RESUMO
ABSTRACT: Introduction: A biomarker strategy based on the quantification of an immune profile could provide a clinical understanding of the inflammatory state in patients with sepsis and its potential implications for the bioenergetic state of lymphocytes, whose metabolism is associated with altered outcomes in sepsis. The objective of this study is to investigate the association between mitochondrial respiratory states and inflammatory biomarkers in patients with septic shock. Methods: This prospective cohort study included patients with septic shock. Routine, complex I, complex II respiration, and biochemical coupling efficiency were measured to evaluate mitochondrial activity. We measured IL-1ß, IL-6, IL-10, total lymphocyte count, and C-reactive protein levels on days 1 and 3 of septic shock management as well as mitochondrial variables. The variability of these measurements was evaluated using delta counts (days 3-1 counts). Results: Sixty-four patients were included in this analysis. There was a negative correlation between complex II respiration and IL-1ß (Spearman ρ, -0.275; P = 0.028). Biochemical coupling efficiency at day 1 was negative correlated with IL-6: Spearman ρ, -0.247; P = 0.05. Delta complex II respiration was negatively correlated with delta IL-6 (Spearman ρ, -0.261; P = 0.042). Delta complex I respiration was negatively correlated with delta IL-6 (Spearman ρ, -0.346; P = 0.006), and delta routine respiration was also negatively correlated with both delta IL-10 (Spearman ρ, -0.257; P = 0.046) and delta IL-6 (Spearman ρ, -0.32; P = 0.012). Conclusions: The metabolic change observed in mitochondrial complex I and complex II of lymphocytes is associated with a decrease in IL-6 levels, which can signal a decrease in global inflammatory activity.
Assuntos
Sepse , Choque Séptico , Humanos , Choque Séptico/complicações , Interleucina-10 , Interleucina-6 , Estudos Prospectivos , Sepse/complicações , Biomarcadores , Metabolismo Energético , LinfócitosRESUMO
Decreasing neurotrophic support and impaired mitochondrial bioenergetics are key mechanisms for long-term neurodegeneration and cognitive decline after traumatic brain injury (TBI). We hypothesize that preconditioning with lower and higher volumes of physical exercise upregulates the CREB-BDNF axis and bioenergetic capability, which might serve as neural reserves against cognitive impairment after severe TBI. Using a running wheel mounted in the home cage, mice were engaged in lower (LV, 48 h free access, and 48 h locked) and higher (HV, daily free access) exercise volumes for thirty days. Subsequently, LV and HV mice remained for additional thirty days in the home cage with the running wheel locked and were euthanized. The sedentary group had the running wheel always locked. For the same type of exercise stimulus in a given time, daily workout presents higher volume than alternate days workout. The total distance ran in the wheel was the reference parameter to confirm distinct exercise volumes. On average, LV exercise ran 27.522 m and HV exercise ran 52.076 m. Primarily, we investigate whether LV and HV protocols increase neurotrophic and bioenergetic support in the hippocampus thirty days after exercise ceased. Regardless of volume, exercise increased hippocampal pCREBSer133-CREB-proBDNF-BDNF signaling and mitochondrial coupling efficiency, excess capacity, and leak control, that may compose the neurobiological basis for neural reserves. Further, we challenge these neural reserves against secondary memory deficits triggered by a severe TBI. After thirty days of exercise LV and HV, and sedentary (SED) mice were submitted to the CCI model. Mice remained for additional thirty days in the home cage with the running wheel locked. The mortality after severe TBI was approximately 20% in LV and HV, while in the SED was 40%. Also, LV and HV exercise sustained hippocampal pCREBSer133-CREB-proBDNF-BDNF signaling, mitochondrial coupling efficiency, excess capacity, and leak control for thirty days after severe TBI. Corroborating these benefits, the mitochondrial H2O2 production linked to complexes I and II was attenuated by exercise regardless of the volume. These adaptations attenuated spatial learning and memory deficits caused by TBI. In summary, preconditioning with LV and HV exercise builds up long-lasting CREB-BDNF and bioenergetic neural reserves that preserve memory fitness after severe TBI.
