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Intracerebral hemorrhage (ICH), which has high mortality and disability rate is associated with microglial pyroptosis and neuroinflammation, and the effective treatment methods are limited Epigallocatechin-3-gallate (EGCG) has been found to play a cytoprotective role by regulating the anti-inflammatory response to pyroptosis in other systemic diseases. However, the role of EGCG in microglial pyroptosis and neuroinflammation after ICH remains unclear. In this study, we investigated the effects of EGCG pretreatment on neuroinflammation-mediated neuronal pyroptosis and the underlying neuroprotective mechanisms in experimental ICH. EGCG pretreatment was found to remarkably improved neurobehavioral performance, and decreased the hematoma volume and cerebral edema in mice. We found that EGCG pretreatment attenuated the release of hemin-induced inflammatory cytokines (IL-1ß, IL-18, and TNF-α). EGCG significantly upregulated the expression of heme oxygenase-1 (HO-1), and downregulated the levels of pyroptotic molecules and inflammatory cytokines including Caspase-1, GSDMD, NLRP3, mature IL-1ß, and IL-18. EGCG pretreatment also decreased the number of Caspase-1-positive microglia and GSDMD along with NLRP3-positive microglia after ICH. Conversely, an HO-1-specific inhibitor (ZnPP), significantly inhibited the anti-pyroptosis and anti-neuroinflammation effects of EGCG. Therefore, EGCG pretreatment alleviated microglial pyroptosis and neuroinflammation, at least in part through the Caspase-1/GSDMD/NLRP3 pathway by upregulating HO-1 expression after ICH. In addition, EGCG pretreatment promoted the polarization of microglia from the M1 phenotype to M2 phenotype after ICH. The results suggest that EGCG is a potential agent to attenuate neuroinflammation via its anti-pyroptosis effect after ICH.
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Hemorragia Cerebral , Hemo-Oxigenasa 1 , Microglía , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores , Animales , Ratones , Caspasas/metabolismo , Caspasas/farmacología , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , Citocinas/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Interleucina-18/metabolismo , Interleucina-18/farmacología , Microglía/efectos de los fármacos , Microglía/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis/efectos de los fármacos , Piroptosis/genética , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
Objective: The complement cascade is activated and contributes to the brain injury after intracerebral hemorrhage (ICH). Complement component 4 (C4), an important component of complement cascade, has been associated with severity of neurological impairment that occurs during ICH. However, the correlation of plasma complement C4 levels with hemorrhagic severity and clinical outcome in ICH patients has not been reported. Materials and methods: This study is a monocentric, real-world, cohort study. In this study, we measured the plasma complement C4 levels of 83 ICH patients and 78 healthy controls. The hematoma volume, the National Institutes of Health Stroke Scale (NIHSS) score, the Glasgow Coma Scale (GCS) score, and the permeability surface (PS) were used to assess and quantify neurological deficit following ICH. Logistic regression analysis was configured to determine the independent relation of plasma complement C4 levels to hemorrhagic severity and clinical outcomes. The contribution of complement C4 to secondary brain injury (SBI) was assessed by changes in plasma C4 levels between admission and at day 7 after ICH. Results: There was a significant elevation of plasma complement C4 levels in ICH patients than in healthy controls (40.48 ± 1.07 vs. 35.25 ± 0.60, p < 0.0001), and the plasma complement C4 levels were closely related to the hemorrhagic severity. Moreover, plasma complement C4 levels of patients were positively correlated with the hematoma volume (r = 0.501, p < 0.001), NIHSS score (r = 0.362, p < 0.001), the GCS score (r = -0.490, p < 0.001), and PS (r = 0.683, p = 0.045) following ICH. Logistic regression analysis also confirmed that patients with high plasma complement C4 levels show a poor clinical outcome after ICH (p < 0.001). Meanwhile, the elevated plasma levels at day 7 after ICH indicated the correlation of complement C4 with SBI (p < 0.01). Conclusion: Plasma complement C4 levels are significantly elevated in ICH patients and positively correlated with the illness severity. Thus, these findings highlight the importance of complement C4 in brain injury after ICH and provide a novel predictor of clinical outcome for this disease.
