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Regenerative approaches towards neuronal loss following traumatic brain or spinal cord injury have long been considered a dogma in neuroscience and remain a cutting-edge area of research. This is reflected in a large disparity between the number of studies investigating primary and secondary injury as therapeutic targets in spinal cord and traumatic brain injuries. Significant advances in biotechnology may have the potential to reshape the current state-of-the-art and bring focus to primary injury neurotrauma research. Recent studies using neural-glial factor/antigen 2 (NG2) cells indicate that they may differentiate into neurons even in the developed brain. As these cells show great potential to play a regenerative role, studies have been conducted to test various manipulations in neurotrauma models aimed at eliciting a neurogenic response from them. In the present study, we systematically reviewed the experimental protocols and findings described in the scientific literature, which were peer-reviewed original research articles (1) describing preclinical experimental studies, (2) investigating NG2 cells, (3) associated with neurogenesis and neurotrauma, and (4) in vitro and/or in vivo, available in PubMed/MEDLINE, Web of Science or SCOPUS, from 1998 to 2022. Here, we have reviewed a total of 1504 papers, and summarized findings that ultimately suggest that NG2 cells possess an inducible neurogenic potential in animal models and in vitro. We also discriminate findings of NG2 neurogenesis promoted by different pharmacological and genetic approaches over functional and biochemical outcomes of traumatic brain injury and spinal cord injury models, and provide mounting evidence for the potential benefits of manipulated NG2 cell ex vivo transplantation in primary injury treatment. These findings indicate the feasibility of NG2 cell neurogenesis strategies and add new players in the development of therapeutic alternatives for neurotrauma.
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Sepsis represents a deranged and exaggerated systemic inflammatory response to infection and is associated with vascular and metabolic abnormalities that trigger systemic organic dysfunction. Mitochondrial function has been shown to be severely impaired during the early phase of critical illness, with a reduction in biogenesis, increased generation of reactive oxygen species and a decrease in adenosine triphosphate synthesis of up to 50%. Mitochondrial dysfunction can be assessed using mitochondrial DNA concentration and respirometry assays, particularly in peripheral mononuclear cells. Isolation of monocytes and lymphocytes seems to be the most promising strategy for measuring mitochondrial activity in clinical settings because of the ease of collection, sample processing, and clinical relevance of the association between metabolic alterations and deficient immune responses in mononuclear cells. Studies have reported alterations in these variables in patients with sepsis compared with healthy controls and non-septic patients. However, few studies have explored the association between mitochondrial dysfunction in immune mononuclear cells and unfavorable clinical outcomes. An improvement in mitochondrial parameters in sepsis could theoretically serve as a biomarker of clinical recovery and response to oxygen and vasopressor therapies as well as reveal unexplored pathophysiological mechanistic targets. These features highlight the need for further studies on mitochondrial metabolism in immune cells as a feasible tool to evaluate patients in intensive care settings. The evaluation of mitochondrial metabolism is a promising tool for the evaluation and management of critically ill patients, especially those with sepsis. In this article, we explore the pathophysiological aspects, main methods of measurement, and the main studies in this field.
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Metabolic syndrome is a serious health condition reaching epidemic proportions worldwide and is closely linked to an increased risk of cardiovascular problems. The lack of appropriate treatment paves the way for developing new therapeutic agents as a high priority in the current research. In this study, we evaluated the protective effects of Capsicum baccatum red pepper on metabolic syndrome scenarios induced by an ultra-processed diet in rats. After four months, the ultra-processed diet increased central obesity, triglycerides, total cholesterol, LDL-cholesterol plasma levels, and impaired glucose tolerance. The oral administration of C. baccatum concomitantly with the ultra-processed diet avoided the accumulation of adipose tissue in the visceral region, reduced the total cholesterol and LDL fraction, and improved glucose homeostasis, factors commonly associated with metabolic syndrome. The data presented herein reveal an important preventive action of C. baccatum in developing metabolic disorders among animals fed a hypercaloric diet, significantly reducing their cardiometabolic risk. Allied with the absence of toxic effects after chronic use, our study suggests C. baccatum red pepper as a secure and enriched source of bioactive compounds promising to protect against pathological processes associated with metabolic syndrome.
