Targeting Rap1b signaling cascades with CDNF: Mitigating platelet activation, plasma oxylipins and reperfusion injury in stroke.

Cerebral reperfusion injury in stroke, stemming from interconnected thrombotic and inflammatory signatures, often involves platelet activation, aggregation and its interaction with various immune cells, contributing to microvascular dysfunction. However, the regulatory mechanisms behind this platelet activation and the resulting inflammation are not well understood, complicating the development of effective stroke therapies. Utilizing animal models and platelets from hemorrhagic stroke patients, our research demonstrates that human cerebral dopamine neurotrophic factor (CDNF) acts as an endogenous antagonist, mitigating platelet aggregation and associated neuroinflammation.

Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage.

During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH.

Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients.

Post-stroke Delivery of Valproic Acid Promotes Functional Recovery and Differentially Modifies Responses of Peri-Infarct Microglia.

The specific role of peri-infarct microglia and the timing of its morphological changes following ischemic stroke are not well understood. Valproic acid (VPA) can protect against ischemic damage and promote recovery. In this study, we first determined whether a single dose of VPA after stroke could decrease infarction area or improve functional recovery.

Clinacanthus nutans Mitigates Neuronal Death and Reduces Ischemic Brain Injury: Role of NF-κB-driven IL-1β Transcription.

Neuroinflammation has been shown to exacerbate ischemic brain injury, and is considered as a prime target for the development of stroke therapies. Clinacanthus nutans Lindau (C. nutans) is widely used in traditional medicine for treating insect bites, viral infection and cancer, due largely to its anti-oxidative and anti-inflammatory properties.

Expression of DHA-Metabolizing Enzyme Alox15 is Regulated by Selective Histone Acetylation in Neuroblastoma Cells.

The omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA) is enriched in neural membranes of the CNS, and recent studies have shown a role of DHA metabolism by 15-lipoxygenase-1 (Alox15) in prefrontal cortex resolvin D1 formation, hippocampo-prefrontal cortical long-term-potentiation, spatial working memory, and anti-nociception/anxiety. In this study, we elucidated epigenetic regulation of Alox15 via histone modifications in neuron-like cells. Treatment of undifferentiated SH-SY5Y human neuroblastoma cells with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate significantly increased Alox15 mRNA expression.

Clinacanthus nutans Mitigates Neuronal Apoptosis and Ischemic Brain Damage Through Augmenting the C/EBPβ-Driven PPAR-γ Transcription.

Clinacanthus nutans Lindau (C. nutans) is a traditional herbal medicine widely used in Asian countries for treating a number of remedies including snake and insect bites, skin rashes, viral infections, and cancer. However, the underlying molecular mechanisms for its action and whether C.

Clinacanthus nutans Extracts Modulate Epigenetic Link to Cytosolic Phospholipase A2 Expression in SH-SY5Y Cells and Primary Cortical Neurons.

Clinacanthus nutans Lindau (C. nutans), commonly known as Sabah Snake Grass in southeast Asia, is widely used in folk medicine due to its analgesic, antiviral, and anti-inflammatory properties. Our recent study provided evidence for the regulation of cytosolic phospholipase A2 (cPLA2) mRNA expression by epigenetic factors (Tan et al.

Clinacanthus nutans Protects Cortical Neurons Against Hypoxia-Induced Toxicity by Downregulating HDAC1/6.

Many population-based epidemiological studies have unveiled an inverse correlation between intake of herbal plants and incidence of stroke. C. nutans is a traditional herbal medicine widely used for snake bite, viral infection and cancer in Asian countries.

PPAR-γ Ameliorates Neuronal Apoptosis and Ischemic Brain Injury via Suppressing NF-κB-Driven p22phox Transcription.

Peroxisome proliferator-activated receptor-gamma (PPAR-γ), a stress-induced transcription factor, protects neurons against ischemic stroke insult by reducing oxidative stress. NADPH oxidase (NOX) activation, a major driving force in ROS generation in the setting of reoxygenation/reperfusion, constitutes an important pathogenetic mechanism of ischemic brain damage. In the present study, both transient in vitro oxygen-glucose deprivation and in vivo middle cerebral artery (MCA) occlusion-reperfusion experimental paradigms of ischemic neuronal death were used to investigate the interaction between PPAR-γ and NOX.

Novel link of anti-apoptotic ATF3 with pro-apoptotic CTMP in the ischemic brain.

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor with diverse functions under disease states in multiple cell types. ATF3 has neuroprotective action against cerebral ischemia, which may involve caspase 3. However, the molecular mechanisms underlying ATF3 regulation of apoptosis are largely unknown.

15-Deoxy-∆12,14-PGJ 2, by activating peroxisome proliferator-activated receptor-gamma, suppresses p22phox transcription to protect brain endothelial cells against hypoxia-induced apoptosis.