Assuntos
Lesões Encefálicas Traumáticas , Reserva Cognitiva , Condicionamento Físico Animal , Camundongos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Peróxido de Hidrogênio , Condicionamento Físico Animal/fisiologia , Hipocampo/metabolismo , Transtornos da Memória/etiologia , Lesões Encefálicas Traumáticas/complicaçõesRESUMO
Antibiotics may trigger alterations in mitochondrial function, which has been explored in cells culture, and in animal model of sepsis. This study sought to evaluate whether antibiotic therapy affects mitochondrial bioenergetics in a 68-patients clinical study. We studied mitochondrial respiratory rates at two time points: the first day of antibiotic administration and three days after. The Δbasal, ΔCI, ΔCII respiration, and ΔBCE respiratory rates were not different between patients administered with polymyxin, vancomycin, amoxicillin-clavulanate, and azithromycin compared to those who were not administered. Specific beta-lactams are associated with specific modifications in mitochondrial respiratory endpoints - patients who used meropenem had higher delta C2 values compared to those who did not (p = 0.03). Patients who used piperacillin-tazobactam had lower delta C1 (p = 0.03) values than those who did not, but higher delta C2 values (p = 0.02). These mitochondrial metabolic signatures in isolated lymphocytes challenges the proposed effects of antibiotics in mitochondrial bioenergetics of cell cultures, but at current status have an uncertain clinical significance.
Assuntos
Choque Séptico , Amoxicilina/uso terapêutico , Antibacterianos , Azitromicina/uso terapêutico , Ácido Clavulânico/uso terapêutico , Metabolismo Energético , Humanos , Linfócitos , Meropeném/uso terapêutico , Mitocôndrias , Combinação Piperacilina e Tazobactam/uso terapêutico , Polimixinas/uso terapêutico , Estudos Prospectivos , Choque Séptico/tratamento farmacológico , Vancomicina/uso terapêutico , beta-Lactamas/uso terapêuticoRESUMO
Severe traumatic brain injury (TBI) is associated with high rates of mortality and long-term disability linked to neurochemical abnormalities. Although purine derivatives play important roles in TBI pathogenesis in preclinical models, little is known about potential changes in purine levels and their implications in human TBI. We assessed cerebrospinal fluid (CSF) levels of purines in severe TBI patients as potential biomarkers that predict mortality and long-term dysfunction. This was a cross-sectional study performed in 17 severe TBI patients (Glasgow Coma Scale <8) and 51 controls. Two to 4 h after admission to ICU, patients were submitted to ventricular drainage and CSF collection for quantification of adenine and guanine purine derivatives by HPLC. TBI patients' survival was followed up to 3 days from admission. A neurofunctional assessment was performed through the modified Rankin Scale (mRS) 2 years after ICU admission. Purine levels were compared between control and TBI patients, and between surviving and non-surviving patients. Relative to controls, TBI patients presented increased CSF levels of GDP, guanosine, adenosine, inosine, hypoxanthine, and xanthine. Further, GTP, GDP, IMP, and xanthine levels were different between surviving and non-surviving patients. Among the purines, guanosine was associated with improved mRS (p = 0.042; r = -0.506). Remarkably, GTP displayed predictive value (AUC = 0.841, p = 0.024) for discriminating survival versus non-survival patients up to 3 days from admission. These results support TBI-specific purine signatures, suggesting GTP as a promising biomarker of mortality and guanosine as an indicator of long-term functional disability.
Assuntos
Lesões Encefálicas Traumáticas , Biomarcadores/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/diagnóstico , Estudos Transversais , Escala de Coma de Glasgow , Guanosina , Guanosina Trifosfato , Humanos , Purinas , XantinaRESUMO
Supraphysiological doses of anabolic-androgenic steroids (AAS) may cause long-term functional abnormalities, particularly in the heart and liver, which may only represent the later-stage of the cumulative damage caused by dysfunctional organelles. We investigated whether mid-term supraphysiological doses of Testosterone and Nandrolone impair mitochondrial Ca2+ and membrane potential (ΔΨm) dynamics, and redox machinery in the heart and liver of mice. CF1 albino mice were treated daily with 15â¯mg/kg of Nandrolone (ND) or Testosterone (T), or oil (vehicle) for 19â¯days. Preparations enriched in mitochondria from the heart or liver were used to perform assays of Ca2+ influx/efflux, ΔΨm, and H2O2 production. ND significantly impaired mitochondrial Ca2+ influx in the heart, and ΔΨm in both organs. ND and T increased H2O2 levels in the heart and liver relative to controls. Also, ND increased oxidative damage to lipids and proteins (TBARS and carbonyls) in the heart, and both AAS decreased glutathione peroxidase activity in the heart and liver. In summary, supraphysiological doses of ND, and in a lesser extend T, impaired mitochondrial Ca2+ influx and ΔΨm, and redox homeostasis being early mechanistic substrates for inducing heart and liver tissue damage.
