We evaluated the healing potential of human fetal aorta-derived CD133 ⁺ progenitor cells and their conditioned medium (CD133 ⁺ CCM) in a new model of ischemic diabetic ulcer. Streptozotocin-induced diabetic mice underwent bilateral limb ischemia and wounding. One wound was covered with collagen containing 2×10 ⁴ CD133 ⁺ or CD133 ⁻ cells or vehicle. The contralateral wound, covered with only collagen, served as control. Fetal CD133 ⁺ cells expressed high levels of wingless ( Wnt ) genes, which were downregulated following differentiation into CD133 ⁻ cells along with upregulation of Wnt antagonists secreted frizzled-related protein (sFRP)-1, -3, and -4. CD133 ⁺ cells accelerated wound closure as compared with CD133 ⁻ or vehicle and promoted angiogenesis through stimulation of endothelial cell proliferation, migration, and survival by paracrine effects. CD133 ⁺ cells secreted high levels of vascular endothelial growth factor (VEGF)-A and interleukin (IL)-8. Consistently, CD133 ⁺ CCM accelerated wound closure and reparative angiogenesis, with this action abrogated by coadministering the Wnt antagonist sFRP-1 or neutralizing antibodies against VEGF-A or IL-8. In vitro, these effects were recapitulated following exposure of high-glucose-primed human umbilical vein endothelial cells to CD133 ⁺ CCM, resulting in stimulation of migration, angiogenesis-like network formation and induction of Wnt expression. The promigratory and proangiogenic effect of CD133 ⁺ CCM was blunted by sFRP-1, as well as antibodies against VEGF-A or IL-8. CD133 ⁺ cells stimulate wound healing by paracrine mechanisms that activate Wnt signaling pathway in recipients. These preclinical findings open new perspectives for the cure of diabetic ulcers.

Rationale : Nerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival, which are both desirable for postinfarction myocardial healing. Nonetheless, the NGF potential for cardiac repair has never been investigated. Objective : To define expression and localization of NGF and its high-affinity receptor TrkA (tropomyosin-related receptor A) in the human infarcted heart and to investigate the cardiac roles of both endogenous and engineered NGF using a mouse model of myocardial infarction (MI). Methods and Results : Immunostaining for NGF and TrkA was performed on heart samples from humans deceased of MI or unrelated pathologies. To study the post-MI functions of endogenous NGF, a NGF-neutralizing antibody (Ab-NGF) or nonimmune IgG (control) was given to MI mice. To investigate the NGF therapeutic potential, human NGF gene or control (empty vector) was delivered to the murine periinfarct myocardium. Results indicate that NGF is present in the infarcted human heart. Both cardiomyocytes and endothelial cells (ECs) possess TrkA, which suggests NGF cardiovascular actions in humans. In MI mice, Ab-NGF abrogated native reparative angiogenesis, increased EC and cardiomyocyte apoptosis and worsened cardiac function. Conversely, NGF gene transfer ameliorated EC and cardiomyocyte survival, promoted neovascularization and improved myocardial blood flow and cardiac function. The prosurvival/proangiogenic Akt/Foxo pathway mediated the therapeutic benefits of NGF transfer. Moreover, NGF overexpression increased stem cell factor (the c-kit receptor ligand) expression, which translated in higher myocardial abundance of c-kit ^pos progenitor cells in NGF -engineered hearts. Conclusions : NGF elicits pleiotropic beneficial actions in the post-MI heart. NGF should be considered as a candidate for therapeutic cardiac regeneration.

Background: The sexual dimorphism represents one of the triggers of the metabolic disparities between the organisms, advising about wild implications in research or diagnostics contexts. Despite the mounting recognition of the importance of sex consideration in the biomedical fields, the identification of male- and female-specific metabolic signatures has not been achieved. Main body: This review pointed the focus on the metabolic differences related to the sex, evidenced by metabolomics studies performed on healthy populations, with the leading aim of understanding how the sex influences the baseline metabolome. The main shared signatures and the apparent dissimilarities between males and females were extracted and highlighted from the metabolome of the most commonly analyzed biological fluids, such as serum, plasma, and urine. Furthermore, the influence of age and the significant interactions between sex and age have been taken into account. Conclusions: The recognition of sex patterns in human metabolomics has been defined in diverse biofluids. The detection of sex- and age-related differences in the metabolome of healthy individuals are helpful for translational applications from the bench to the bedside to set targeted diagnostic and prevention approaches in the context of personalized medicine. Graphical

Research on the specific effects of sex and gender on pharmacokinetics and pharmacodynamics, as well as safety profile tolerability and drug efficacy, of medications remain meager because female animals and women have only recently been included in the pharmacological domain. To date, the influence of sex and gender on access to care and emotional factors, including patients and care provider dyads, the placebo effect, adherence, and safety profiles, are discussed. Furthermore, differences in drug responses, mainly for antidiabetic drugs, have been described. However, further studies are needed to explore the impact of sex and gender on reaching the most appropriate and tailored prescription for each patient, regardless of sex and gender.