Browsing by Subject "Metformin"

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    Involvement of ferritin heavy chain in the preventive effect of metformin against doxorubicin-induced cardiotoxicity
    (Elsevier, 2013-04) Asensio López, Maria del Carmen; Sánchez Mas, Jesús; Pascual Figal, Domingo A; Abenza, Sergio; Perez Martinez, Maria T; Valdés, Mariano; Lax Pérez, Antonio Manuel; Medicina
    Doxorubicin is a wide-spectrum chemotherapeutic agent, although a cumulative dose may cause cardiac damage and lead to heart failure. Doxorubicin cardiotoxicity is dependent on the intracellular iron pool and manifests itself by increasing oxidative stress. Our group has recently shown the ability of metformin, an oral antidiabetic with cardiovascular benefits, to protect cardiomyocytes from doxorubicin-induced damage. This work aimed to study whether metformin is able to modulate the expression of ferritin, the major intracellular iron storage protein, in cardiomyocytes and whether it is involved in their protection. The addition of metformin to adult mouse cardiomyocytes (HL-1 cell line) induced both gene and protein expression of the ferritin heavy chain (FHC) in a time-dependent manner. The silencing of FHC expression with siRNAs inhibited the ability of metformin to protect cardiomyocytes from doxorubicin-induced damage, in terms of the percentage of cell viability, the levels of reactive oxygen species, and the activity of antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase). In addition, metformin induced the activation of NF-κB in HL-1 cells, whereas preincubation with SN50, an inhibitor of NF-κB, blocked the upregulation of the FHC and the protective effect mediated by metformin. Taken together, these results provide new knowledge on the protective actions of metformin against doxorubicin-induced cardiotoxicity by identifying FHC and NF-κB as the major mediators of this beneficial effect.
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    Metformin protects against doxorubicin-induced cardiotoxicity: involvement of the adiponectin cardiac system
    (Elsevier, 2011-11-15) Asensio López, María del Carmen; Lax Pérez, Antonio Manuel; Pascual Figal, Domingo A; Valdés, Mariano; Sánchez Mas, Jesús; Medicina
    Doxorubicin has cardiotoxic effects that limit its clinical benefit in cancer patients. Metformin exerts cardioprotective actions via AMP-activated protein kinase (AMPK) and increases the expression of adiponectin and its receptors (adipoR1 and adipoR2) in skeletal muscle and adipose tissue, but its effect on cardiac tissue is still unknown. This work aimed to study whether metformin exerts any protective action against the cardiotoxicity of doxorubicin and whether the cardiac system of adiponectin is involved in any such action. The addition of doxorubicin (5μM) to adult mouse cardiomyocytes (HL-1 cell line) induced apoptosis, which was characterized by a loss of cell viability, activation of caspases, and fragmentation of the genetic material. Doxorubicin treatment also caused a decrease in the activity of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase. Pretreatment with metformin (4mM, 24h) provided protection against doxorubicin-induced damage. This pretreatment significantly increased cell viability, attenuated the activation of caspases and the fragmentation of genetic material, and restored the antioxidant activity. In addition, metformin up-regulated the expression of adiponectin and its receptors, adipoR1 and adipoR2, in cardiomyocytes. In contrast, silencing either adipoR1 or adipoR2 with siRNA inhibited the AMPK activation and the protective effects of metformin. Taken together, these results demonstrate that metformin protects cardiomyocytes from doxorubicin-induced damage and that the cardiac adiponectin system plays an important role in this protective action.
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    Pharmacokinetics of Metformin in Combination With Sitagliptin in Adult Horses After Enteral Administration
    (Elsevier, 2019-01) Cárceles-Rodríguez, Carlos M.; Fernández-Varón, Emilio; Martín-Gimenez, Tamara; Aguirre, Carla; Arion, Alexandra; Rodríguez, María J.; Ayala de la Peña, Ignacio; Medicina y Cirugía Animal
    Insulin dysregulation (ID) is a common metabolic disorder in horses. Recently, incretin hormone release has been suggested to be involved in ID in horses. In human medicine, metformin and sitagliptin are commonly used in combination for metabolic syndrome. This combination could be useful in treating ID in horses. However, no pharmacokinetics data have been reported in this species. The objective of the present study was to establish the plasma concentration–time profile and to derive pharmacokinetics data for a combination of metformin and sitagliptin in horses after enteral administration. Six healthy adult Purebred Spanish horses were used. A metformin (15 mg/kg) plus sitagliptin (1.5 mg/kg) preparation was administered by intragastric route (IG) as an enteral solution. Blood samples were collected from 0 to 48 hours after IG drug administration. Plasma concentrations of metformin and sitagliptin were measured using HPLC methods. The t½λz for metformin was 2.9 hours and for sitagliptin 21 hours. The Cmax was 442 ± 84 mg/L within 0.9 hours for metformin and 94 ± 14 mg/L within 1.3 hours for sitagliptin. No adverse effects were observed, and the combination of metformin and sitagliptin was well tolerated. Therefore, these results suggest that metformin plus sitagliptin might be a combination to consider in horses with ID. Additional studies are needed to establish the effectiveness and tolerance in equids affected by endocrine disorders.