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BACKGROUND: We investigate the probable effect of anatomic asymmetry of transverse sinus (TS) on the outcomes of acute intracerebral hemorrhage (ICH), to provide reference for customized treatment. METHODS: Consecutive patients with imaging-confirmed acute ICH were enrolled from October 2015 through October 2019, and divided into 2 groups: symmetrical and unilateral (left or right) slender TS groups, based on the status of TS in imaging maps. Brain computed tomography (CT) maps of all patients at baseline and half-month post-ICH were obtained, and the volumes of hematoma and the perihematomal edemas (PHE), as well as the modified Rankin Scale (mRS) scores at the month-3 post-ICH between the 2 groups were assessed and analyzed. RESULTS: A total of 46 eligible patients entered into final analysis, including 18 cases in the slender TS group (14 cases involved the left side while 4 cases involved the right side), and 28 cases in the symmetrical TS group. The mRS scores, hematoma absorption rates, and the residual volumes of PHE of all patients in the 2 groups at half-month post-ICH showed no statistical significance (all P >0.05), and all of the items mentioned above were related to the hematoma volume at baseline (all P <0.001). At the month-3 follow-up post-ICH, the mRS scores between the 2 groups showed no statistical significance as well ( P =0.551). CONCLUSIONS: Anatomic asymmetry of TS may not affect the prognosis of PHE and clinical outcome after ICH.
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Edema Encefálico , Senos Transversos , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/terapia , Hematoma/diagnóstico por imagen , Humanos , PronósticoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, accompanied by amyloid-ß (Aß) overload and hyperphosphorylated tau accumulation in the brain. Synaptic dysfunction, an important pathological hallmark in AD, is recognized as the main cause of the cognitive impairments. Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD. Pathological tau, which is detached from axonal microtubules and mislocalized into pre- and postsynaptic neuronal compartments, is suggested to induce synaptic dysfunction in several ways, including reducing mobility and release of presynaptic vesicles, decreasing glutamatergic receptors, impairing the maturation of dendritic spines at postsynaptic terminals, disrupting mitochondrial transport and function in synapses, and promoting the phagocytosis of synapses by microglia. Here, we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD. We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Humanos , Sinapsis/patología , Proteínas tauRESUMEN
Cell death is a common phenomenon in the progression of Alzheimer's disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. Moreover, several hallmarks of AD pathogenesis were consistent with the characteristics of ferroptosis, such as excess iron accumulation, elevated lipid peroxides, and reactive oxygen species (ROS), reduced glutathione (GSH), and glutathione peroxidase 4 (GPX4) levels. Besides, some ferroptosis inhibitors can relieve AD-related pathological symptoms in AD mice and exhibit potential clinical benefits in AD patients. Therefore, ferroptosis is gradually being considered as a distinct cell death mechanism in the pathogenesis of AD. However, direct evidence is still lacking. In this review, we summarize the features of ferroptosis in AD, its underlying mechanisms in AD pathology, and review the application of ferroptosis inhibitors in both AD clinical trials and mice/cell models, to provide valuable information for future treatment and prevention of this devastating disease.
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S-ribosylhomocysteine lyase (LuxS) has been shown to regulate bacterial multicellular behaviors, typically biofilm formation. However, the mechanisms for the regulation are still mysterious. We previously identified a malonylation modification on K124 and K130 of the LuxS in the plant growth-promoting rhizobacterium B. velezensis (FZB42). In this work, we investigated the effects of the two malonylation sites on biofilm formation and other biological characteristics of FZB42. The results showed that the K124R mutation could severely impair biofilm formation, swarming, and sporulation but promote AI-2 production, suggesting inhibitory effects of high-level AI-2 on the features. All mutations (K124R, K124E, K130R, and K130E) suppressed FZB42 sporulation but increased its antibiotic production. The double mutations generally had a synergistic effect or at least equal to the effects of the single mutations. The mutation of K130 but not of K124 decreased the in vitro enzymatic activity of LuxS, corresponding to the conservation of K130 among various Bacillus LuxS proteins. From the results, we deduce that an alternative regulatory circuit may exist to compensate for the roles of LuxS upon its disruption. This study broadens the understanding of the biological function of LuxS in bacilli and underlines the importance of the two post-translational modification sites.
