Distinct role of heme oxygenase-1 in early- and late-stage intracerebral hemorrhage in 12-month-old mice.
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ABSTRACT:
SUBMITTER: Zhang Z
PROVIDER: S-EPMC5363754 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Differences in microRNA (miRNA) expression after intracerebral hemorrhage (ICH) have been reported in human and animal models, and miRNAs are being investigated as a new treatment for inflammation and oxidative stress after ICH. In this study, we found that microRNA-183-5p expression was decreased in the mouse brain after ICH. To investigate the effect of miRNA-183-5p on injury and repair of brain tissue after ICH, saline, miRNA-183-5p agomir, or miRNA-183-5p antagomir were injected into the lateral ventricles of 8-week-old mice with collagenase-induced ICH. Three days after ICH, mice treated with exogenous miRNA-183-5p showed less brain edema, neurobehavioral defects, inflammation, oxidative stress, and ferrous deposition than control mice. In addition, by alternately treating mice with a heme oxygenase-1 (HO-1) inducer, a HO-1 inhibitor, a nuclear factor erythroid 2-related factor (Nrf2) activator, and Nrf2 knockout, we demonstrated an indirect, HO-1-dependent regulatory relationship between miRNA-183-5p and Nrf2. Our results indicate that miRNA-183-5p and HO-1 are promising therapeutic targets for controlling inflammation and oxidative damage after hemorrhagic stroke.
| S-EPMC7377845 | biostudies-literature
Project description:Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms.
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Project description:Mutations in the type IV collagen alpha 1 gene (COL4A1) cause dominantly inherited cerebrovascular disease. We seek to determine the extent to which COL4A1 mutations contribute to sporadic, nonfamilial, intracerebral hemorrhages (ICHs).We sequenced COL4A1 in 96 patients with sporadic ICH. The presence of putative mutations was tested in 145 ICH-free controls. The effects of rare coding variants on COL4A1 biosynthesis were compared to previously validated mutations that cause porencephaly, small vessel disease, and hereditary angiopathy, nephropathy, aneurysms, and cramps (HANAC) syndrome.We identified 2 rare nonsynonymous variants in ICH patients that were not detected in controls, 2 rare nonsynonymous variants in controls that were not detected in patients, and 2 common nonsynonymous variants that were detected in patients and controls. No variant found in controls affected COL4A1 biosynthesis. Both variants (COL4A1(P352L) and COL4A1(R538G)) found only in patients changed conserved amino acids and impaired COL4A1 secretion much like mutations that cause familial cerebrovascular disease.This is the first assessment of the broader role for COL4A1 mutations in the etiology of ICH beyond a contribution to rare and severe familial cases and the first functional evaluation of the biosynthetic consequences of an allelic series of COL4A1 mutations that cause cerebrovascular disease. We identified 2 putative mutations in 96 patients with sporadic ICH and showed that these and other previously validated mutations inhibit secretion of COL4A1. Our data support the hypothesis that increased intracellular accumulation of COL4A1, decreased extracellular COL4A1, or both, contribute to sporadic cerebrovascular disease and ICH.
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Project description:Early life nutrition and feeding practices are important modifiable determinants of subsequent obesity, yet little is known about the circadian feeding pattern of 12-month-old infants. We aimed to describe the 24-h feeding patterns of 12-month-old infants and examine their associations with maternal and infant characteristics. Mothers from a prospective birth cohort study (n 431) reported dietary intakes of their 12-month-old infants and respective feeding times using 24-h dietary recall. Based on their feeding times, infants were classified into post-midnight (00.00-05.59 hours) and pre-midnight (06.00-23.59 hours) feeders. Mean daily energy intake was 3234 (sd 950) kJ (773 (sd 227) kcal), comprising 51·8 (sd 7·8) % carbohydrate, 33·9 (sd 7·2) % fat and 14·4 (sd 3·2) % protein. Mean hourly energy intake and proportion of infants fed were lower during post-midnight than pre-midnight hours. There were 251 (58·2 %) pre-midnight and 180 (41·8 %) post-midnight feeders. Post-midnight feeders consumed higher daily energy, carbohydrate, fat and protein intakes than pre-midnight feeders (all P<0·001). The difference in energy intake originated from energy content consumed during the post-midnight period. Majority (n 173) of post-midnight feeders consumed formula milk during the post-midnight period. Using multivariate logistic regression with confounder adjustment, exclusively breast-feeding during the first 6 months of life was negatively associated with post-midnight feeding at 12 months (adjusted OR 0·31; 95 % CI 0·11, 0·82). This study provides new insights into the circadian pattern of energy intake during infancy. Our findings indicated that the timing of feeding at 12 months was associated with daily energy and macronutrient intakes, and feeding mode during early infancy.
