NATHALIA JUOCYS DIAS MOREIRA
Projetos de Pesquisa
Unidades Organizacionais
LIM/59 - Laboratório de Biologia Celular, Hospital das Clínicas, Faculdade de Medicina
6 resultados
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conferenceObject EFFECTS OF ENTERAL PROTEASE INHIBITION ON COAGULATION PROTEOLYSIS AFTER TRAUMA-HEMORRHAGIC SHOCK(2023) SANTOS, Fernando Dos; LI, Joyce; MAFFIOLI, Elisa; TEDESCHI, Gabriella; ALETTI, Federico; JUOCYS, Nathalia; KISTLER, Erik- Enteral administration of the protease inhibitor gabexate mesilate preserves vascular function in experimental trauma/hemorrhagic shock(2023) MOREIRA, Nathalia J. D.; SANTOS, Fernando dos; LI, Joyce B.; ALETTI, Federico; IRIGOYEN, Maria Claudia C.; KISTLER, Erik B.Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration-response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10(-10) to 10(-5) M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration-response curve to the & alpha;(1) adrenergic agonist phenylephrine compared to arteries from Shock-control animals (- logEC(50): - 5.73 & PLUSMN; 0.25 vs. - 6.48 & PLUSMN; 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (- logEC(50): - 6.62 & PLUSMN; 0.21 vs. - 7.13 & PLUSMN; 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 & PLUSMN; 9 vs. 17.63 & PLUSMN; 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r(2) = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 & PLUSMN; 7.91 vs. 64.95 & PLUSMN; 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS.
- Acute renal denervation normalizes aortic function and decreases blood pressure in spontaneously hypertensive rats(2020) MOREIRA, Nathalia Juocys Dias; SANTOS, Fernando dos; MOREIRA, Edson Dias; FARAH, Daniela; SOUZA, Leandro Eziquiel de; SILVA, Maikon Barbosa da; MORAES-SILVA, Ivana Cinthya; LINCEVICIUS, Gisele Silverio; CALDINI, Elia Garcia; IRIGOYEN, Maria Claudia CostaMechanisms involved in the acute responses to renal denervation (RDN) have yet to be fully understood. We assessed urinary volume, autonomic control and aorta vascular reactivity after acute RDN. Male normotensive Wistar rats and spontaneously hypertensive rats (SHR) were divided into normotensive+RDN (ND) or sham surgery (NS), and hypertensive+RDN (HD) or sham surgery (HS). Metabolic parameters and hemodynamic measurements were recorded 72h and 4 days after intervention, respectively. Aortic rings were studied 7 days post RDN in an isometric myograph. Concentration-response curves to phenylephrine, sodium nitroprusside and acetylcholine (10(-10)-10(-5) M) were performed. Two-way ANOVA was used for group comparisons and differences reported when p < 0.05. Results are presented as mean +/- SEM. Urinary volume was 112% higher in HD vs. HS (HS=14.94 +/- 2.5 mL; HD=31.69 +/- 2.2 mL) and remained unchanged in normotensive rats. Systolic BP was lower in HD rats (HS=201 +/- 12 vs. HD=172 +/- 3 mmHg) without changes in normotensive group. HD group showed increased HF and LF modulation (HS=5.8 +/- 0.7 ms(2) vs. HD=13.4 +/- 1.4 ms(2); HS=3.5 +/- 0.7 ms(2) vs. HD=10.5 +/- 1.7 ms(2), respectively). RDN normalized vascular reactivity in HD rats and increased phenylephrine response in ND rats. Acute fall in BP induced by RDN is associated with increased urinary volume, which in turn may also have contributed to functional changes of the aorta.