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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.
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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
The influence of temperament traits on bipolar disorder (BD) has been investigated. Both temperament traits and BD are partially genetically determined and seem to be influenced by variations in the CACNA1C gene. These variations presented a significant interactive effect with biological sex, although studies that evaluate this relationship are scarce. Here, we assessed the mediation effect of temperament traits on the relationship between two polymorphisms in the CACNA1C gene (rs1006737 and rs4765913) and BD according to sex. This is a cross-sectional study consisting of 878 Caucasian individuals (508 women and 370 men), aged 18-35, enrolled in a population-based study in the city of Pelotas, Southern Brazil. BD diagnosis was evaluated using the clinical interview MINI 5.0, and temperament traits were assessed via the application of the Affective and Emotional Composite Temperament Scale (AFECTS). Mediation models were tested using the modeling tool PROCESS (version 3.3) for SPSS. Bootstrapping-enhanced mediation analyses in women indicated that traits anger (39%) and caution (27%) mediated the association between the rs4765913 SNP and BD, while traits volition (29%), anger (35%), and caution (29%) mediated the association between the AA haplotype (rs1006737-rs4765913) and the BD. No effect was encountered for cisgender men. Our model revealed that paths from CACNA1C SNPs to BD are mediated by specific temperament traits in women, reinforcing the definition of temperament traits as endophenotypes.
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Transtorno Bipolar , Feminino , Humanos , Masculino , Transtorno Bipolar/psicologia , Canais de Cálcio Tipo L/genética , Estudos Transversais , Emoções , Polimorfismo de Nucleotídeo Único , Temperamento , Adolescente , Adulto Jovem , AdultoRESUMO
The CACNA1C gene encodes the pore-forming alpha-1c subunit of L-type voltage-gated calcium channels. The calcium influx through these channels regulates the transcription of the brain-derived neurotrophic factor (BDNF). Polymorphisms in this gene have been consistently associated with psychiatric disorders, and alterations in BDNF levels are a possible biological mechanism to explain such associations. Here, we sought to investigate the effect of the CACNA1C rs1006737 and rs4765913 polymorphisms and their haplotypes on serum BDNF concentration. We further aim to investigate the regulatory function of these SNPs and the ones linked to them. The study enrolled 641 young adults (362 women and 279 men) in a cross-sectional population-based survey. Linear regression was used to test the effects of polymorphisms and haplotypes on BDNF levels adjusted for potential confounders. Moreover, regulatory putative functional roles were assessed using in silico approach. BDNF levels were not associated with CACNA1C polymorphisms/haplotype in the total sample. When the sample was stratified by sex, checking the effect of polymorphisms on men and women separately, the A-allele of rs4765913 was associated with lower BDNF levels in women compared with the TT genotype (p = 0.010). The AA (rs1006737-rs4765913) haplotype was associated with BDNF levels in opposite directions regarding sex, with lower levels of BDNF in women (p = 0.040) compared to those without this haplotype, while with higher levels in men (p = 0.027). These findings were supported by the presence of regulatory marks only on the male fetal brain. Our results suggest that the BDNF levels regulation may be a potential mechanism underpinning the association between CACNA1C and psychiatric disorders, with a differential role in women and men.
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Fator Neurotrófico Derivado do Encéfalo , Predisposição Genética para Doença , Adulto Jovem , Humanos , Masculino , Feminino , Fator Neurotrófico Derivado do Encéfalo/genética , Estudos Transversais , Canais de Cálcio Tipo L/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
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.
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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.
