RESUMEN
BACKGROUND: Obesity is a chronic and multifactorial disease characterized by increased adipose tissue. In females, obesity leads to reduced ovulation and lower chances of conception in diseases like polycystic ovary syndrome, making it important to characterize complementary medicine to attenuate such deleterious effects. Therefore, the aim of this study was to assess the effects of a hydroethanolic extract from Syzigium cumini leaves in female reproductive impairments present in the obesity model of neonatal L-monosodium glutamate injection. METHODS: Newborn Wistar rats received saline (CTRL) or L-monosodium glutamate 4 mg/g BW (MSG). At 90 days of age, CTRL and some MSG rats received saline, while others received hydroethanolic extract of S. cumini leaves (HESc 500 mg/kg/day, MSG-Syz group) for 30 consecutive days. Estrous cycle was determined by daily vaginal washes. On days 26 and 28 of treatment, oral glucose tolerance test and blood collection were performed for biochemical assessment. At the end, animals were euthanized during estrous phase; blood was collected to measure sex hormones and organs collected for weighing and histological evaluation. RESULTS: MSG-Syz showed reduced Lee Index, retroperitoneal fat pads and restored gluco-insulin axis. Moreover, HESc treatment reduced serum cholesterol levels when compared to MSG. Treatment with HESc did not restore the oligociclicity observed in obese animals, though MSG-Syz reestablished ovarian follicle health back to CTRL levels, with proliferating primordial follicles - these effects were followed by a decrease on periovarian adipocyte area. CONCLUSIONS: This is the first report to show the reversibility of the reproductive dysfunctions seen in MSG female rats through ethnopharmacological treatment. Moreover, it expands the use of HESc as a prominent tool to treat metabolic and reproductive disorders. Finally, we provide novel evidence that, without a functioning hypothalamus-pituitary-gonads axis, metabolic improvement is ineffective for estrous cyclicity, but critical for ovarian follicle health.
Asunto(s)
Obesidad/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Syzygium , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Colesterol/metabolismo , Femenino , Hipotálamo , Hígado/efectos de los fármacos , Hígado/metabolismo , Obesidad/inducido químicamente , Obesidad/metabolismo , Ovario/efectos de los fármacos , Ovario/metabolismo , Hipófisis , Hojas de la Planta , Síndrome del Ovario Poliquístico/metabolismo , Ratas Wistar , Glutamato de SodioRESUMEN
Essentials Inhibitors of protein disulfide isomerase (PDI) have been considered a new antithrombotic class. CxxC is a PDI-targeted peptide that has been previously shown to inhibit its reductase activity. CxxC binds to surface PDI and inhibits ADP- and thrombin-evoked platelet activation and aggregation. CxxC binds to Cys400 on CGHC redox motif of PDI a' domain, a site for PDI prothrombotic activity. SUMMARY: Background Protein disulfide isomerase (PDI) plays a major role in platelet aggregation, and its inhibitors have emerged as novel antithrombotic drugs. In previous work, we designed a peptide based on a PDI redox motif (CGHC) that inhibited both PDI reductase activity and PDI-modulated superoxide generation by neutrophil Nox2. Thus, we hypothesized that this peptide would also inhibit platelet aggregation by association with surface PDI. Methods Three peptides were used: CxxC, containing the PDI redox motif; Scr, presenting a scrambled sequence of the same residues and AxxA, with cysteines replaced by alanine. These peptides were tested under platelet aggregation and flow cytometry protocols to identify their possible antiplatelet activity. We labeled membrane free thiol and electrospray ionization liquid chromatography tandem mass spectrometry to test for an interaction. Results CxxC decreased platelet aggregation in a dose-dependent manner, being more potent at lower agonist concentrations, whereas neither AxxA nor Scr peptides exerted any effect. CxxC decreased aIIbb3 activation, but had no effect on the other markers. CxxC also decreased cell surface PDI pulldown without interfering with the total thiol protein content. Finally, we detected the addition of one CxxC molecule to reduced PDI through binding to Cys400 through mass spectrometry. Interestingly, CxxC did not react with oxidized PDI. Discussion CxxC has consistently shown its antiplatelet effects, both in PRP and washed platelets, corroborated by decreased aIIbb3 activation. The probable mechanism of action is through a mixed dissulphide bond with Cys400 of PDI, which has been shown to be essential for PDI's actions. Conclusion In summary, our data support antiplatelet activity for CxxC through binding to Cys400 in the PDI a0 domain, which can be further exploited as a model for sitedriven antithrombotic agent development.
Asunto(s)
Inhibidores de Agregación Plaquetaria/química , Procolágeno-Prolina Dioxigenasa/química , Proteína Disulfuro Isomerasas/química , Alanina/química , Secuencias de Aminoácidos , Plaquetas/metabolismo , Dominio Catalítico , Cisteína/química , Disulfuros , Humanos , Oxidación-Reducción , Péptidos/química , Activación Plaquetaria , Agregación Plaquetaria , Unión Proteica , Dominios Proteicos , Pliegue de ProteínaRESUMEN
OBJECTIVES: This study sought to evaluate the effects of inspiratory muscle training in inspiratory muscle strength, as well as in functional capacity, ventilatory responses to exercise, recovery oxygen uptake kinetics, and quality of life in patients with chronic heart failure (CHF) and inspiratory muscle weakness. BACKGROUND: Patients with CHF may have reduced strength and endurance in inspiratory muscles, which may contribute to exercise intolerance and is associated with a poor prognosis. METHODS: Thirty-two patients with CHF and weakness of inspiratory muscles (maximal inspiratory pressure [Pi(max)] <70% of predicted) were randomly assigned to a 12-week program of inspiratory muscle training (IMT, 16 patients) or to a placebo-inspiratory muscle training (P-IMT, 16 patients). The following measures were obtained before and after the program: Pi(max) at rest and 10 min after maximal exercise; peak oxygen uptake, circulatory power, ventilatory oscillations, and oxygen kinetics during early recovery (VO2/t-slope); 6-min walk test; and quality of life scores. RESULTS: The IMT resulted in a 115% increment Pi(max), 17% increase in peak oxygen uptake, and 19% increase in the 6-min walk distance. Likewise, circulatory power increased and ventilatory oscillations were reduced. The VO2/t-slope was improved during the recovery period, and quality of life scores improved. CONCLUSIONS: In patients with CHF and inspiratory muscle weakness, IMT results in marked improvement in inspiratory muscle strength, as well as improvement in functional capacity, ventilatory response to exercise, recovery oxygen uptake kinetics, and quality of life.