As a consequence of intracerebral hemorrhage (ICH), blood components enter brain parenchyma causing progressive damage to the surrounding brain. Unless hematoma is cleared, reservoirs continue inflict injury neurovascular structures and blunt repair processes. Microglia/macrophages (MMΦ) represent primary phagocytic system that mediates cleanup hematoma. Thus, efficacy function by MMΦ an essential step in limiting ICH-mediated damage. Using microglia model red cell (main component hematoma)...

Shortly after intracerebral hemorrhage, neutrophils infiltrate the hemorrhage-injured brain. Once within brain, degranulate, releasing destructive molecules that may exacerbate brain damage. However, also release beneficial molecules, including iron-scavenging lactoferrin limit hematoma/iron-mediated injury hemorrhage. Here, we show immunoregulatory cytokine interleukin-27 is upregulated centrally and peripherally Data from rodent models indicate modifies neutrophil maturation in bone...

Background and Purpose— Intracerebral hemorrhage (ICH) represents a devastating form of stroke for which there is no effective treatment. This preclinical study was designed to evaluate dimethyl fumarate (DMF), substance recently approved the treatment multiple sclerosis, as therapy ICH. We hypothesized that DMF through activating master regulator cellular self-defense responses, transcription factor nuclear erythroid 2–related 2 (Nrf2), would act ICH-mediated damage. Methods— Male rats...

Astrocytes are an integral component of the neurovascular unit where they act as homeostatic regulators, especially after brain injuries, such stroke. One process by which astrocytes modulate homeostasis is release functional mitochondria (Mt) that taken up other cells to improve their function. However, mechanisms underlying beneficial effect Mt transfer unclear and likely multifactorial. Using a cell culture system, we established both intact humanin (HN), small bioactive peptide normally...

Background and Purpose- Phagocytic cells, such as microglia blood-derived macrophages, are a key biological modality responsible for phagocytosis-mediated clearance of damaged, dead, or displaced cells that compromised during senescence pathological processes, including after stroke. This process is essential to eliminate the source inflammation allow optimal brain repair functional recovery. Transcription factor, RXR (retinoic-X-receptor) strongly implicated in phagocytic functions...

Intracerebral hemorrhage (ICH) is a devastating disease with 30-day mortality of ~50%. There are no effective therapies for ICH. ICH results in brain damage 2 major ways: through the mechanical forces extravasated blood and then toxicity intraparenchymal components including hemoglobin/iron. LTF (lactoferrin) an iron-binding protein, uniquely abundant polymorphonuclear neutrophils (PMNs). After ICH, circulating PMNs enter ICH-afflicted where they release LTF. By virtue sequestrating iron,...

Excitotoxicity and microglia/macrophage over-activation are the important pathogenic steps in brain damage caused by ischemic stroke. Recent studies from our group suggest that neurons penumbra generate an anti-inflammatory cytokine, interleukin-4 (IL-4). This neuron-produced IL-4 could subsequently convert surrounding microglia/macrophages to a reparative (M2)-phenotype. The present study was designed establish mechanisms which under transient condition produce/secrete IL-4. We employed...

Intracerebral hemorrhage (ICH) is the deadliest form of stroke for which there no effective treatment, despite an endless number pre-clinical studies and clinical trials. The obvious therapeutic target neutralization toxic products red blood cell (RBC) lysis that lead to cytotoxicity, inflammation, oxidative damage. We used rigorous approaches translationally relevant experimental ICH models show lactoferrin-(LTF)-based monotherapy uniquely robust in reducing brain damage after ICH....

The seven canonical members of transient receptor potential (TRPC) proteins form cation channels that evoke membrane depolarization and intracellular calcium concentration ([Ca 2+ ] i ) rise, which are not only important for regulating cell function but their deregulation can also lead to damage. Recent studies have implicated complex roles TRPC in neurodegenerative diseases including ischemic stroke. Brain ischemia reduces oxygen glucose supply neurons, i.e., Oxygen Glucose Deprivation...

BACKGROUND: Within hours after intracerebral hemorrhage (ICH) onset, masses of polymorphonuclear neutrophils (PMNs) infiltrate the ICH-affected brain. After degranulation involving controlled release many toxic antimicrobial molecules, PMNs undergo rapid apoptosis and then are removed by phagocytic microglia/macrophages (MΦ) through a process called efferocytosis. Effective removal may limit secondary brain damage inflammation; however, molecular mechanisms governing these cleanup activities...

Objective Pancreatic ductal adenocarcinoma (PDAC) microenvironment is primarily composed of cancer-associated fibroblasts and immune cells. Gremlin1 (Grem1) a profibrogenic factor that promotes tumorigenesis in several cancers. However, the role Grem1 PDAC not defined. Materials Methods We correlated levels with activated stroma cells human using The Cancer Genome Atlas RNA-sequencing data characterized expression transcripts isoforms pancreatic cell lines tissues. assessed by vitro studies....