article Enteral gabexate mesilate improves volume requirements and autonomic cardiovascular function after experimental trauma/hemorrhagic shock in the absence of blood reperfusion(2022) SANTOS, Fernando Dos; LI, Joyce B.; MOREIRA, Nathalia Jd; MAZOR, Rafi; ALETTI, Federico; KISTLER, Erik B.The standard of care for fluid resuscitation of trauma/hemorrhagic shock (T/HS) is the infusion of blood. However, in many instances, blood product transfusion may not be feasible. Consequently, crystalloid solutions may be utilized as temporizing cost-effective resuscitation fluids. In this study, we explored an alternative therapeutic strategy of enteral protease inhibition adjunctive to intravenous Lactated Ringer's (LR) reperfusion after T/HS. Male Wistar rats underwent midline laparotomy (trauma) and an enteral catheter was inserted orally and positioned postpyloric for the infusion of vehicle (Golytely (R)) with or without the serine protease inhibitor gabexate mesilate (GM) (n=8/group). Hemorrhagic shock was induced by blood removal to reduce the mean arterial blood pressure (MAP) to 35-40 mmHg for 90 minutes, before resuscitation with LR. Animals treated with enteral GM required significantly less crystalloid volume to achieve hemodynamic stability and displayed improvements in both blood pressure and autonomic function (via increased baroreflex sensitivity to vasopressors, heightened vascular sympathetic modulation, elevated levels of circulating catecholamines, and increased alpha 1-adrenergic receptor density) compared to untreated (control) shocked animals. Resistance arteries isolated from healthy donor animals and perfused with plasma from untreated T/HS animals revealed impaired vascular response to the alpha 1 adrenergic agonist phenylephrine and decreased reactivity to sodium nitroprusside that was preserved in the GM-treated group. These findings suggest that blockade of serine proteases within the intestinal lumen in non-blood resuscitated experimental T/HS preserves and enhances peripheral sympathetic modulation, improving hemodynamics. Enteral infusion of gabexate mesilate may be a new and promising approach to the management of trauma/hemorrhagic shock.conferenceObject Acute vascular and autonomic responses of renal denervation in spontaneously hypertensive rats(2017) MOREIRA, N. J. D.; SANTOS, F. Dos; MOREIRA, E. D.; FARAH, D.; SOUZA, L. E. De; SILVA, M. B. Da; IRIGOYEN, M. C.- Plasma enzymatic activity, proteomics and peptidomics in COVID-19-induced sepsis: A novel approach for the analysis of hemostasis(2023) SANTOS, Fernando Dos; LI, Joyce B. B.; JUOCYS, Nathalia; MAZOR, Rafi; BERETTA, Laura; COUFAL, Nicole G.; LAM, Michael T. Y.; ODISH, Mazen F.; IRIGOYEN, Maria Claudia; O'DONOGHUE, Anthony J.; ALETTI, Federico; KISTLER, Erik B.Introduction: Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis. We investigated plasma protease activity patterns in COVID-19-induced sepsis with bacterial superinfection, as well as plasma proteomics and peptidomics in order to assess the possible implications of enhanced proteolysis on major protein systems (e.g., coagulation).Methods: Patients (=4) admitted to the intensive care units (ICUs) at the University of California, San Diego (UCSD) Medical Center with confirmed positive test for COVID-19 by real-time reverse transcription polymerase chain reaction (RT-PCR) were enrolled in a study approved by the UCSD Institutional Review Board (IRB# 190699, Protocol #20-0006). Informed consent was obtained for the collection of blood samples and de-identified use of the data. Blood samples were collected at multiple time points and analyzed to quantify a) the circulating proteome and peptidome by mass spectrometry; b) the aminopeptidase activity in plasma; and c) the endopeptidase activity in plasma using fluorogenic substrates that are cleaved by trypsin-like endopeptidases, specific clotting factors and plasmin. The one patient who died was diagnosed with bacterial superinfection on day 7 after beginning of the study.Results: Spikes in protease activity (factor VII, trypsin-like activity), and corresponding increases in the intensity of peptides derived by hydrolysis of plasma proteins, especially of fibrinogen degradation products and downregulation of endogenous protease inhibitors were detected on day 7 for the patient who died. The activity of the analyzed proteases was stable in survivors.Discussion: The combination of multiomics and enzymatic activity quantification enabled to i) hypothesize that elevated proteolysis occurs in COVID-19-induced septic shock with bacterial superinfection, and ii) provide additional insight into malfunctioning protease-mediated systems, such as hemostasis.