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BACKGROUND/OBJECTIVES: Aneurysmal subarachnoid haemorrhage (aSAH) is a life-threatening event with major complications. Delayed cerebral infarct (DCI) occurs most frequently 7 days after aSAH and can last for a prolonged period. To determine the most predictive radiological scales in grading subarachnoid or ventricular haemorrhage or both for functional outcome at 3 months in a large aSAH population, we conducted a single-centre retrospective study. METHODS: A 3-year single-centre retrospective cohort study of 230 patients hospitalised for aSAH was analysed. Initial computed tomography (CT) scans in patients hospitalised for aSAH were blindly assessed using eight grading systems: the Fisher grade, modified Fisher grade, Barrow Neurological Institute scale, Hijdra scale, Intraventricular Haemorrhage (IVH) score, Graeb score and LeRoux score. RESULTS: Of 200 patients with aSAH who survived to day 7 and were included for DCI analysis, 39% of cases were complicated with DCI. The Hijdra scale was the best predictor for DCI, with a receiver operating characteristic area under the curve (ROCAUC) of 0.80 (95% confidence interval (CI), 0.74-0.85). The IVH score was the most effective grading system for predicting acute hydrocephalus, with a ROCAUC of 0.85 (95% CI, 0.79-0.89). In multivariate analysis, the Hijdra scale was the best predictor of the occurrence of DCI (hazard ratio, 1.18; 95% CI, 1.10-1.25). CONCLUSIONS: Although these results have yet to be prospectively confirmed, our findings suggest that the Hijdra scale may be a good predictor of DCI and could be useful in daily clinical practice. CLINICAL RELEVANCE STATEMENT: Better assessment of subarachnoid haemorrhage patients would allow for better prognostication and management of expectations, as well as referral for appropriate services and helping to appropriate use limited critical care resources. KEY POINTS: Aneurysmal subarachnoid haemorrhage is a life-threatening event that causes severe disability and leads to major complications such as delayed cerebral infarction. Accurate assessment of the amount of blood in the subarachnoid spaces on computed tomography with the Hijdra scale can better predict the risk of delayed cerebral infarct. The Hijdra scale could be a good triage tool for subarachnoid haemorrhage patients.
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Metabolic disorders are risk factors for stroke exacerbating subsequent complications. Rapidly after brain injury, a glial scar forms, preventing excessive inflammation and limiting axonal regeneration. Despite the growing interest in wound healing following brain injury, the formation of a glial scar in the context of metabolic disorders is poorly documented. In this study, we used db/db mice to investigate the impact of metabolic perturbations on brain repair mechanisms, with a focus on glial scarring. First, we confirmed the development of obesity, poor glucose regulation, hyperglycaemia and liver steatosis in these mice. Then, we observed that 3 days after a 30-min middle cerebral artery occlusion (MCAO), db/db mice had larger infarct area compared with their control counterparts. We next investigated reactive gliosis and glial scar formation in db/+ and db/db mice. We demonstrated that astrogliosis and microgliosis were exacerbated 3 days after stroke in db/db mice. Furthermore, we also showed that the synthesis of extracellular matrix (ECM) proteins (i.e., chondroitin sulphate proteoglycan, collagen IV and tenascin C) was increased in db/db mice. Consequently, we demonstrated for the first time that metabolic disorders impair reactive gliosis post-stroke and increase ECM deposition. Given that the damage size is known to influence glial scar, this study now raises the question of the direct impact of hyperglycaemia/obesity on reactive gliosis and glia scar. It paves the way to promote the development of new therapies targeting glial scar formation to improve functional recovery after stroke in the context of metabolic disorders.
