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Toll-like receptor 4-dependent innate immune responses are mediated by intracrine corticosteroids and activation of glycogen synthase kinase-3β in astrocytes.

Reactive astrocytes are important pathophysiologically and synthesize neurosteroids. We observed that LPS increased immunoreactive TLR4 and key steroidogenic enzymes in cortical astrocytes of rats and investigated whether corticosteroids are produced and mediate astrocytic TLR4-dependent innate immune responses. We found that LPS increased steroidogenic acute regulatory protein (StAR) and StAR-dependent aldosterone production in purified astrocytes. Both increases were blocked by the TLR4 antagonist TAK242. LPS also increased 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and corticosteron…

Increased neurotoxicity of high-density lipoprotein secreted from murine reactive astrocytes deficient in a peroxisomal very-long-chain fatty acid transporter Abcd1.

X-linked adrenoleukodystrophy (X-ALD) is a genetic neurodegenerative disorder caused by pathogenic variants in ABCD1, resulting in the accumulation of very-long-chain fatty acids (VLCFAs) in tissues. The etiology of X-ALD is unclear. Activated astrocytes play a pathological role in X-ALD. Recently, reactive astrocytes have been shown to induce neuronal cell death via saturated lipids in high-density lipoprotein (HDL), although how HDL from reactive astrocytes exhibits neurotoxic effects has yet to be determined. In this study, we obtained astrocytes from wild-type and Abcd1-deficient mice. HDL…

Inhibition of angiotensin converting enzyme increases PKCβI isoform expression via activation of substance P and bradykinin receptors in cultured astrocytes of mice.

OBJECTIVE: To evaluate the feasibility of ultrasound shear wave elastography (SWE) for predicting hepatic fibrosis and native liver outcomes in patients with biliary atresia. MATERIALS AND METHODS: This prospective study included 33 consecutive patients with biliary atresia (median age, 8 weeks [interquartile range, 6-10 weeks]; male:female ratio, 15:18) from Severance Children's Hospital between May 2019 and February 2022. Preoperative (within 1 week from surgery) and immediate postoperative (on postoperative days [PODs] 3, 5, and 7) ultrasonographic findings were obtained and analyzed, incl

Short-Chain Fatty Acids Reduce Oligodendrocyte Precursor Cells Loss by Inhibiting the Activation of Astrocytes via the SGK1/IL-6 Signalling Pathway.

Short-chain fatty acids (SCFAs) are known to be actively involved in neurological diseases, but their roles in hypoxic-ischaemic brain injury (HIBI) are unclear. In this study, a rat model of HIBI was established, and this study measured the changes in IL-6 and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), in addition to proliferation and apoptosis indicators of oligodendrocyte precursor cells (OPCs). The mechanism of action of SCFA on astrocytes was also investigated. Astrocytes were subjected to hypoxia in vitro, and OPCs were treated with IL-6. The results showed th…

Rapid Generation of Ventral Spinal Cord-like Astrocytes from Human iPSCs for Modeling Non-Cell Autonomous Mechanisms of Lower Motor Neuron Disease.

Astrocytes play important roles in the function and survival of neuronal cells. Dysfunctions of astrocytes are associated with numerous disorders and diseases of the nervous system, including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Human-induced pluripotent stem cell (iPSC)-based approaches are becoming increasingly important for the study of the mechanisms underlying the involvement of astrocytes in non-cell autonomous processes of motor neuron degeneration in ALS. These studies must account for the molecular and functional diversity among astrocytes in different re…

Retinal ganglion cell expression of cytokine enhances occupancy of NG2 cell-derived astrocytes at the nerve injury site: Implication for axon regeneration.