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Lesões Encefálicas Traumáticas , Biomarcadores/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/diagnóstico , Estudos Transversais , Escala de Coma de Glasgow , Guanosina , Guanosina Trifosfato , Humanos , Purinas , XantinaRESUMO
INTRODUCTION: In septic shock, mitochondrial dysfunction, and hypoperfusion are the main triggers of multi-organ failure. Little is known about the crosstalk between mitochondrial dysfunction and hemodynamic alterations, especially in the post-resuscitation phase. Here, we assess whether hypoperfusion and lactate levels are associated with oxygen consumption linked to mitochondrial bioenergetic activity in lymphocytes of patients admitted with septic shock. PATIENTS AND METHODS: Prospective cohort study in patients with septic shock defined as the requirement of vasopressors to maintain a mean arterial pressure 65 mm Hg after initial fluid administration. Basal mitochondrial and Complex I respiration was measured to evaluate mitochondrial activity. Both variables and capillary refill time were compared with arterial lactate post-fluid resuscitation. We also compared mitochondrial activity measurements between patients with and without hypoperfusion status. RESULTS: A total of 90 patients were included in analysis. The median arterial lactate at the time of septic shock diagnosis was 2.0 mmol/Dl (IQR 1.3-3.0). Baseline respiration at the time of septic shock diagnosis was correlated with lactate (Spearman -0.388, 95% CI -0.4893 to -0.1021; Pâ=â0.003), as well as Complex I respiration (Spearman -0.403, 95% CI -0.567 to -0.208; Pâ<â0.001). Patients with hypoperfusion status had no difference in basal respiration when compared with patients who did not have hypoperfusion status (Pâ=â0.22) nor in Complex I respiration (Pâ=â0.09). CONCLUSION: Changes in lymphocytic mitochondrial metabolism are associated with post-resuscitation arterial lactate in septic shock; however, they are not associated with the presence of a hypoperfusional status. In this scenario, it is therefore suggested that systemic perfusion and mitochondrial metabolism have different courses.
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Hiperlactatemia/etiologia , Linfócitos/fisiologia , Doenças Mitocondriais/etiologia , Consumo de Oxigênio/fisiologia , Choque Séptico/complicações , Choque Séptico/fisiopatologia , Idoso , Feminino , Hemodinâmica/fisiologia , Humanos , Hiperlactatemia/diagnóstico , Hiperlactatemia/fisiopatologia , Ácido Láctico/sangue , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/sangue , Doenças Mitocondriais/fisiopatologia , Estudos Prospectivos , Ressuscitação , Choque Séptico/sangue , Vasoconstritores/uso terapêuticoRESUMO
BACKGROUND: Septic shock is a life-threatening condition that challenges immune cells to reprogram their mitochondrial metabolism towards to increase ATP synthesis for building an appropriate immunity. This could print metabolic signatures in mitochondria whose association with disease progression and clinical outcomes remain elusive. METHOD: This is a single-center prospective cohort study performed in the ICU of one tertiary referral hospital in Brazil. Between November 2017 and July 2018, 90 consecutive patients, aged 18 years or older, admitted to the ICU with septic shock were enrolled. Seventy-five patients had Simplified Acute Physiology Score (SAPS 3) assessed at admission, and Sequential Organ Failure Assessment (SOFA) assessed on the first (D1) and third (D3) days after admission. Mitochondrial respiration linked to complexes I, II, V, and biochemical coupling efficiency (BCE) were assessed at D1 and D3 and Δ (D3-D1) in isolated lymphocytes. Clinical and mitochondrial endpoints were used to dichotomize the survival and death outcomes. Our primary outcome was 6-month mortality, and secondary outcomes were ICU and hospital ward mortality. RESULTS: The mean SAPS 3 and SOFA scores at septic shock diagnosis were 75.8 (± 12.9) and 8 (± 3) points, respectively. The cumulative ICU, hospital ward, and 6-month mortality were 32 (45%), 43 (57%), and 50 (66%), respectively. At the ICU, non-surviving patients presented elevated arterial lactate (2.8 mmol/L, IQR, 2-4), C-reactive protein (220 mg/L, IQR, 119-284), and capillary refill time (5.5 s, IQR, 3-8). Respiratory rates linked to CII at D1 and D3, and ΔCII were decreased in non-surviving patients. Also, the BCE at D1 and D3 and the ΔBCE discriminated patients who would evolve to death in the ICU, hospital ward, and 6 months after admission. After adjusting for possible confounders, the ΔBCE value but not SOFA scores was independently associated with 6-month mortality (RR 0.38, CI 95% 0.18-0.78; P = 0.009). At a cut-off of - 0.002, ΔBCE displayed 100% sensitivity and 73% specificity for predicting 6-month mortality CONCLUSIONS: The ΔBCE signature in lymphocytes provided an earlier recognition of septic shock patients in the ICU at risk of long-term deterioration of health status.