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Cicatriz , Gliose , Infarto da Artéria Cerebral Média , Animais , Gliose/metabolismo , Gliose/patologia , Camundongos , Cicatriz/metabolismo , Cicatriz/patologia , Infarto da Artéria Cerebral Média/metabolismo , Neuroglia/metabolismo , Neuroglia/patologia , Masculino , Camundongos Endogâmicos C57BL , Doenças Metabólicas/metabolismo , Doenças Metabólicas/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Obesidade/metabolismo , Obesidade/complicações , Proteínas da Matriz Extracelular/metabolismo , Hiperglicemia/metabolismoRESUMO
BACKGROUND: Optimisation of brain oxygenation might improve neurological outcome after traumatic brain injury. The OXY-TC trial explored the superiority of a strategy combining intracranial pressure and brain tissue oxygen pressure (PbtO2) monitoring over a strategy of intracranial pressure monitoring only to reduce the proportion of patients with poor neurological outcome at 6 months. METHODS: We did an open-label, randomised controlled superiority trial at 25 French tertiary referral centres. Within 16 h of brain injury, patients with severe traumatic brain injury (aged 18-75 years) were randomly assigned via a website to be managed during the first 5 days of admission to the intensive care unit either by intracranial pressure monitoring only or by both intracranial pressure and PbtO2 monitoring. Randomisation was stratified by age and centre. The study was open label due to the visibility of the intervention, but the statisticians and outcome assessors were masked to group allocation. The therapeutic objectives were to maintain intracranial pressure of 20 mm Hg or lower, and to keep PbtO2 (for those in the dual-monitoring group) above 20 mm Hg, at all times. The primary outcome was the proportion of patients with an extended Glasgow Outcome Scale (GOSE) score of 1-4 (death to upper severe disability) at 6 months after injury. The primary analysis was reported in the modified intention-to-treat population, which comprised all randomly assigned patients except those who withdrew consent or had protocol violations. This trial is registered with ClinicalTrials.gov, NCT02754063, and is completed. FINDINGS: Between June 15, 2016, and April 17, 2021, 318 patients were randomly assigned to receive either intracranial pressure monitoring only (n=160) or both intracranial pressure and PbtO2 monitoring (n=158). 27 individuals with protocol violations were not included in the modified intention-to-treat analysis. Thus, the primary outcome was analysed for 144 patients in the intracranial pressure only group and 147 patients in the intracranial pressure and PbtO2 group. Compared with intracranial pressure monitoring only, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with GOSE score 1-4 (51% [95% CI 43-60] in the intracranial pressure monitoring only group vs 52% [43-60] in the intracranial pressure and PbtO2 monitoring group; odds ratio 1·0 [95% CI 0·6-1·7]; p=0·95). Two (1%) of 144 participants in the intracranial pressure only group and 12 (8%) of 147 participants in the intracranial pressure and PbtO2 group had catheter dysfunction (p=0.011). Six patients (4%) in the intracranial pressure and PbtO2 group had an intracrebral haematoma related to the catheter, compared with none in the intracranial pressure only group (p=0.030). No significant difference in deaths was found between the two groups at 12 months after injury. At 12 months, 33 deaths had occurred in the intracranial pressure group: 25 (76%) were attributable to the brain trauma, six (18%) were end-of-life decisions, and two (6%) due to sepsis. 34 deaths had occured in the intracranial pressure and PbtO2 group at 12 months: 25 (74%) were attributable to the brain trauma, six (18%) were end-of-life decisions, one (3%) due to pulmonary embolism, one (3%) due to haemorrhagic shock, and one (3%) due to cardiac arrest. INTERPRETATION: After severe non-penetrating traumatic brain injury, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with poor neurological outcome at 6 months. Technical failures related to intracerebral catheter and intracerebral haematoma were more frequent in the intracranial pressure and PbtO2 group. Further research is needed to assess whether a targeted approach to multimodal brain monitoring could be useful in subgroups of patients with severe traumatic brain injury-eg, those with high intracranial pressure on admission. FUNDING: The French National Program for Clinical Research, La Fondation des Gueules Cassées, and Integra Lifesciences.