| S-EPMC5564492 | biostudies-literature
Project description:Intracerebral hemorrhage (ICH) is a life-threatening condition associated with significant morbidity and mortality. Understanding the molecular mechanisms underlying ICH and its severe form is crucial for developing effective therapeutic strategies. This study investigates transcriptomic alterations in rodent models of ICH and severe intracerebral hemorrhage to shed light on the genetic pathways involved in hemorrhagic brain injury. We performed principal component analysis, revealing distinct principal component segments of normal rats compared to intracerebral hemorrhage and severe intracerebral hemorrhage rats. We further employed heatmaps and volcano plots to identify differentially expressed genes and utilized bar plots and KEGG pathway analysis to elucidate the different molecular pathways involved. Using comprehensive RNA sequencing and bioinformatics analyses, we identified a multitude of differentially expressed genes in both the ICH and severe ICH models. Our results revealed 5679 common genes among the normal, intracerebral hemorrhage, and severe intracerebral hemorrhage groups in the upregulated genes group, and 1196 common genes in the downregulated genes. A volcano plot comparing the groups further highlighted common genes, including PDPN, TIMP1, SERPINE1, TUBB6, and CD44. These findings underscore the complex interplay of genes involved in inflammation, oxidative stress, and neuronal damage. Furthermore, pathway enrichment analysis uncovered key signaling pathways, including the TNF signaling pathway, protein processing in the endoplasmic reticulum, MAPK signaling pathway, and Fc gamma R-mediated phagocytosis, implicated in the pathogenesis of ICH.
2024-06-11 | GSE264394 | GEO
Project description:In cerebellar atrophy of 12-month-old ATM-null mice, transcriptome upregulations concern most neurotransmission and neuropeptide pathways, while downregulations affect prominently Itpr1, Usp2 and non-coding RNA In cerebellar atrophy of 12-month-old ATM-null mice, transcriptome upregulations concern most neurotransmission and neuropeptide pathways, while downregulations affect prominently Itpr1, Usp2 and non-coding RNA The autosomal recessive disorder Ataxia-Telangiectasia is caused by dysfunction of stress response protein ATM. In the nucleus of proliferating cells, ATM senses DNA double-strand breaks and coordinates their repair. This role explains T-cell dysfunction and tumor risk. However, it remains unclear whether this function is relevant for postmitotic neurons and underlies the cerebellar atrophy, since ATM is cytoplasmic in postmitotic neurons. Here, we used ATM-null mice that survived early immune deficits by bone-marrow transplantation, and reached initial neurodegeneration stages at 12 months of age. Global cerebellar transcriptomics demonstrated ATM depletion to trigger upregulations in most neurotransmission and neuropeptide systems. Downregulated transcripts were found for the ATM interactome component Usp2, many non-coding RNAs, ataxia genes Itpr1, Grid2, immediate early genes and immunity factors. Allelic splice changes affected prominently neuropeptide machinery, e.g. Oprm1. Validation experiments with stressors were performed in human neuroblastoma cells, where ATM localized only to cytoplasm, similar to brain. Effect confirmation in SH-SY5Y cells occurred better after ATM depletion and osmotic stress better than nutrient / oxidative stress, rather than ATM kinase inhibition or DNA stressor bleomycin. Overall, we provide pioneer observations from a faithful A-T mouse model, which suggest general changes in synaptic and dense-core vesicle stress adaptation.
2023-10-24 | GSE241955 | GEO
Project description:BACKGROUND AND PURPOSE:As survival rates have increased for intracerebral hemorrhage (ICH) patients, there is limited information regarding recovery beyond 3-6 months. This study was conducted to examine recovery curves using the modified Rankin Scale (mRS) and Barthel Index (BI) up to 12 months post-injury. METHODS:We prospectively enrolled 173 patients admitted with ICH who were subsequently evaluated using the mRS and BI at discharge as well as 3, 6, and 12 months. Repeated measures nonparametric testing was conducted to assess functional trajectories across time. RESULTS:The mRS scores showed significant improvement between discharge (median 4) and 3 (median 4), 6 (median 4), and 12 months (median 3) (p values <0.001). However, the mRS scores did not differ between follow-up time-points (i.e., 3-6, 6-12 months). There was significant improvement in scores using the BI (p values <0.001), showing improvement between discharge (mean 43.0) and 3 (mean 73.0), 6 (mean 78.2), and 12 months (mean 83.4). Additionally, there were differences in the BI between 3 and 12 months (p = 0.013), as well as between 6 and 12 months (p = 0.025). CONCLUSIONS:The BI may be a more sensitive measure of long-term recovery post-injury than the mRS, which shows minimal improvement for some survivors after 3 months. BI scores indicate survivors continually improve till 12 months post-injury. These results may have implications for the prognostication of ICH and design of clinical trial outcome measures.