Assuntos
Anabolizantes/toxicidade , Coração/fisiopatologia , Fígado/patologia , Mitocôndrias/patologia , Nandrolona/toxicidade , Testosterona/toxicidade , Androgênios/farmacologia , Animais , Coração/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , OxirreduçãoRESUMO
The astrocytic glutamate transporter GLT-1 performs glutamate uptake thereby mediating NMDAr responses in neurons. Ceftriaxone (CEF) upregulates astrocytic GLT-1 expression/activity, which could counteract excessive glutamate levels and aggressive behavior induced by anabolic synthetic steroids such as nandrolone decanoate (ND). Here, adult male CF-1 mice were allocated to oil (VEH), ND, CEF, and ND/CEF groups. Mice were subcutaneously (s.c.) injected with ND (15 mg/kg) or VEH for 19 days, and received intraperitoneal (i.p.) injections of CEF (200 mg/kg) or saline for 5 days. The ND/CEF group received ND for 19 days plus coadministration of CEF in the last 5 days. On the 19th day, the aggressive phenotypes were evaluated through the resident-intruder test. After 24 h, cerebrospinal fluid was collected to measure glutamate levels, and the pre-frontal cortex was used to assess GLT-1, pGluN2BTyr1472, and pGluN2ATyr1246 by Western blot. Synaptosomes from the left brain hemisphere was used to evaluate mitochondrial function including complex II-succinate dehydrogenase (SDH), Ca2+ handling, membrane potential (ΔÑ°m), and H2O2 production. ND decreased the latency for the first attack and increased the number of attacks by the resident mice against the intruder, mechanistically associated with an increase in glutamate levels and pGluN2BTyr1472 but not pGluN2ATyr1244, and GLT-1 downregulation. The abnormalities in mitochondrial Ca2+ influx, SDH, ΔÑ°m, and H2O2 implies in deficient energy support to the synaptic machinery. The ND/CEF group displayed a decreased aggressive behavior, normalization of glutamate and pGluN2BTyr1472levels, and mitochondrial function at synaptic terminals. In conclusion, the pharmacological modulation of GLT-1 highlights its relevance as an astrocytic target against highly impulsive and aggressive phenotypes.
Assuntos
Agressão/efeitos dos fármacos , Astrócitos/fisiologia , Transportador de Glucose Tipo 1/fisiologia , Psicoses Induzidas por Substâncias/psicologia , Congêneres da Testosterona/efeitos adversos , Agressão/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nandrolona/efeitos adversos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Psicoses Induzidas por Substâncias/metabolismo , Psicoses Induzidas por Substâncias/fisiopatologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVE: Clinical neurological assessment is challenging for severe traumatic brain injury (TBI) patients in the acute setting. Waves of neurochemical abnormalities that follow TBI may serve as fluid biomarkers of neurological status. We assessed the cerebrospinal fluid (CSF) levels of glutamate, lactate, BDNF, and GDNF, to identify potential prognostic biomarkers of neurological outcome. METHODS: This cross-sectional study was carried out in a total of 20 consecutive patients (mean [SD] age, 29 [13] years; M/F, 9:1) with severe TBI Glasgow Coma Scale ≤ 8 and abnormal computed tomography scan on admission. Patients were submitted to ventricular drainage and had CSF collected between 2 and 4 h after hospital admission. Patients were then stratified according to two clinical outcomes: deterioration to brain death (nonsurvival, n = 6) or survival (survival, n = 14), within 3 days after hospital admission. CSF levels of brain-derived substances were compared between nonsurvival and survival groups. Clinical and neurological parameters were also assessed. RESULTS: Glutamate and lactate are significantly increased in nonsurvival relative to survival patients. We tested the accuracy of both biomarkers to discriminate patient outcome. Setting a cutoff of >57.75, glutamate provides 80.0% of sensitivity and 84.62% of specificity (AUC: 0.8214, 95% CL: 54.55-98.08%; and a cutoff of >4.65, lactate has 100% of sensitivity and 85.71% of specificity (AUC: 0.8810, 95% CL: 54.55-98.08%). BDNF and GDNF did not discriminate poor outcome. INTERPRETATION: This early study suggests that glutamate and lactate concentrations at hospital admission accurately predict death within 3 days after severe TBI.