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Lesões Encefálicas Traumáticas , Oxigênio , Humanos , Pressão Intracraniana , Lesões Encefálicas Traumáticas/terapia , Encéfalo , França , Hematoma , MorteRESUMO
SARS-CoV-2 infection goes beyond acute pneumonia, as it also impacts lipid metabolism. Decreased HDL-C and LDL-C levels have been reported in patients with COVID-19. The lipid profile is a less robust biochemical marker than apolipoproteins, components of lipoproteins. However, the association of apolipoprotein levels during COVID-19 is not well described and understood. The objective of our study is to measure plasma levels of 14 apolipoproteins in patients with COVID-19 and to evaluate the relationships between apolipoprotein levels, severity factors and patient outcomes. From November to March 2021, 44 patients were recruited on admission to the intensive care unit because of COVID-19. Fourteen apolipoproteins and LCAT were measured by LC-MS/MS in plasma of 44 COVID-19 patients on admission to the ICU and 44 healthy control subjects. Absolute apolipoprotein concentrations were compared between COVID-19 patients and controls. Plasma apolipoproteins (Apo) A (I, II, IV), C(I, II), D, H, J and M and LCAT were lower in COVID-19 patients, whereas Apo E was higher. COVID-19 severity factors such as PaO2/FiO2 ratio, SO-FA score and CRP were correlated with certain apolipoproteins. Lower Apo B100 and LCAT levels were observed in non-survivors of COVID-19 versus survivors. To conclude, in this study, lipid and apolipoprotein profiles are altered in COVID-19 patients. Low Apo B100 and LCAT levels may be predictive of non-survival in COVID-19 patients.
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COVID-19 , Colesterol , Humanos , Estudos de Coortes , Cromatografia Líquida , Colesterol/metabolismo , SARS-CoV-2/metabolismo , Espectrometria de Massas em Tandem , Apolipoproteínas , Apolipoproteínas A , Apolipoproteína B-100 , Unidades de Terapia Intensiva , Apolipoproteína A-I , Apolipoproteínas B , Apolipoproteína A-IIRESUMO
AIM: Subjects with Familial Partial Lipodystrophy type 2 (FPLD2) are at high risk to develop diabetes. To better understand the natural history and variability of this disease, we studied glucose tolerance, insulin response to an oral glucose load, and metabolic markers in the largest cohort to date of subjects with FPLD2 due to the same LMNA variant. METHODS: A total of 102 patients aged > 18 years, with FPLD2 due to the LMNA 'Reunionese' variant p.(Thr655Asnfs*49) and 22 unaffected adult relatives with normal glucose tolerance (NGT) were enrolled. Oral Glucose Tolerance Tests (OGTT) with calculation of derived insulin sensitivity and secretion markers, and measurements of HbA1c, C-reactive protein, leptin, adiponectin and lipid profile were performed. RESULTS: In patients with FPLD2: 65% had either diabetes (41%) or prediabetes (24%) despite their young age (median: 39.5 years IQR 29.0-50.8) and close-to-normal BMI (median: 25.5 kg/m2 IQR 23.1-29.4). Post-load OGTT values revealed insulin resistance and increased insulin secretion in patients with FPLD2 and NGT, whereas patients with diabetes were characterized by decreased insulin secretion. Impaired glucose tolerance with normal fasting glucose was present in 86% of patients with prediabetes. Adiponectin levels were decreased in all subjects with FPLD2 and correlated with insulin sensitivity markers. CONCLUSIONS: OGTT reveals early alterations of glucose and insulin metabolism in patients with FPLD2, and should be systematically performed before excluding a diagnosis of prediabetes or diabetes to adapt medical care. Decreased adiponectin is an early marker of the disease. Adiponectin replacement therapy warrants further study in FPLD2.