Following injury in the central nervous system, a population of astrocytes occupy the lesion site, form glial bridges and facilitate axon regeneration. These astrocytes originate primarily from resident astrocytes or NG2+ oligodendrocyte progenitor cells. However, the extent to which these cell types give rise to the lesion-filling astrocytes, and whether the astrocytes derived from different cell types contribute similarly to optic nerve regeneration remain unclear. Here we examine the distribution of astrocytes and NG2+ cells in an optic nerve crush model. We show that optic nerve astrocytes…

Prenatal Zinc Supplementation Ameliorates Hippocampal Astrocytes Activation and Inflammatory Cytokines Expression Induced by Lipopolysaccharide in a Rat Model of Maternal Immune Activation.

INTRODUCTION: Evidence suggests that gestational exposure to Lipopolysaccharide (LPS) results in fetal zinc deficiency and eventually neurodevelopmental abnormalities. In this study, we utilized a rat model of Maternal Immune Activation (MIA) to investigate the possible neuroprotective effects of zinc supplementation during pregnancy on hippocampal astrocytes activation as well as inflammatory cytokines expression in adult offspring. METHODS: Pregnant rats received intraperitoneal injections of either LPS (0.5 mg/kg) or saline on Gestational Days (GD) 15 and 16, and orally gavaged with zinc s…

Homeostasis Imbalance of Microglia and Astrocytes Leads to Alteration in the Metabolites of the Kynurenine Pathway in LPS-Induced Depressive-Like Mice.

In the pathology-oriented study of depression, inflammation hypothesis has received increasing attention for recent years. To mimic the depr … -HK) and kynurenic acid (KYNA), in the brain were analyzed by LC-MS/MS. Activation of microglia and astrocytes in the brain were also determined by immunohistochemistry and western blotting, respectively. The results showed that, compared with the control group, the mice in the 0.8 mg/kg LPS-treated group exhibited a remarkable increase of immobility time in …

Isoflurane inhibits a Kir4.1/5.1-like conductance in neonatal rat brainstem astrocytes and recombinant Kir4.1/5.1 channels in a heterologous expression system.

All inhalation anesthetics used clinically including isoflurane can suppress breathing; since this unwanted side effect can persist during the postoperative period and complicate patient recovery, there is a need to better understand how isoflurane affects cellular and molecular elements of respiratory control. Considering that astrocytes in a brainstem region known as the retrotrapezoid nucleus (RTN) contribute to the regulation of breathing in response to changes in CO2/H+ (i.e., function as respiratory chemoreceptors), and astrocytes in other brain regions are highly sensitive to isoflurane…

HIV Nef and Antiretroviral Therapy Have an Inhibitory Effect on Autophagy in Human Astrocytes that May Contribute to HIV-Associated Neurocognitive Disorders.

A significant number of people living with HIV (PLWH) develop HIV-associated neurocognitive disorders (HAND) despite highly effective antiretroviral therapy (ART). Dysregulated macroautophagy (autophagy) is implicated in HAND pathogenesis. The viral protein Nef, expressed even with suppressive ART, and certain antiretrovirals affect autophagy in non-CNS cells. Astrocytes, vital for CNS microenvironment homeostasis and neuronal health, require autophagy for their own homeostasis. We hypothesized that extracellular Nef and/or ART impact astrocyte autophagy, thus contributing to HAND. We studied …

Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection.

BACKGROUND: Tick-borne encephalitis virus (TBEV) is a member of the Flaviviridae family, Flavivirus genus, which includes several important … eir rate of infection and by performing PCR array and qRT-PCR. The specific response of neurons and astrocytes was analyzed using the same approaches after enrichment of the neuronal/glial cultures for each cellular subtype. RESULTS: We showed that infection of human neuronal/glial cells mimicked three major hallmarks of TBEV infection in the human brain, n …

Cortical Neuron-Derived Exosomal MicroRNA-181c-3p Inhibits Neuroinflammation by Downregulating CXCL1 in Astrocytes of a Rat Model with Ischemic Brain Injury.

