Publications by authors named "Sidnéia Sousa Santos"

4 Publications

  • Page 1 of 1

Repurposing of Clinically Approved Poly-(Adp-Ribose) Polymerase Inhibitors For The Therapy of Sepsis.

Shock 2021 Jun 10. Epub 2021 Jun 10.

Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de Sao Paulo - Sao Paulo - Brazil Laboratory of Medical Research - Faculty of Medicine of the University of São Paulo-USP, São Paulo, Brazil Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.

Abstract: Sepsis' pathogenesis involves multiple mechanisms that lead to a dysregulation of the host's response. Significant efforts have been made in search of interventions that can reverse this situation and increase patient survival. Poly (ADP-polymerase) (PARP) is a constitutive nuclear and mitochondrial enzyme, which functions as a co-activator and co-repressor of gene transcription, thus regulating the production of inflammatory mediators. Several studies have already demonstrated an overactivation of PARP1 in various human pathophysiological conditions and that its inhibition has benefits in regulating intracellular processes. The PARP inhibitor olaparib, originally developed for cancer therapy, paved the way for the expansion of its clinical use for non-oncological indications. In this review we discuss sepsis as one of the possible indications for the use of olaparib and other clinically approved PARP inhibitors as a modulators of the inflammatory response and cellular dysfunction. The benefit of olaparib and other clinically approved PARP inhibitors has already been demonstrated in several experimental models of human diseases, such as neurodegeneration and neuroinflammation, acute hepatitis, skeletal muscle disorders, aging and acute ischemic stroke, protecting, for example, from the deterioration of the blood-brain barrier, restoring the cellular levels of NAD+, improving mitochondrial function and biogenesis and, among other effects, reducing oxidative stress and pro-inflammatory mediators, such as TNF-α, IL1-β, IL-6 and VCAM1. These data demonstrated that repositioning of clinically approved PARP inhibitors may be effective in protecting against hemodynamic dysfunction, metabolic dysfunction, and multiple organ failure in patients with sepsis. Age and gender affect the response to PARP inhibitors, the mechanisms underlying the lack of many protective effects in females and aged animals should be further investigated and be cautiously considered in designing clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SHK.0000000000001820DOI Listing
June 2021

Immunophenotyping of Monocytes During Human Sepsis Shows Impairment in Antigen Presentation: A Shift Toward Nonclassical Differentiation and Upregulation of FCγRi-Receptor.

Shock 2018 09;50(3):293-300

Division of Infectious Diseases, Sao Paulo Hospital, Escola Paulista de Medicina.

Monocytes and macrophages are pivotal in the host response to sepsis, recognizing the infecting microorganism and triggering an inflammatory response. These functions are, at least in part, modulated by the expression of cell surface receptors. We aimed to characterize the monocyte phenotype from septic patients during an ongoing sepsis process and its association with clinical outcomes. Sixty-one septic patients and 31 healthy volunteers (HVs) were enrolled in the study. Samples were obtained from patients at baseline (D0, N = 61), and after 7 (D7, N = 36) and 14 days of therapy (D14, N = 22). Monocytes from septic patients presented decreased expression of CD86, HLA-DR, CD200R, CCR2, CXCR2, and CD163 compared with HV monocytes. In contrast, the PD-1, PD-L1, CD206, CD64, and CD16 expression levels were upregulated in patients. HLA-DR, CD64, PD-1, and PD-L1 expression levels were higher in survivors than in nonsurvivors. Increased CD86, HLA-DR, and CXCR2 expression levels were observed in follow-up samples; in contrast, CD64 and CD16 GMFI decreased over time. In conclusion, monocytes from septic patients show antigen presentation impairment as characterized by decreased HLA-DR and costimulatory CD86 expression and increased PD-1 and PD-L1 expression. On the contrary, increased monocyte inflammatory and phagocytic activities may be inferred by the increased CD16 and CD64 expression. We found conflicting results regarding differentiation toward the M2 phenotype, with increased CD206 expression and decreased CD163 expression on monocytes from septic patients, whereas the subset of nonclassical monocytes was demonstrated by increased CD16.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SHK.0000000000001078DOI Listing
September 2018

Effect of natural porcine surfactant in Staphylococcus aureus induced pro-inflammatory cytokines and reactive oxygen species generation in monocytes and neutrophils from human blood.

Int Immunopharmacol 2014 Aug 27;21(2):369-74. Epub 2014 May 27.

Division of Infectious Diseases, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil. Electronic address:

Surfacen® is a clinical surfactant preparation of porcine origin. In the present study, we have evaluated the effect of Surfacen® in the modulation of oxidative burst in monocytes and neutrophils in human blood and pro-inflammatory cytokine production in peripheral blood mononuclear cells (PBMC). Reactive oxygen species (ROS) level was measured in monocytes and neutrophils by flow cytometry using 2,7-dichlorofluorescein diacetate (DCFH-DA) as substrate, while, tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were estimated in PBMC supernatant by enzyme-linked immunosorbent assays (ELISA). Our results show that Staphylococcus aureus-induced ROS level was slightly affected by Surfacen® added to whole blood monocytes and neutrophils. The time course experiments of pre-incubation with Surfacen® showed no significant increase of ROS level at 2h; however, the ROS level decreased when pre incubated for 4h and 6h with Surfacen®. Pre-incubation of PBMC cells with Surfacen® at 0.125 and 0.5mg/mL showed a dose-dependent suppression of TNF-α levels measured after 4h of S. aureus stimulation, an effect less impressive when cells were stimulated for 24h. A similar behavior was observed in IL-6 release. In summary, the present study provides experimental evidence supporting an anti-inflammatory role of Surfacen® in human monocytes and neutrophils in vitro.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.intimp.2014.05.020DOI Listing
August 2014

Generation of nitric oxide and reactive oxygen species by neutrophils and monocytes from septic patients and association with outcomes.

Shock 2012 Jul;38(1):18-23

Division of Infectious Diseases, Department of Medicine, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.

In this study, our aims were to evaluate the reactive oxygen species (ROS) and nitric oxide (NO) generation by monocytes and neutrophils from septic patients and to correlate their levels with clinical outcomes. Forty-nine septic patients and 19 healthy volunteers were enrolled in the study. The ROS and NO production was quantified in monocytes and neutrophils in whole blood by flow cytometry, constitutively, and after stimulation with Staphylococcus aureus and Pseudomonas aeruginosa. Nitric oxide production by monocytes was higher in septic patients compared with healthy volunteers for all conditions and by neutrophils at baseline, and ROS generation in monocytes and neutrophils was higher in septic patients than in healthy volunteers for all conditions. Nitric oxide production by monocytes and neutrophils was decreased at day 7 compared with that at admission (day 0) in survivors at baseline and after stimulation with S. aureus. Reactive oxygen species production by the monocytes and neutrophils was decreased in survivors at day 7 compared with day 0 under all conditions, except by neutrophils at baseline. No difference was found in NO and ROS generation by monocytes and neutrophils between day 7 and day 0 in nonsurvivors. Generation of NO and ROS by neutrophils and monocytes is increased in septic patients, and their persistence is associated with poor outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SHK.0b013e318257114eDOI Listing
July 2012
-->