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Diabetes Mellitus Lipoatrófica , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Lipodistrofia Parcial Familiar , Estado Pré-Diabético , Adulto , Humanos , Adiponectina , Insulina , Glucose , Glicemia/metabolismoRESUMO
Metabolic disorders related to obesity and type 2 diabetes are associated with aggravated cerebrovascular damages during stroke. In particular, hyperglycemia alters redox and inflammatory status, leading to cerebral endothelial cell dysfunction, blood-brain barrier (BBB) disruption and brain homeostasis loss. Polyphenols constitute the most abundant dietary antioxidants and exert anti-inflammatory effects that may improve cerebrovascular complications in stroke. This study evaluated the effects of the characterized polyphenol-rich extract of Antirhea borbonica medicinal plant and its major constituent caffeic acid on a high-fat diet (HFD)-induced obesity mouse model during ischemic stroke, and murine bEnd3 cerebral endothelial cells in high glucose condition. In vivo, polyphenols administered by oral gavage for 12 weeks attenuated insulin resistance, hyperglycemia, hyperinsulinemia and dyslipidemia caused by HFD-induced obesity. Polyphenols limited brain infarct, hemorrhagic transformation and BBB disruption aggravated by obesity during stroke. Polyphenols exhibited anti-inflammatory and antioxidant properties by reducing IL-1ß, IL-6, MCP-1, TNF-α and Nrf2 overproduction as well as total SOD activity elevation at the cerebral or peripheral levels in obese mice. In vitro, polyphenols decreased MMP-2 activity that correlated with MCP-1 secretion and ROS intracellular levels in hyperglycemic condition. Protective effects of polyphenols were linked to their bioavailability with evidence for circulating metabolites including caffeic acid, quercetin and hippuric acid. Altogether, these findings show that antioxidant polyphenols reduced cerebrovascular, inflammatory and metabolic disorders aggravated by obesity in a mouse model of stroke. It will be relevant to assess polyphenol-based strategies to improve the clinical consequences of stroke in the context of obesity and diabetes.
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Adiponectin exhibits pleiotropic effects, including anti-inflammatory, anti-apoptotic, anti-oxidant, and neuroprotective ones. Although some studies have documented brain expression in different rodent models of its receptors, AdipoR1 and AdipoR2, their global distribution remains incomplete. Here, we demonstrated that both AdipoR are widely distributed in the brains of adult mice. Furthermore, by double immunostaining studies, we showed that AdipoR1 and AdipoR2 are mainly expressed in neurons and blood vessels. Then, considering the wide distribution of both receptors and the neuroprotective effects of adiponectin, we tested the therapeutic effect of a single injection of the adiponectin receptor agonist, AdipoRON (5 mg.kg-1), 24 h after stroke in a model of middle cerebral artery occlusion technique (MCAO). Under our experimental conditions, we demonstrated that AdipoRON did not modulate the infarct volume, cell death, neuroinflammatory parameters including microglia activation and oxidative stress. This study suggests that a protocol based on multiple injections of AdipoRON at a higher dose after MCAO could be considered to promote the therapeutic properties of AdipoRON on the brain repair mechanism and recovery.
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OBJECTIVES: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE. METHODS: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders. RESULTS: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83). CONCLUSIONS: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.
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Doenças Autoimunes , Leucemia Mielomonocítica Crônica , Síndromes Mielodisplásicas , Tromboembolia Venosa , Doenças Autoimunes/complicações , Doenças Autoimunes/epidemiologia , Estudos de Casos e Controles , Humanos , Leucemia Mielomonocítica Crônica/complicações , Leucemia Mielomonocítica Crônica/epidemiologia , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/epidemiologia , Estudos Retrospectivos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologiaRESUMO
The newly identified coronavirus SARS-CoV-2 is responsible for the worldwide pandemic COVID-19. Considerable efforts have been devoted for the development of effective vaccine strategies against COVID-19. The SARS-CoV-2 spike protein has been identified as the major antigen candidate for the development of COVID-19 vaccines. The Pfizer-BioNTech COVID-19 vaccine COMIRNATY is a lipid nanoparticle-encapsulated mRNA encoding a full-length and prefusion-stabilized SARS-CoV-2 spike protein. In the present study, synthetic peptide-based ELISA assays were performed to identify linear B-cell epitopes into the spike protein that contribute to elicitation of antibody response in COMIRNATY-vaccinated individuals. The synthetic S2P6 peptide containing the spike residues 1138/1169 and to a lesser extent, the synthetic S1P4 peptide containing the spike residues 616/644 were recognized by the immune sera from COMIRNATY vaccine recipients but not COVID-19 recovered patients. We assume that the synthetic S2P6 peptide and to a lesser extent the synthetic S1P4 peptide, could be of interest to measure the dynamic of antibody response to COVID-19 mRNA vaccines. The S2P6 peptide has been identified as immunogenic in adult BALB/c mice that received protein-peptide conjugates in a prime-boost schedule. This raises the question on the role of the B-cell epitope peptide containing the SARS-CoV-2 spike residues 1138/1169 in protective efficacy of the Pfizer-BioNTech COVID-19 vaccine COMIRNATY.