15-Deoxy-∆(12,14)-PGJ(2) (15d-PGJ(2)) and thiazolidinedione attenuate reactive oxygen species (ROS) production via a peroxisome proliferator-activated receptor-gamma (PPAR-γ)-dependent pathway. Nonetheless, how PPAR-γ mediates ROS production to ameliorate ischemic brain injury is not clear. Recent studies indicated that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the major source of ROS in the vascular system.

Peroxisome proliferator-activated receptor gamma (PPAR-γ) and neurodegenerative disorders.

As the growth of the aging population continues to accelerate globally, increased prevalence of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke, has generated substantial public concern. Unfortunately, despite of discoveries of common factors underlying these diseases, few drugs are available to effectively treat these diseases. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated transcriptional factor that belongs to the nuclear hormone receptor superfamily.

Stroke, angiogenesis and phytochemicals.

Stroke, or brain attack, is the third leading cause of death and the leading cause of adult disability worldwide. There is a great demand for intervention therapy. Unfortunately, although more than 700 drugs that target neuroprotection showed beneficial effects in preclinical animal studies, none of them proved efficacious in treating stroke patients.

Anti-apoptotic actions of PPAR-gamma against ischemic stroke.

Stroke is a leading cause of adult disability and mortality. Diabetes is a major risk factor for stroke. Patients with diabetes have a higher incidence of stroke and a poorer prognosis after stroke.

Rosiglitazone and PPAR-gamma overexpression protect mitochondrial membrane potential and prevent apoptosis by upregulating anti-apoptotic Bcl-2 family proteins.

To determine the involvement of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in cytoprotection, we subjected N2-A cells to oxygen-glucose deprivation followed by reoxygenation (H-R). Following H-R insults, H(2)O(2) production was increased while cell viability declined, which was accompanied by loss of mitochondrial membrane potential (MMP), cytochrome c release, caspases 9 and 3 activation, poly(ADP-ribose)polymerase (PARP) cleavage and apoptosis. Rosiglitazone up to 5 microM protected cell viability, normalized MMP, and prevented apoptotic signals.

Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation.

Background: Thiazolidinediones have been reported to protect against ischemia-reperfusion injury. Their protective actions are considered to be peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-dependent; however, it is unclear how PPAR-gamma activation confers resistance to ischemia-reperfusion injury.

Methods And Results: We evaluated the effects of rosiglitazone or PPAR-gamma overexpression on cerebral infarction in a rat model and investigated the antiapoptotic actions in the N2-A neuroblastoma cell model.

15d-prostaglandin J2 protects brain from ischemia-reperfusion injury.

Objective: Brain expresses abundant lipocalin-type prostaglandin (PG) D2 (PGD2) synthase but the role of PGD2 and its metabolite, 15-deoxy-Delta(12,14) PGJ2 (15d-PGJ2) in brain protection is unclear. The aim of this study is to assess the effect of 15d-PGJ2 on neuroprotection.

Methods And Results: Adenoviral transfer of cyclooxygenase-1 (Adv-COX-1) was used to amplify the production of 15d-PGJ2 in ischemic cortex in a rat focal infarction model.

Induction of prostacyclin/PGI2 synthase expression after cerebral ischemia-reperfusion.

Prostacyclin (PGI2), a potent vasodilator and inhibitor of platelet aggregation and leukocyte activation, is crucial in vascular diseases such as stroke. Prostacyclin synthase (PGIS) is the key enzyme for PGI2 synthesis. Although expression of PGIS was noted in the brain, its role in ischemic insult remains unclear.

Detection of apoptosis and necrosis in normal human lung cells using 1H NMR spectroscopy.

This study aimed to detect apoptosis and necrosis in MRC-5, a normal human lung cell line, by using noninvasive proton nuclear magnetic resonance (1H NMR). Live MRC-5 cells were processed first for 1H NMR spectroscopy; subsequently their types and the percentage of cell death were assessed on a flow cytometer. Cadmium (Cd) and mercury (Hg) induced apoptosis and necrosis in MRC-5 cells, respectively, as revealed by phosphatidylserine externalization on a flow cytometer.

Mediating of caspase-independent apoptosis by cadmium through the mitochondria-ROS pathway in MRC-5 fibroblasts.

Cadmium (Cd) is an environmental pollutant of global concern with a 10-30-year biological half-life in humans. Accumulating evidence suggests that the lung is one of the major target organs of inhaled Cd compounds. Our previous report demonstrated that 100 microM Cd induces MRC-5 cells, normal human lung fibroblasts, to undergo caspase-independent apoptosis mediated by mitochondrial membrane depolarization and translocation of apoptosis-inducing factor (AIF) from mitochondria into the nucleus.

Mitochondria-mediated caspase-independent apoptosis induced by cadmium in normal human lung cells.

Cadmium, a well-known environmental hazard, has caused serious health problems in humans and animals. Accumulating evidence suggests the cadmium toxicity is mediated by oxidative stress-induced cell death. However, the molecular signaling underlying cadmium-induced apoptosis remains unclear.