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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.
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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: Postoperative cognitive dysfunction (POCD) may be related to brain injury. S100B protein and neuron-specific enolase (NSE) have been investigated as potential biochemical markers of neural cell injury in animals and humans. This study aimed to investigate the association between POCD, brain injury and serum concentrations of S100B and NSE after periodontal surgery in aged dogs. STUDY DESIGN: Prospective observational animal study. ANIMALS: A total of 24 male and female dogs undergoing periodontal surgery. METHODS: Dogs were separated into two groups based on age: control group, 10 dogs ≤ 8 years and aged group, 14 dogs > 8 years. Cognitive function was measured preoperatively and on the seventh postoperative day using the Canine Cognitive Dysfunction Rating scale and the Age-Related Cognitive and Affective Disorders scale. S100B protein and NSE serum concentrations were measured before and immediately after the surgery. RESULTS: POCD was not observed after surgery in the present study. Serum concentrations of S100B and NSE were increased postoperatively in the control group but not in the aged group (p = 0.04 and 0.03, respectively). Preoperative S100B serum concentrations were significantly higher in the aged group (p = 0.01). CONCLUSIONS: There was no association between POCD and high concentrations of S100B and NSE in dogs. However, increased postoperative serum concentrations of S100B and NSE were found in the control group after surgery, an effect that may indicate neural damage. CLINICAL RELEVANCE: The results suggest that anesthesia and oral surgery are associated with higher postoperative serum concentrations of S100B and NSE in dogs ≤ 8 years old, which may indicate neural damage. Serum concentrations of S100B were elevated in aged dogs before anesthesia, a finding that might be related to chronic preoperative brain damage.
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Anestesia/veterinária , Doenças do Cão/diagnóstico , Fosfopiruvato Hidratase/sangue , Complicações Cognitivas Pós-Operatórias/diagnóstico , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Envelhecimento , Animais , Estudos de Casos e Controles , Doenças do Cão/sangue , Doenças do Cão/enzimologia , Cães , Feminino , Masculino , Complicações Cognitivas Pós-Operatórias/sangueRESUMO
Early life stressors, such as childhood trauma, have been associated to alterations in immune response that can last until adulthood. In this context, interleukin 1ß (IL-1ß) emerges as a pro-inflammatory cytokine with a pivotal role. Also, considering the temperament differences in stress susceptibility, and even immune dysfunction, studies investigating the complex interaction between these factors are scarce. Thus, the aim of the present study was to evaluate the moderating role of temperament traits in the relationship between childhood trauma and serum IL-1ß levels. This cross-sectional study consisted of 325 individuals, men and women, aged 18-35, enrolled from a population-based study in the city of Pelotas, Southern Brazil. Our main results indicate that higher serum levels of IL-1ß were associated with trauma severity (p < 0.01), and the variance of anger could explain 29% of IL-1ß increase in individuals who suffered severe trauma (p < 0.05). The effect of anger was considerably stronger in men than in women (46% and 25%, respectively). Moreover, the variance of sensitivity also explained 15% of IL-1ß increase (p < 0.05) as well as the variance of volition explained 11% of IL-1ß decrease (p < 0.05) in individuals who suffered severe trauma in the general population. Our results indicate that emotional individual differences can moderate the impact of childhood trauma on low-grade inflammation in young adults.