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Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Epitopos de Linfócito B , Glicoproteína da Espícula de Coronavírus , Animais , Anticorpos Antivirais/imunologia , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , Lipossomos , Camundongos , Nanopartículas , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
BACKGROUND: Traumatic brain injury (TBI) lesions are known to evolve over time, but the duration and consequences of cerebral remodelling are unclear. Degenerative mechanisms occurring in the chronic phase after TBI could constitute "tertiary" lesions related to the neurological outcome. OBJECTIVE: The objective of this prospective study of severe TBI was to longitudinally evaluate the volume of white and grey matter structures and white matter integrity with 2 time-point multimodal MRI. METHODS: Longitudinal MRI follow-up was obtained for 11 healthy controls (HCs) and 22 individuals with TBI (mean [SD] 60 [15] months after injury) along with neuropsychological assessments. TBI individuals were classified in the "favourable" recovery group (Glasgow Outcome Scale Extended [GOSE] 6-8) and "unfavourable" recovery group (GOSE 3-5) at 5 years. Variation in brain volumes (3D T1-weighted image) and white matter integrity (diffusion tensor imaging [DTI]) were quantitatively assessed over time and used to predict neurological outcome. RESULTS: TBI individuals showed a marked decrease in volumes of whole white matter (median -11.4% [interquartile range -5.8; -14.6]; p < 0.001) and deep grey nuclear structures (-17.1% [-10.6; -20.5]; p < 0.001). HCs did not show any significant change over the same time period. Median volumetric loss in several brain regions was higher with GOSE 3-5 than 6-8. These lesions were associated with lower fractional anisotropy and higher mean diffusivity at baseline. Volumetric variations were positively correlated with normalized fractional anisotropy and negatively with normalized mean diffusivity at baseline and follow-up. A computed predictive model with baseline DTI showed good accuracy to predict neurological outcome (area under the receiver operating characteristic curve 0.82 [95% confidence interval 0.81-0.83]) CONCLUSIONS: We characterised the striking atrophy of deep brain structures after severe TBI. DTI imaging in the subacute phase can predict the occurrence and localization of these tertiary lesions as well as long-term neurological outcome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00577954. Registered on October 2006.
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Lesões Encefálicas Traumáticas , Imagem de Tensor de Difusão , Humanos , Encéfalo/patologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/patologia , Seguimentos , Imageamento por Ressonância Magnética , Estudos Prospectivos , Estudos de Casos e ControlesRESUMO
INTRODUCTION: The pleiotropic protective effects of high-density lipoproteins (HDLs) on cerebral ischemia have never been tested under acute hyperglycemic conditions. The aim of this study is to evaluate the potential neuroprotective effect of HDL intracarotid injection in a mouse model of middle cerebral artery occlusion (MCAO) under hyperglycemic conditions. METHODS: Forty-two mice were randomized to receive either an intracarotid injection of HDLs or saline. Acute hyperglycemia was induced by an intraperitoneal injection of glucose (2.2 g/kg) 20 min before MCAO. Infarct size (2,3,5-triphenyltetrazolium chloride (TTC)-staining), blood-brain barrier leakage (IgG infiltration), and hemorrhagic changes (hemoglobin assay by ELISA and hemorrhagic transformation score) were analyzed 24 h post-stroke. Brain tissue inflammation (IL-6 by ELISA, neutrophil infiltration and myeloperoxidase by immunohisto-fluorescence) and apoptosis (caspase 3 activation) were also assessed. RESULTS: Intraperitoneal D-glucose injection allowed HDL- and saline-treated groups to reach a blood glucose level of 300 mg/dl in the acute phase of cerebral ischemia. HDL injection did not significantly reduce mortality (19% versus 29% in the saline-injected group) or cerebral infarct size (p = 0.25). Hemorrhagic transformations and inflammation parameters were not different between the two groups. In addition, HDL did not inhibit apoptosis under acute hyperglycemic conditions. Conclusion: We observed a nonsignificant decrease in cerebral infarct size in the HDL group. The deleterious consequences of reperfusion such as hemorrhagic transformation or inflammation were not improved by HDL infusion. In acute hyperglycemia, HDLs are not potent enough to counteract the adverse effects of hyperglycemia. The addition of antioxidants to therapeutic HDLs could improve their neuroprotective capacity.