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Intracerebral hemorrhage (ICH) has the highest mortality rate of all stroke subtypes but an effective treatment has yet to be clinically implemented. Transforming growth factorß1 (TGFß1) has been reported to modulate microgliamediated neuroinflammation after ICH and promote functional recovery; however, the underlying mechanisms remain unclear. Noncoding RNAs such as microRNAs (miRNAs) and competitive endogenous RNAs (ceRNAs) have surfaced as critical regulators in human disease. A known miR93 target, nuclear factor erythroid 2related factor 2 (Nrf2), has been shown to be neuroprotective after ICH. It was hypothesized that TGFß1 functions as a ceRNA that sponges miR935p and thereby ameliorates ICH injury in the brain. Short interfering RNA (siRNA) was used to knock down TGFß1 and miR93 expression was also pharmacologically manipulated to elucidate the mechanistic association between miR935p, Nrf2, and TGFß1 in an in vitro model of ICH (thrombintreated human microglial HMO6 cells). Bioinformatics predictive analyses showed that miR935p could bind to both TGFß1 and Nrf2. It was found that neuronal miR935p was dramatically decreased in these HMO6 cells, and similar changes were observed in fresh brain tissue from patients with ICH. Most importantly, luciferase reporter assays were used to demonstrate that miR935p directly targeted Nrf2 to inhibit its expression and the addition of the TGFß1 untranslated region restored the levels of Nrf2. Moreover, an miR935p inhibitor increased the expression of TGFß1 and Nrf2 and decreased apoptosis. Collectively, these results identified a novel function of TGFß1 as a ceRNA that sponges miR935p to increase the expression of neuroprotective Nrf2 and decrease cell death after ICH. The present findings provided evidence to support miR935p as a potential therapeutic target for the treatment of ICH.
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Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Adulto , Anciano , Apoptosis/genética , Línea Celular , Niño , Biología Computacional , Femenino , Voluntarios Sanos , Humanos , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neuroprotección/genética , Transducción de Señal/genética , Trombina/farmacologíaRESUMEN
BACKGROUND: All of the existing medication and surgical therapies currently cannot completely inhibit intracerebral hemorrhage (ICH)-mediated brain damage, resulting in disability in different degrees in the involved patients. Normobaric oxygenation (NBO) was reported attenuating ischemic brain injury. Herein, we aimed to explore the safety and efficacy of NBO on rescuing the damaged brain tissues secondary to acute ICH, especially those in the perihematoma area being threatened by ischemia and hypoxia. METHODS: A total of 150 patients confirmed as acute spontaneous ICH by computed tomography (CT) within 6 h after symptoms onset, will enroll in this study after signing the informed consent, and enter into the NBO group or control group randomly according to a random number. In the NBO group, patients will inhale high-flow oxygen (8 L/min, 1 h each time for 6 cycles daily) and intake low-flow oxygen (2 L/min) in intermittent periods by mask for a total of 7 days. While in the control group, patients will breathe in only low-flow oxygen (2 L/min) by mask for 7 consecutive days. Computed tomography and perfusion (CT/CTP) will be used to evaluate cerebral perfusion status and brain edema. CT and CTP maps in the two groups at baseline and day 7 and 14 after NBO or low-flow oxygen control will be compared. The primary endpoint is mRS at both Day14 post-ICH and the end of the 3rd month follow-up. The secondary endpoints include NIHSS and plasma biomarkers at baseline and Day-1, 7, and 14 after treatment, as well as the NIHSS at the end of the 3rd month post-ICH and the incidence of bleeding recurrence and the mortalities within 3 months post-ICH. DISCUSSION: This study will provide preliminary clinical evidence about the safety and efficacy of NBO on correcting acute ICH and explore some mechanisms accordingly, to offer reference for larger clinical trials in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04144868 . Retrospectively registered on October 29, 2019.
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Edema Encefálico/terapia , Lesiones Encefálicas/terapia , Hemorragia Cerebral/terapia , Terapia por Inhalación de Oxígeno/efectos adversos , Oxígeno/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Edema Encefálico/diagnóstico , Edema Encefálico/etiología , Lesiones Encefálicas/diagnóstico , Lesiones Encefálicas/etiología , Corteza Cerebral/diagnóstico por imagen , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Máscaras , Persona de Mediana Edad , Oxígeno/administración & dosificación , Terapia por Inhalación de Oxígeno/instrumentación , Terapia por Inhalación de Oxígeno/métodos , Imagen de Perfusión/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
The gene frequency of 5 characters was reported in Buyi, Miao, Shui, Maonan, Dong, and Han nationalities in southern Guizhou, and analyzed for statistical significance among these nationalities. The results showed that: (1) For Hair forms and Nasal profile, the frequency of the dominant gene was lower than that of theirs recessive gene, but the opposite was true for Nostril forms. (2) Among different nationalities, the difference of gene frequency of Mongoloid fold, Nasal profile, Hair forms and Eye fold of the upper eyelid was quite significant, which was followed by that of Nostril forms.