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Experiências Adversas da Infância , Ira/fisiologia , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-1beta/sangue , Trauma Psicológico/imunologia , Trauma Psicológico/fisiopatologia , Temperamento/fisiologia , Adolescente , Adulto , Estudos Transversais , Feminino , Humanos , Individualidade , Inflamação/sangue , Masculino , Trauma Psicológico/sangue , Índice de Gravidade de Doença , Fatores Sexuais , Adulto JovemRESUMO
OBJECTIVE: The aim of this study was to assess if cytokines levels (IL-6 and IL-10) are related to major depressive disorder (MDD) and bipolar disorder (BD), in a population-based study. METHODS: This was a cross-sectional study population-based, involving 1037 people aged 18-35. MDD, BD, anxiety and suicide risk were assessed using the Mini International Neuropsychiatric Interview. Serum IL-6 and IL-10 were measured by ELISA using a commercial kit. RESULTS: The total sample comprised 1034 young adults, being 14.4% with MDD and 13.7% with BD. MDD and BD groups showed significantly higher serum IL-6 levels (pâ¯≤â¯0.001) and IL-10 levels (pâ¯≤â¯0.001) when compared to healthy control group. No correlation was found between serum IL-6 and IL-10 levels in health control group (pâ¯=â¯0.830; râ¯=â¯-0.008), non-suicide risk (pâ¯=â¯0.337; râ¯=â¯0.032) and non-anxiety disorder (pâ¯=â¯0.375; râ¯=â¯0.031). Covariance analysis showed that mood disorders alone, increase both interleukin levels (IL-6, pâ¯=â¯0.019; and IL-10, pâ¯=â¯0.026), whilst the interaction of mood disorders and suicide risk or anxiety disorders did not. CONCLUSION: Our results suggest that inflammatory dysregulation may be involved in the physiopathology of mood disorders and serum IL-6 and IL-10 levels are putative biomarkers for these disorders.
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Transtorno Bipolar/sangue , Transtorno Depressivo Maior/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Transtornos do Humor/sangue , Adolescente , Adulto , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Adulto JovemRESUMO
We hypothesized that supraphysiological administration of the anabolic-androgenic steroids (AAS) like testosterone (TEST) and nandrolone decanoate (NAND) might differentially affect synaptic and extrasynaptic components of mitochondrial bioenergetics, thereby resulting in memory impairment. Oil (VEH), NAND or TEST (15 mg/Kg) were daily administered to male CF-1 albino mice for 19-days. We evaluated in the synaptosomes and extrasynaptic mitochondria, Ca2+ influx/efflux, membrane potential ΔÑ°m, oxidative respiratory states, dehydrogenases activity, H2O2 production, Tau phosphorylation, and spatial memory in the Morris water maze (MWM). In synaptosomes, both AAS increased Ca2+ influx and Na+ dependent efflux. In extrasynaptic mitochondria, NAND increased the Ca2+ influx. NAND prominently impaired ΔÑ°m formation and dissipation in synaptosomal and extrasynaptic mitochondria, while the effect of TEST was less pronounced. TEST increased the Reserve Respiratory Capacity in synaptosomes, and NAND decreased dehydrogenases activity in synaptic and extrasynaptic mitochondria. Also, NAND increased H2O2 production by synaptosomes and extrasynaptic mitochondria. NAND increased pTauSer396 in synaptosomes. Both AAS did not impair memory performance on MWM. We highlight that high doses of NAND cause neurotoxic effects to components of synaptic and extrasynaptic mitochondrial bioenergetics, like calcium influx, membrane potential and H2O2 production. TEST was less neurotoxic to synaptic and extrasynaptic mitochondrial bioenergetics responses.
