Endothelin-1 increases Na-K-2Cl cotransporter-1 expression in cultured astrocytes and in traumatic brain injury model: An involvement of HIF1α activation.

Na-K-2Cl cotransporter-1 (NKCC1) is present in brain cells, including astrocytes. The expression of astrocytic NKCC1 increases in the acute phase of traumatic brain injury (TBI), which induces brain edema. Endothelin-1 (ET-1) is a factor that induces brain edema and regulates the expression of several pathology-related genes in astrocytes.

Roles of astrocytic sonic hedgehog production and its signal for regulation of the blood-brain barrier permeability.

Sonic hedgehog (Shh) is a secreted glycopeptide belonging to the hedgehog family that is essential for morphogenesis during embryonic development. The Shh signal is mediated by two membrane proteins, Patched-1 (Ptch-1) and Smoothened (Smo), following the activation of transcription factors such as Gli. Shh decreases the permeability of the blood-brain barrier (BBB) and plays a key role in its function.

Histamine H Receptor-Mediated JNK Phosphorylation Is Regulated by G Protein-Dependent but Arrestin-Independent Pathways.

Arrestins are known to be involved not only in the desensitization and internalization of G protein-coupled receptors but also in the G protein-independent activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), to regulate cell proliferation and inflammation. Our previous study revealed that the histamine H receptor-mediated activation of ERK is dually regulated by G proteins and arrestins. In this study, we investigated the roles of G proteins and arrestins in the H receptor-mediated activation of JNK in Chinese hamster ovary (CHO) cells expressing wild-type (WT) human H receptors, the G protein-biased mutant S487TR, and the arrestin-biased mutant S487A.

Drug Discovery Research for Traumatic Brain Injury Focused on Functional Molecules in Astrocytes.

Traumatic brain injury (TBI) is severe damage to the head caused by traffic accidents, falls, and sports. Because TBI-induced disruption of the blood-brain barrier (BBB) causes brain edema and neuroinflammation, which are major causes of death or serious disabilities, protection and recovery of BBB function may be beneficial therapeutic strategies for TBI. Astrocytes are key components of BBB integrity, and astrocyte-derived bioactive factors promote and suppress BBB disruption in TBI.

Overexpression of lysophospholipid acyltransferase, LPLAT10/LPCAT4/LPEAT2, in the mouse liver increases glucose-stimulated insulin secretion.

Postprandial hyperglycemia is an early indicator of impaired glucose tolerance that leads to type 2 diabetes mellitus (T2DM). Alterations in the fatty acid composition of phospholipids have been implicated in diseases such as T2DM and nonalcoholic fatty liver disease. Lysophospholipid acyltransferase 10 (LPLAT10, also called LPCAT4 and LPEAT2) plays a role in remodeling fatty acyl chains of phospholipids; however, its relationship with metabolic diseases has not been fully elucidated.

Roles of Astrocytic Endothelin ET Receptor in Traumatic Brain Injury.

Traumatic brain injury (TBI) is an intracranial injury caused by accidents, falls, or sports. The production of endothelins (ETs) is increased in the injured brain. ET receptors are classified into distinct types, including ET receptor (ET-R) and ET receptor (ET-R).

Selective histamine H receptor agonists alleviate blood-brain barrier disruption by promoting the expression of vascular protective factors following traumatic brain injury in mice.

Histamine is a major neurotransmitter and alleviates neuronal damage after ischemic injury via H receptors. Herein, we investigated the effects of H receptor agonists on the blood-brain barrier (BBB) disruption after traumatic brain injury (TBI). Male ddY mice were used to generate the TBI model, in which a fluid percussion injury (FPI) was induced by a hydraulic impact.

Liver-specific overexpression of lipoprotein lipase improves glucose metabolism in high-fat diet-fed mice.

The liver is the main organ that regulates lipid and glucose metabolism. Ectopic lipid accumulation in the liver impairs insulin sensitivity and glucose metabolism. Lipoprotein lipase (LPL), mainly expressed in the adipose tissue and muscle, is a key enzyme that regulates lipid metabolism via the hydrolysis of triglyceride in chylomicrons and very-low-density lipoproteins.

Pathophysiological Responses and Roles of Astrocytes in Traumatic Brain Injury.

Traumatic brain injury (TBI) is immediate damage caused by a blow to the head resulting from traffic accidents, falls, and sporting activity, which causes death or serious disabilities in survivors. TBI induces multiple secondary injuries, including neuroinflammation, disruption of the blood-brain barrier (BBB), and brain edema. Despite these emergent conditions, current therapies for TBI are limited or insufficient in some cases.