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Hiperglicemia/complicações , Lipoproteínas HDL/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Hemorragia/patologia , Hiperglicemia/metabolismo , Lipoproteínas HDL/farmacologia , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Resultado do TratamentoRESUMO
[Figure: see text].
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Isquemia Encefálica/metabolismo , Hemorragia/genética , AVC Isquêmico/metabolismo , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Isquemia Encefálica/genética , AVC Isquêmico/genética , Camundongos , Camundongos Obesos , Fatores de Risco , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismoRESUMO
BACKGROUND: Stroke in context of type 2 diabetes (T2D) is associated with a poorer outcome than in non-diabetic conditions. We aimed at creating a new reproducible mouse model of stroke in impaired glucose tolerance conditions induced by high-fat diet. METHODS: Adult C57BL6 mice were fed for 2 months with either normal diet (ND) or high-fat diet (HFD). We used a model of Middle Cerebral Artery Occlusion (MCAO) for 90 min. Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT) were used to assess pre-diabetic status. Brain infarct volume, hemorrhagic transformation (HT) as well as systemic and cerebral inflammatory markers were evaluated. RESULTS: HFD was associated with an increased body weight and glycemia following OGTT. The HFD group presented a significant increase in brain infarct volume (38.7 (IQR 30-46.7%) vs. 28.45 (IQR 21-30%); p = 0.016) and HT (HFD: 2 (IQR 1-5) vs. ND: 0 (IQR 0-1); p = 0.012) and higher levels of IL-6 and MCP-1 in infarcted hemisphere compared to the ND group. CONCLUSION: Two months of HFD in adult mice were sufficient to alter the lipid profile and the control of hyperglycemia. These metabolic perturbations were significantly associated with increased infarct volume and hemorrhagic complications.
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Isquemia Encefálica/etiologia , Infarto Cerebral/etiologia , Dieta Hiperlipídica/efeitos adversos , Encefalite/etiologia , Animais , Biomarcadores/sangue , Peso Corporal , Encéfalo/patologia , Isquemia Encefálica/patologia , Infarto Cerebral/patologia , Modelos Animais de Doenças , Encefalite/sangue , Encefalite/patologia , Feminino , Intolerância à Glucose , Masculino , Camundongos Endogâmicos C57BLRESUMO
Adult neurogenesis is an evolutionary conserved process occurring in all vertebrates. However, striking differences are observed between the taxa, considering the number of neurogenic niches, the neural stem cell (NSC) identity, and brain plasticity under constitutive and injury-induced conditions. Zebrafish has become a popular model for the investigation of the molecular and cellular mechanisms involved in adult neurogenesis. Compared to mammals, the adult zebrafish displays a high number of neurogenic niches distributed throughout the brain. Furthermore, it exhibits a strong regenerative capacity without scar formation or any obvious disabilities. In this review, we will first discuss the similarities and differences regarding (i) the distribution of neurogenic niches in the brain of adult zebrafish and mammals (mainly mouse) and (ii) the nature of the neural stem cells within the main telencephalic niches. In the second part, we will describe the cascade of cellular events occurring after telencephalic injury in zebrafish and mouse. Our study clearly shows that most early events happening right after the brain injury are shared between zebrafish and mouse including cell death, microglia, and oligodendrocyte recruitment, as well as injury-induced neurogenesis. In mammals, one of the consequences following an injury is the formation of a glial scar that is persistent. This is not the case in zebrafish, which may be one of the main reasons that zebrafish display a higher regenerative capacity.