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Mitocôndrias/efeitos dos fármacos , Nandrolona/farmacologia , Sinapses/efeitos dos fármacos , Congêneres da Testosterona/farmacologia , Testosterona/farmacologia , Animais , Western Blotting , Cálcio/metabolismo , Metabolismo Energético/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Nandrolona/efeitos adversos , Consumo de Oxigênio/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Sinapses/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Testosterona/efeitos adversos , Congêneres da Testosterona/efeitos adversos , Proteínas tau/metabolismoRESUMO
Generalized seizures trigger excessive neuronal firing that imposes large demands on the brain glucose/lactate availability and utilization, which synchronization requires an integral mitochondrial oxidative capability. We investigated whether a single convulsive crisis affects brain glucose/lactate availability and mitochondrial energy production. Adult male Wistar rats received a single injection of pentylentetrazol (PTZ, 60 mg/kg, i.p.) or saline. The cerebrospinal fluid (CSF) levels of glucose and lactate, mitochondrial respirometry, [14C]-2-deoxy-D-glucose uptake, glycogen content and cell viability in hippocampus were measured. CSF levels of glucose and lactate (mean ± SD) in control animals were 68.08 ± 11.62 mg/dL and 1.17 ± 0.32 mmol/L, respectively. Tonic-clonic seizures increased glucose levels at 10 min (96.25 ± 13.19) peaking at 60 min (113.03 ± 16.34) returning to control levels at 24 h (50.12 ± 12.81), while lactate increased at 10 min (3.23 ± 1.57) but returned to control levels at 360 min after seizures (1.58 ± 0.21). The hippocampal [14C]-2-deoxy-D-glucose uptake, glycogen content, and cell viability decreased up to 60 min after the seizures onset. Also, an uncoupling between mitochondrial oxygen consumption and ATP synthesis via FoF1-ATP synthase was observed at 10 min, 60 min and 24 h after seizures. In summary, after a convulsive seizure glucose and lactate levels immediately rise within the brain, however, considering the acute impact of this metabolic crisis, mitochondria are not able to increase energy production thereby affecting cell viability.
Assuntos
Glucose/líquido cefalorraquidiano , Ácido Láctico/líquido cefalorraquidiano , Mitocôndrias/metabolismo , Convulsões/líquido cefalorraquidiano , Animais , Desoxiglucose/metabolismo , Modelos Animais de Doenças , Transporte de Elétrons/efeitos dos fármacos , Etanolaminas/toxicidade , Glicogênio/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Masculino , Mitocôndrias/efeitos dos fármacos , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Fatores de TempoRESUMO
Traumatic brain injury (TBI) increases Ca2+ influx into neurons and desynchronizes mitochondrial function leading to energy depletion and apoptosis. This process may be influenced by brain testosterone (TS) levels, which are known to decrease after TBI. We hypothesized that a TS-based therapy could preserve mitochondrial neuroenergetics after TBI, thereby reducing neurodegeneration. C57BL/6J mice were submitted to sham treatment or severe parasagittal controlled cortical impact (CCI) and were subcutaneously injected with either vehicle (VEH-SHAM and VEH-CCI) or testosterone cypionate (15 mg/kg, TS-CCI) for 10 days. Cortical tissue homogenates ipsilateral to injury were used for neurochemical analysis. The VEH-CCI group displayed an increased Ca2+-induced mitochondrial swelling after the addition of metabolic substrates (pyruvate, malate, glutamate, succinate, and adenosine diphosphate [PMGSA]). The addition of Na+ stimulated mitochondrial Ca2+ extrusion through Na+/Ca2+/Li+ exchanger (NCLX) in VEH-SHAM and TS-CCI, but not in the VEH-CCI group. Reduction in Ca2+ efflux post-injury was associated with impaired mitochondrial membrane potential formation/dissipation, and decreased mitochondrial adenosine triphosphate (ATP)-synthase coupling efficiency. Corroborating evidence of mitochondrial uncoupling was observed with an increase in H2O2 production post-injury, but not in superoxide dismutase (SOD2) protein levels. TS administration significantly reduced these neuroenergetic alterations. At molecular level, TS prevented the increase in pTauSer396 and alpha-Spectrin fragmentation by the Ca2+dependent calpain-2 activation, and decreased both caspase-3 activation and Bax/BCL-2 ratio, which suggests a downregulation of mitochondrial apoptotic signals. Search Tool for the Retrieval of Interacting Genes/Proteins database provided two distinct gene/protein clusters, "upregulated and downregulated," interconnected through SOD2. Therefore, TS administration after a severe CCI improves the mitochondrial Ca2+extrusion through NCLX exchanger and ATP synthesis efficiency, ultimately downregulating the overexpression of molecular drivers of neurodegeneration.
Assuntos
Androgênios/farmacologia , Lesões Encefálicas Traumáticas/patologia , Mitocôndrias/efeitos dos fármacos , Degeneração Neural/patologia , Testosterona/análogos & derivados , Animais , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/patologia , Distribuição Aleatória , Testosterona/farmacologiaRESUMO
BACKGROUND: A plethora of reactive cellular responses emerge immediately after a traumatic spinal cord injury (SCI) and may influence the patient's outcomes. We investigated whether serum concentrations of neuron-specific enolase, interleukin-6, glial-derived neurotrophic factor, and neurotrophic growth factor reflect the acute-phase responses to different etiologies of SCI and may serve as predictive biomarkers of neurologic and functional outcomes. METHODS: Fifty-two patients were admitted to the intensive care unit after SCI due to traffic accidents, falls, and firearm wounds and had blood samples collected within 48 hours and 7 days after SCI. Thirty-six healthy subjects with no history of SCI were included as controls. Neurologic and functional status was evaluated on the basis of American Spinal Injury Association and Functional Independence Measure scores over a period of 48 hours and 6 months after SCI. RESULTS: Serum NSE increased significantly 48 hours and 7 days after SCI compared with controls, while interleukin-6 increased only at 48 hours. In contrast, the neurotrophic growth factor level significantly decreased 48 hours and 7 days after SCI. Serum glial-derived neurotrophic factor level did not differ from control at any time point. Also, there was no significant difference in biomarker concentrations between the etiologies of SCI or the level of spinal injury. There were no correlations between biomarker levels at 48 hours with neurologic or functional outcomes 7 days and 6 months after SCI. CONCLUSIONS: Our results suggest expansive axonal damage coupled with an acute proinflammatory response after SCI. However, in our study biomarker concentration did not correlate with short- or long-term prognosis, such as survival rate or sensory and motor function.
Assuntos
Traumatismos da Medula Espinal/sangue , Traumatismos da Medula Espinal/terapia , Adulto , Biomarcadores/sangue , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/lesões , Estudos de Coortes , Feminino , Humanos , Interleucina-6/sangue , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/lesões , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Neural/sangue , Estudos Prospectivos , Traumatismos da Medula Espinal/diagnóstico por imagem , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/lesões , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: The aim of this study was to verify the serum GDNF levels in individuals with anxiety disorder (AD) in a population-based study. METHODS: This was a cross-sectional study population-based, with people aged 18 to 35. AD's assessment was performed using the Mini International Neuropsychiatric Interview (M.I.N.I). Serum GDNF was measured by ELISA using a commercial kit. RESULTS: The prevalence was 3.3% for post-traumatic stress disorder, 6.7% for panic disorders, 17% generalized anxiety disorder, 5.1% for obsessive- compulsive disorder and 7.5% for social phobia. Serum GDNF levels was higher in individuals with panic disorders (pâ¯=â¯0.013), generalized anxiety (pâ¯=â¯0.035), obsessive- compulsive disorder (pâ¯=â¯0.005) and social phobia (pâ¯=â¯0.004), when compared to individuals without ADs. Only post traumatic stress disorder is not associated with serum GDNF levels (pâ¯=â¯0.119). CONCLUSION: In this paper, we observed increased serum levels of GDNF in individuals with anxiety disorders, suggesting that this biomarker can be used as a putative marker for AD's. The knowledge of the physiological changes related to anxiety disorders can provide a better understanding of AD's pathogenesis, as well as, mechanisms involved in the progression of this condition.