Down-regulation of astrocytic sonic hedgehog by activation of endothelin ET receptors: Involvement in traumatic brain injury-induced disruption of blood brain barrier in a mouse model.

In the adult brain, sonic hedgehog acts on cerebral microvascular endothelial cells to stabilize the blood-brain barrier. The expression of sonic hedgehog by astrocytes is altered during brain injury, and this change has been shown to affect permeability of blood-brain barrier. However, much remains unknown about the regulation of astrocytic sonic hedgehog production.

ZFAND3 Overexpression in the Mouse Liver Improves Glucose Tolerance and Hepatic Insulin Resistance.

Genome-wide association studies have identified more than 300 loci associated with type 2 diabetes mellitus; however, the mechanisms underlying their role in type 2 diabetes mellitus susceptibility remain largely unknown. Zinc finger AN1-type domain 3 (ZFAND3), known as testis-expressed sequence 27, is a type 2 diabetes mellitus-susceptibility gene. Limited information is available regarding the physiological role of ZFAND3 .

Endothelin receptor antagonists alleviate blood-brain barrier disruption and cerebral edema in a mouse model of traumatic brain injury: A comparison between bosentan and ambrisentan.

Traumatic brain injury (TBI) is induced by the immediate physical disruption of brain tissue. TBI causes disruption of the blood-brain barrier (BBB) and brain edema. In the cerebrospinal fluid (CSF) of TBI patients, endothelin-1 (ET-1) is increased, suggesting that ET-1 aggravates TBI-induced brain damage.

Angiopoietin-1/Tie-2 signal after focal traumatic brain injury is potentiated by BQ788, an ET receptor antagonist, in the mouse cerebrum: Involvement in recovery of blood-brain barrier function.

Angiopoietin-1, an angiogenic factor, stabilizes brain microvessels through Tie-2 receptor tyrosine kinase. In traumatic brain injury, blood-brain barrier (BBB) disruption is an aggravating factor that induces brain edema and neuroinflammation. We previously showed that BQ788, an endothelin ET receptor antagonist, promoted recovery of BBB function after lateral fluid percussion injury (FPI) in mice.

Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage.

The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage.

Endothelin-1 stimulates expression of cyclin D1 and S-phase kinase-associated protein 2 by activating the transcription factor STAT3 in cultured rat astrocytes.

Brain injury-mediated induction of reactive astrocytes often leads to glial scar formation in damaged brain regions. Activation of signal transducer and activator of transcription 3 (STAT3), a member of the STAT family of transcription factors, plays a pivotal role in inducing reactive astrocytes and glial scar formation. Endothelin-1 (ET-1) is a vasoconstrictor peptide, and its levels increase in brain disorders and promote astrocytic proliferation through ETB receptors.

Effects of irradiation with narrowband-ultraviolet B on up-regulation of histamine H receptor mRNA and induction of apoptosis in HeLa cells and nasal mucosa of rats.

Narrowband-ultraviolet B (NB-UVB) phototherapy is used for the treatment of atopic dermatitis. Previously, we reported that irradiation with 200 mJ/cm of 310 nm NB-UVB suppressed phorbol-12-myristate-13-acetate (PMA)-induced up-regulation of histamine H receptor (H1R) gene expression without induction of apoptosis in HeLa cells. However, the effect of NB-UVB irradiation on nasal symptoms is still unclear.

Protection of the Blood-Brain Barrier as a Therapeutic Strategy for Brain Damage.

Severe brain damage by trauma, ischemia, and hemorrhage lead to fatal conditions including sudden death, subsequent complications of the extremities and cognitive dysfunctions. Despite the urgent need for treatments for these complications, currently available therapeutic drugs are limited. Blood-brain barrier (BBB) disruption is a common pathogenic feature in many types of brain damage.

Improvement of cold injury-induced mouse brain edema by endothelin ETB antagonists is accompanied by decreases in matrixmetalloproteinase 9 and vascular endothelial growth factor-A.

Brain edema is a potentially fatal pathological state that often occurs after brain injuries such as ischemia and trauma. However, therapeutic agents that fundamentally treat brain edema have not yet been established. We previously found that endothelin ETB receptor antagonists attenuate the formation and maintenance of vasogenic brain edema after cold injury in mice.

Pathogenesis of brain edema and investigation into anti-edema drugs.

Brain edema is a potentially fatal pathological state that occurs after brain injuries such as stroke and head trauma. In the edematous brain, excess accumulation of extracellular fluid results in elevation of intracranial pressure, leading to impaired nerve function. Despite the seriousness of brain edema, only symptomatic treatments to remove edema fluid are currently available.

Amelioration of cold injury-induced cortical brain edema formation by selective endothelin ETB receptor antagonists in mice.

Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice).