ inflammatory (IFN-γ, IL-12, IL-23, IL-6, TNF-α, TGF-ß, IL-4 and IL-10) markers were studied. Secondary progressive MS- supplemented patients showed C reactive protein concentrations significantly lower compared to the placebo group (p.

Introducción: La inflamación es uno de los principales factores que contribuyen en la etiopatogénesis de la esclerosis múltiple (EM). Se ha demostrado que las intervenciones en la dieta con extractos de Lipia citriadora (hierbaluisa) son efectivas en la prevención de las enfermedades inflamatorias. Objectivos: El objetivo de este estudio es evaluar el efecto de la suplementación con extractos de hierbaluisa en los biomarcadores de inflamación en suero de pacientes con diferentes subtipos clínicos de esclerosis múltiple. Métodos: El efecto de la suplementación con hierbaluisa (10 % p/p verbascósido) se evaluó mediante un estudio aleatorizado de doble ciego controlado con grupo placebo, constituido por 30 participantes clasificados según la forma de presentación de EM en: remitentes-recaídas (n=10), primaria progresiva (n=5) y secundaria progresiva (n=15). Los niveles de citoquinas y proteína C reactiva en suero se valoraron en los grupos intervención y control de cada uno de los subtipos clínicos de EM después de 28 días de suplementación en la dieta. Resultados: Se estudiaron los niveles en suero de proteína C reactiva y de 8 citoquinas como biomarcadores de inflamación (IFN-, IL-12, IL-23, IL-6, TNF-, TGF-, IL-4 e IL-10). Los pacientes del grupo de intervención con EM secundaria progresiva presentaron concentraciones de proteína C reactiva significativamente más bajos comparados con el grupo placebo (p.

Low doses of insulin-like growth factor-I induce mitochondrial protection in aging rats.

Serum IGF-I levels decline with age. We have recently reported that in aging rats the exogenous administration of IGF-I restores IGF-I circulating levels and age related-changes, improving glucose and lipid metabolisms, increasing testosterone levels and serum total antioxidant capability, and reducing oxidative damage in the brain and liver associated with a normalization of antioxidant enzyme activities. Understanding that mitochondria are one of the most important cellular targets of IGF-I, the aims of this study were to characterize mitochondrial dysfunction and study the effect of IGF-I therapy on mitochondria, leading to cellular protection in the following experimental groups: young controls, untreated old rats, and aging rats treated with IGF-I. Compared with young controls, untreated aging rats showed an increase of oxidative damage in isolated mitochondria with a mitochondrial dysfunction characterized by: depletion of membrane potential with increased proton leak rates and intramitochondrial free radical production, and a significant reduction of ATPase and complex IV activities. In addition, mitochondrial respiration from untreated aging rats was atractyloside insensitive, suggesting that the adenine nucleotide translocator was uncoupled. The adenine nucleotide translocator has been shown to be one of the most sensitive locations for pore opening. Accordingly, untreated aging rats showed a significant overexpression of the active fragment of caspases 3 and 9. IGF-I therapy corrected these parameters of mitochondrial dysfunction and reduced caspase activation. In conclusion, these results show that the cytoprotective effect of IGF-I is closely related to a mitochondrial protection, leading to reduce free radical production, oxidative damage, and apoptosis, and to increased ATP production.

Low doses of insulin-like growth factor I improve insulin resistance, lipid metabolism, and oxidative damage in aging rats.

GH and IGF-I concentrations decline with age. Age-related changes appear to be linked to decreases in the anabolic hormones, GH and IGF-I. The aim of this study was to investigate the antioxidant, anabolic, and metabolic effects of the IGF-I replacement therapy, at low doses, in aging rats. Three experimental groups were included in this protocol: young healthy controls (17 wk old); untreated old (O) rats (103 wk old); and aging rats (103 wk old) treated with IGF-I during 1 month (2.25 microg IGF-I/100 g body weight(-1).d(-1)). Compared with young controls, untreated aging rats showed a reduction of IGF-I and testosterone levels, and a decrease of serum total antioxidant status, which were corrected by IGF-I therapy. In addition, untreated O presented increased levels of serum glucose with hyperinsulinemia, cholesterol, and triglycerides, and a reduction of free fatty acid concentrations. IGF-I therapy was able to revert insulin resistance, and to reduce cholesterol and triglycerides levels increasing significantly free fatty acid concentrations. The O group showed higher oxidative damage in brain and liver tissues associated with alterations in antioxidant enzyme activities. IGF-I therapy reduced oxidative damage in brain and liver, normalizing antioxidant enzyme activities and mitochondrial dysfunction. In conclusion, low doses of IGF-I restore circulating IGF-I, improve glucose and lipid metabolism, increase testosterone levels and serum total antioxidant capability, and reduce oxidative damage in brain and liver associated with a normalization of antioxidant enzyme activities and mitochondrial function.

Little effects of insulin-like Growth Factor-I on testicular atrophy induced by hypoxia.

BACKGROUND: Insulin-like Growth Factor-I (IGF-I) supplementation restores testicular atrophy associated with advanced liver cirrhosis that is a condition of IGF-I deficiency. The aim of this work was to evaluate the effect of IGF-I in rats with ischemia-induced testicular atrophy (AT) without liver disease and consequently with normal serum level of IGF-I. METHODS: Testicular atrophy was induced by epinephrine (1, 2 mg/Kg intra-scrotal injection five times per week) during 11 weeks. Then, rats with testicular atrophy (AT) were divided into two groups (n = 10 each): untreated rats (AT) receiving saline sc, and AT+IGF, which were treated with IGF-I (2 microg.100 g b.w.(-1).day(-1), sc.) for 28 d. Healthy controls (CO, n = 10) were studied in parallel. Animals were sacrificed on day 29th. Hypophyso-gonadal axis, IGF-I and IGFBPs levels, testicular morphometry and histopathology, immuno-histochemical studies and antioxidant enzyme activity phospholipid hydroperoxide glutathione peroxidase (PHGPx) were assessed. RESULTS: Compared to controls, AT rats displayed a reduction in testicular size and weight, with histological testicular atrophy, decreased cellular proliferation and transferrin expression, and all of these alterations were slightly improved by IGF-I at low doses. IGF-I therapy increased significantly steroidogenesis and PHGPx activity (p < 0.05). Interestingly, plasma IGF-I did not augment in rats with testicular atrophy treated with IGF-I, while IGFBP3 levels, that reduces IGF-I availability, was increased in this group (p < 0.05). CONCLUSION: In testicular atrophy by hypoxia, condition without IGF-I deficiency, IGF-treatment induces only partial effects. These findings suggest that IGF-I therapy appears as an appropriate treatment in hypogonadism only when this is associated to conditions of IGF-I deficiency (such as Laron Syndrome or liver cirrhosis).