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Project description:Subarachnoid hemorrhage is a specific, life-threatening form of hemorrhagic stroke linked to high morbidity and mortality. It has been found that the choroid plexus of the brain ventricles forming the blood-cerebrospinal fluid barrier plays an important role in subarachnoid hemorrhage pathophysiology. Heme oxygenase-1 and biliverdin reductase are two of the key enzymes of the hemoglobin degradation cascade. Therefore, the aim of present study was to investigate changes in protein levels of heme oxygenase-1 and biliverdin reductase in the rat choroid plexus after experimental subarachnoid hemorrhage induced by injection of non-heparinized autologous blood to the cisterna magna. Artificial cerebrospinal fluid of the same volume as autologous blood was injected to mimic increased intracranial pressure in control rats. Immunohistochemical and Western blot analyses were used to monitor changes in the of heme oxygenase-1 and biliverdin reductase levels in the rat choroid plexus after induction of subarachnoid hemorrhage or artificial cerebrospinal fluid application for 1, 3, and 7 days. We found increased levels of heme oxygenase-1 and biliverdin reductase protein in the choroid plexus over the entire period following subarachnoid hemorrhage induction. The level of heme oxygenase-1 was the highest early (1 and 3 days) after subarachnoid hemorrhage indicating its importance in hemoglobin degradation. Increased levels of heme oxygenase-1 were also observed in the choroid plexus epithelial cells at all time points after application of artificial cerebrospinal fluid. Biliverdin reductase protein was detected mainly in the choroid plexus epithelial cells, with levels gradually increasing during subarachnoid hemorrhage. Our results suggest that heme oxygenase-1 and biliverdin reductase are involved not only in hemoglobin degradation but probably also in protecting choroid plexus epithelial cells and the blood-cerebrospinal fluid barrier from the negative effects of subarachnoid hemorrhage.
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Project description:Infants register and react to informational uncertainty in the environment. They also form expectations about the probability of future events as well as update the expectation according to changes in the environment. A novel line of research has started to investigate infants' and toddlers' behavior under uncertainty. By combining these research areas, the present research investigated 12- and 24-month-old infants' searching behaviors under varying degree of informational uncertainty. An object was hidden in one of three possible locations and probabilistic information about the hiding location was manipulated across trials. Infants' time delay in search initiation for a hidden object linearly increased across the level of informational uncertainty. Infants' successful searching also varied according to probabilistic information. The findings suggest that infants modulate their behaviors based on probabilistic information. We discuss the possibility that infants' behavioral reaction to the environmental uncertainty constitutes the basis for the development of subjective uncertainty.
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Project description:A foundation of human cognition is the flexibility with which we can represent any object as either a unique individual (my dog Fred) or a member of an object category (dog, animal). This conceptual flexibility is supported by language; the way we name an object is instrumental to our construal of that object as an individual or a category member. Evidence from a new recognition memory task reveals that infants are sensitive to this principled link between naming and object representation by age 12 mo. During training, all infants (n = 77) viewed four distinct objects from the same object category, each introduced in conjunction with either the same novel noun (Consistent Name condition), a distinct novel noun for each object (Distinct Names condition), or the same sine-wave tone sequence (Consistent Tone condition). At test, infants saw each training object again, presented in silence along with a new object from the same category. Infants in the Consistent Name condition showed poor recognition memory at test, suggesting that consistently applied names focused them primarily on commonalities among the named objects at the expense of distinctions among them. Infants in the Distinct Names condition recognized three of the four objects, suggesting that applying distinct names enhanced infants' encoding of the distinctions among the objects. Infants in the control Consistent Tone condition recognized only the object they had most recently seen. Thus, even for infants just beginning to speak their first words, the way in which an object is named guides infants' encoding, representation, and memory for that object.
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