Translational research : the journal of laboratory and clinical medicine
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The aim of this phase 1 clinical trial was to test the safety and feasibility of a single dose of allogeneic umbilical cord-derived mesenchymal stem cells (MSCs) in patients with severe sepsis. This is a single-center, open-label, dose-escalation phase 1 clinical trial of a single dose of intravenous MSCs in patients with severe sepsis. We enrolled 15 patients who averagely divided into low (1 × 106 cells/kg), intermediate (2 × 106 cells/kg), and high (3 × 106 cells/kg) dosing cohorts. ⋯ This study enrolled 15 patients (10 male and 5 female), with a median age of 58. Compared to those in the historical, case-matched group, neither there were infusion-associated serious events or treatment-related adverse events in any of the 15 patients in this trial, nor were there any safety or efficacy signals for serious adverse events or the measured cytokines. A single intravenous infusion of allogeneic MSCs up to a dose of 3 × 106 cells/kg was safe and well tolerated in 15 patients with severe sepsis.
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Oxidative stress has been implicated in the unfavorable changes in cardiac function and remodeling that occur after ovarian estrogen loss. Using ovariectomized rat models, we previously reported that the cardioprotective actions of estrogen are mediated by the G protein-coupled estrogen receptor (GPER). Here, in 9-month-old, female cardiomyocyte-specific GPER knockout (KO) mice vs sex- and age-matched wild-type (WT) mice, we found increased cardiac oxidative stress and oxidant damage, measured as a decreased ratio of reduced glutathione to oxidized glutathione, increased 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine (8-oxo-DG) staining, and increased expression of oxidative stress-related genes. ⋯ Treatment of GPER KO mice for 8 weeks with phosphonium [10-(4,5-dimethoxy-2-methyl 3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenyl-,mesylate (MitoQ), a mitochondria-targeted antioxidant, significantly attenuated these measures of cardiac dysfunction, and MitoQ decreased 8-oxo-DG intensity compared with treatment with an inactive comparator compound, (1-decyl)triphenylphosphonium bromide (P <0.05). A real-time polymerase chain reaction array analysis of 84 oxidative stress and antioxidant defense genes revealed that MitoQ attenuates the increase in NADPH oxidase 4 and prostaglandin-endoperoxide synthase 2 and the decrease in uncoupling protein 3 and glutathione S-transferase kappa 1 seen in GPER KO mice. Our findings suggest that the cardioprotective effects of GPER include an antioxidant role and that targeted strategies to limit oxidative stress after early noncancerous surgical extirpation of ovaries or menopause may help limit alterations in cardiac structure and function related to estrogen loss.