Iron released after intracerebral hemorrhage (ICH) is damaging to the brain. Measurement of content and distribution iron in hematoma could predict brain damage. In this study, 16 Yorkshire piglets were subjected autologous blood injection ICH model studied longitudinally using quantitative susceptibility mapping R2* relaxivity MRI on day 1 7 post-ICH. Phantom calibration demonstrated (1) heterogeneity within (2) natural absorption from 154 ± 78 µg/mL (day 1) 127 33 7). decreased at 7. This...

Purpose Perihematomal edema (PHE) occurs in patients with intracerebral hemorrhage (ICH) and is often used as surrogate of secondary brain injury. PHE resolves over time, but little known about the functional integrity tissues that recover from edema. In a pig ICH model, we aimed to assess metabolic perihematoma by using noninvasive magnetic resonance spectroscopy (MRS). Material Methods Fourteen male Yorkshire pigs an average age 8 weeks were intracerebrally injected autologous blood...

Clearance of dead brain tissue including the neurons through phagocytosis is an endogenous function microglia in brain, which critical for inflammation resolution after ischemic stroke or head trauma. By regulating polarization status microglia, we may control their efficacy and therefore cleanup process tissue. We cultured rat cortical from same litter embryos. The are subjected to irradiation inducing neuronal apoptosis. After labeling with propidium iodide (PI), (DNs) exposed assay....

Background and Purpose: Astrocytes are the integral components of neurovascular unit where they act as homeostatic regulator, including after brain injury such stroke. One mechanism by which astrocytes could improve homeostasis is through release functional mitochondria (Mt) that subsequently enter recipient cell, adopt to environment, provide effect. However, mechanisms underlying beneficial effect Mt transfer unclear. Methods Results: Using cell culture system, we found not only intact...

After stroke, microglia and blood macrophages (MΦ) clear dead cells cellular debris in the infarcted brain through phagocytosis. However, phagocytic capability of MΦ declines with age. Age-related dysfunctions also include reduced secretion trophic factors, resulting poor recovery after stroke. Retinoid-X-receptor (RXR) is a pleiotropic transcription factor. Our earlier studies suggest that RXR enhances functions improves post-stroke young mice. To assess age, were FACS-sorted from brains...

Background: Red blood cells ( RBC ) and other components deposited in brain parenchyma during intracerebral hemorrhage ICH are the source of secondary injury, inflammation, oxidative stress. Therefore, a fast efficient removal from is essential for ameliorating injury recovery repair process. Microglia/macrophages MΦ )-mediated phagocytosis key component hematoma clearance after ICH. However, high levels pro-oxidative molecules (including H 2 O generated by could be highly cytotoxic not only...

Microglia/macrophage (MΦ) are immune response cells with function in clearing cell debris and tissue repair after ischemic brain damage. Retinoid X receptor alpha (RXRα) is a pleiotropic transcription factor regulating differentiation, lipid/glucose metabolism responses, including MΦ. Studies from this lab suggest that the dimerization of RXRα peroxisome proliferator-activated γ (PPARγ) to form transcriptionally active structure plays critical roles enhancing MΦ polarization toward “healing”...

After cerebral ischemia, the loss of blood supply triggers a series pathological changes known as ischemic cascades. One key components this cascade is excitotoxicity, triggered by excessive extracellular glutamate level, overactivation N-methyl-D-aspartate (NMDA)-glutamate subtype receptor, calcium overload and neuronal injury. Another component microglia (MΦ) over-activation with harmful pro-inflammatory responses. Recent studies from our group suggest that viable neurons in penumbra...

Background: Lactoferrin (LTF) is an essential, high-affinity iron-binding protein that abundant in the secondary granules of neutrophils. After intracerebral hemorrhage (ICH), circulating blood neutrophils (PMNs) enter ICH-afflicted brain and secrete LTF into damaged tissue. This can bind to iron hemoglobin (key toxic components hematoma) thereby neutralizing toxicity hematoma. Here we study role rodent after ICH. Methods Results: In autologous injection model ICH rats using RT-PCR Western...

Background: Multipotent adult progenitor cells (MAPC) are an adherent stem cell being evaluated as a treatment for ischemic stroke in humans under the name MultiStem®. However, efficacy of MAPC intracerebral hemorrhage (ICH), most devastating form which there is no effective treatment, not clear Method: The therapeutic administration was both autologous blood injection (ABI) and collagenase (COL) rat ICH models. We treated rats intravenously with 1.2x10 6 (sub-optimal dose based on stroke) 7...