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Encéfalo/metabolismo , Diferenciação Celular/fisiologia , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Animais , Regeneração Nervosa/fisiologia , Neurônios/fisiologia , Peixe-Zebra/fisiologiaRESUMO
Coronavirus disease 2019 (COVID-19) pandemic is affecting millions of patients worldwide. The consequences of initial exposure to SARS-CoV-2 go beyond pulmonary damage, with a particular impact on lipid metabolism. Decreased levels in HDL-C were reported in COVID-19 patients. Since HDL particles display antioxidant, anti-inflammatory and potential anti-infectious properties, we aimed at characterizing HDL proteome and functionality during COVID-19 relative to healthy subjects. HDLs were isolated from plasma of 8 severe COVID-19 patients sampled at admission to intensive care unit (Day 1, D1) at D3 and D7, and from 16 sex- and age-matched healthy subjects. Proteomic analysis was performed by LC-MS/MS. The relative amounts of proteins identified in HDLs were compared between COVID-19 and controls. apolipoprotein A-I and paraoxonase 1 were confirmed by Western-blot analysis to be less abundant in COVID-19 versus controls, whereas serum amyloid A and alpha-1 antitrypsin were higher. HDLs from patients were less protective in endothelial cells stiumalted by TNFα (permeability, VE-cadherin disorganization and apoptosis). In these conditions, HDL inhibition of apoptosis was blunted in COVID-19 relative to controls. In conclusion, we show major changes in HDL proteome and decreased functionality in severe COVID-19 patients.
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COVID-19/sangue , Lipoproteínas HDL/sangue , Apolipoproteína A-I/sangue , Arildialquilfosfatase/análise , Arildialquilfosfatase/sangue , COVID-19/epidemiologia , COVID-19/patologia , COVID-19/virologia , Estudos de Casos e Controles , Cromatografia Líquida/métodos , Células Endoteliais/patologia , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Proteoma/metabolismo , Proteômica/métodos , SARS-CoV-2/isolamento & purificação , Proteína Amiloide A Sérica/metabolismo , Espectrometria de Massas em Tandem/métodos , Fator de Necrose Tumoral alfa/sangue , alfa 1-Antitripsina/sangueRESUMO
High-density lipoproteins (HDLs) display endothelial protective effects. We tested the role of SR-BI, an HDL receptor expressed by endothelial cells, in the neuroprotective effects of HDLs using an experimental model of acute ischemic stroke. After transient intraluminal middle cerebral artery occlusion (tMCAO), control and endothelial SR-BI deficient mice were intravenously injected by HDLs or saline. Infarct volume and blood-brain barrier (BBB) breakdown were assessed 24 h post tMCAO. The potential of HDLs and the role of SR-BI to maintain the BBB integrity was assessed by using a human cellular model of BBB (hCMEC/D3 cell line) subjected to oxygen-glucose deprivation (OGD). HDL therapy limited the infarct volume and the BBB leakage in control mice relative to saline injection. Interestingly, these neuroprotective effects were thwarted by the deletion of SR-BI in endothelial cells and preserved in mice deficient for SR-BI in myeloid cells. In vitro studies revealed that HDLs can preserve the integrity of the BBB in OGD conditions, and that this effect was reduced by the SR-BI inhibitor, BLT-1. The protection of BBB integrity plays a pivotal role in HDL therapy of acute ischemic stroke. Our results show that this effect is partially mediated by the HDL receptor, SR-BI expressed by endothelial cells.
Assuntos
Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Lipoproteínas HDL/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores Depuradores Classe B/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Linhagem Celular , Ciclopentanos/farmacologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Receptores Depuradores Classe B/antagonistas & inibidores , Receptores Depuradores Classe B/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Tiossemicarbazonas/farmacologiaRESUMO
Modifications in high-density lipoprotein (HDL) particle sizes and HDL-binding proteins have been reported in stroke patients. We evaluated whether the lipoprotein profile, HDL composition and functionality were altered in stroke patients according to their clinical outcome using the modified Rankin Score at 3 months. Plasma samples were obtained from stroke patients treated with intravenous thrombolysis. Levels of cardiovascular and inflammatory markers in plasma were measured using the Human CVD Panel 1 (Milliplex® MAP). Lipoprotein subfractions from plasma were quantified by non-denaturing acrylamide gel electrophoresis, using the Lipoprint®-System (Quantimetrix®), and HDLs were isolated by ultracentrifugation. Relative amounts of paraoxonase-1 (PON1) and alpha-1 anti-trypsin (AAT) in the isolated HDLs were determined by Western blot. HDL anti-inflammatory function was evaluated in human blood-brain barrier endothelial cells stimulated with 100 ng/mL TNFα, and HDL antioxidant function was evaluated via their capacity to limit copper-induced low-density lipoprotein oxidation. Stroke patients with unfavorable outcomes had a lower proportion of small-sized HDLs and increased plasma levels of E-selectin (SELE) and the intercellular adhesion molecule 1 (ICAM1). HDLs from patients with unfavorable outcomes had lower levels of PON1 and displayed a blunted capacity to reduce the expression of SELE, interleukin 8 (IL8) and the monocyte chemoattractant protein-1 (MCP1) mRNA induced by TNFα in endothelial cells. These HDLs also had a reduced antioxidant capacity relative to HDLs from healthy donors. In conclusion, an increased ratio of large/small HDLs with impaired anti-inflammatory and antioxidant capacities was associated with unfavorable outcomes in stroke patients. Alteration of HDL functionality was mainly associated with a low amount of PON1 and high amount of AAT.
RESUMO
SCOPE: Hyperglycemia alters cerebral endothelial cell and blood-brain barrier functions, aggravating cerebrovascular complications such as stroke during diabetes. Redox and inflammatory changes play a causal role. This study evaluates polyphenol protective effects in cerebral endothelial cells and a mouse stroke model during hyperglycemia. METHODS AND RESULTS: Murine bEnd.3 cerebral endothelial cells and a mouse stroke model are exposed to a characterized, polyphenol-rich extract of Antirhea borbonica or its predominant constituent caffeic acid, during hyperglycemia. Polyphenol effects on redox, inflammatory and vasoactive markers, infarct volume, and hemorrhagic transformation are determined. In vitro, polyphenols improve reactive oxygen species levels, Cu/Zn superoxide dismutase activity, and both NAPDH oxidase 4 and nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression deregulated by high glucose. Polyphenols reduce Nrf2 nuclear translocation and counteract nuclear factor-ĸappa B activation, interleukin-6 secretion, and the altered production of vasoactive markers mediated by high glucose. In vivo, polyphenols reduce cerebral infarct volume and hemorrhagic transformation aggravated by hyperglycemia. Polyphenols attenuate redox changes, increase vascular endothelial-Cadherin production, and decrease neuro-inflammation in the infarcted hemisphere. CONCLUSION: Polyphenols protect against hyperglycemia-mediated alterations in cerebral endothelial cells and a mouse stroke model. It is relevant to assess polyphenol benefits to improve cerebrovascular damages during diabetes.
Assuntos
Antioxidantes/farmacologia , Infarto Cerebral/tratamento farmacológico , Hiperglicemia/fisiopatologia , Polifenóis/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Glicemia/metabolismo , Barreira Hematoencefálica/química , Barreira Hematoencefálica/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Infarto Cerebral/patologia , Infarto Cerebral/fisiopatologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Plantas Medicinais/química , Polifenóis/química , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/fisiopatologia , Rubiaceae/química , Acidente Vascular Cerebral/etiologiaRESUMO
High-density lipoproteins (HDLs) represent a family of particle characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to transport cholesterol from peripheral tissues back to the liver conferring them a cardioprotective function. HDLs also display pleiotropic properties including antioxidant, anti-apoptotic, anti-thrombotic, anti-inflammatory, or anti-infectious functions. Clinical data demonstrate that HDL cholesterol levels decrease rapidly during sepsis and that these low levels are correlated with morbi-mortality. Experimental studies emphasized notable structural and functional modifications of HDL particles in inflammatory states, including sepsis. Finally, HDL infusion in animal models of sepsis improved survival and provided a global endothelial protective effect. These clinical and experimental studies reinforce the potential of HDL therapy in human sepsis. In this review, we will detail the different effects of HDLs that may be relevant under inflammatory conditions and the lipoprotein changes during sepsis and we will discuss the potentiality of HDL therapy in sepsis.