OBJECTIVES: Cortical neuron-released exosomes have been demonstrated to block inflammasome activation in the central nervous system. This study aimed to investigate whether cortical neuron-released exosomal microRNA-181c-3p (miR-181c-3p) affected ischemic brain injury (IBI). METHODS: An IBI rat model was established by middle cerebral artery occlusion (MCAO). Astrocytes collected from rats were exposed to exosomes derived from cortical neurons to investigate the effect of exosomes on chemokine (C-X-C motif) ligand 1 (CXCL1) expression and inflammatory response. Then, ectopic expression was in…

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255-257 and regulated by mTOR.

The electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), is the major bicarbonate transporter expressed in astrocytes. It is highly sensitive for bicarbonate and the main regulator of intracellular, extracellular, and synaptic pH, thereby modulating neuronal excitability. However, despite these essential functions, the molecular mechanisms underlying NBCe1-mediated astrocytic response to extracellular pH changes are mostly unknown. Using primary mouse cortical astrocyte cultures, we investigated the effect of long-term extracellular metabolic alkalosis on regulation of NBCe1 and el…

Клеточная смерть противодействует митофагии в ВИЧ-инфицированных астроцитах, но поощряется инфламативным действием среди непродуктивно инфицированных клеток.

Несмотря на более чем 30-летнюю обширную исследовательскую деятельность, полное понимание неврологических последствий инфекции центральной нервной системы (КНС) ВИЧ по-прежнему остается недостижимым. ВИЧ может не только создать вирусный резервуар в ЦНС, но и инициировать проявления нейродегенеративных заболеваний. Эти неврологические расстройства могут возникнуть в связи с активацией вируса воспаления клеток CNS, включая астроциты. Тем не менее в некоторых производственных сценариях вирусной инфекции избирательная автофагия может уменьшить воспаление посредством митохондриального разложения ("

Совпадение в аннотации оригинала
Despite more than 30 years of extensive research efforts, a complete understanding of the neurological consequences of HIV central nervous s … disorders may arise because of virus-induced activation of the inflammasome in CNS cells, including astrocytes. Nevertheless, in some productive viral infection scenarios, selective autophagy may reduce inflammation through mitochondrial degradation ("mitophagy") to counteract inflammasome activation. In this study, using cultured human astrocytes, we demons …

Activation of autophagic flux and the Nrf2/ARE signaling pathway by hydrogen sulfide protects against acrylonitrile-induced neurotoxicity in primary rat astrocytes.

Hydrogen sulfide (H2S), the third gasotransmitter, has been shown to act as a neuroprotective factor in numerous pathological processes; however, its underlying mechanism(s) of action remain unclear. It is widely accepted that activation of moderate autophagy and the Nrf2/ARE signaling pathway play important roles in the biological self-defense systems. In the present study, we investigated whether exogenous H2S protects against the cytotoxicity of acrylonitrile (AN), a neurotoxin, in primary rat astrocytes. We found that pretreatment for 1 h with sodium hydrosulfide (NaHS), a donor of H2S (20…

Novel Inflammatory Neuropathology in Immature Brain: (1) Fetal Tuberous Sclerosis, (2) Febrile Seizures, (3) α-B-crystallin, and (4) Role of Astrocytes.

Though the term "inflammation" is traditionally defined as proliferation or infiltration of lymphatic cells of the lymphatic immune system a … ulation in glial cells and neurons at sites of chronic epileptic foci, and (4) the emerging role of astrocytes in the presence of and participation in inflammation. Novel evidence shows that cerebral inflammation plays a role in some genetic diseases as early as midgestation and thus is not always acquired postnatally or in adult life.

A sub-threshold dose of pilocarpine increases glutamine synthetase in reactive astrocytes and enhances the progression of amygdaloid-kindling epilepsy in rats.

The prognosis of patients exposed to a sub-threshold dose of a proconvulsant is difficult to establish. In this study, we investigated the e … c GS may play a role in this phenomenon. Thus, a future therapy for epilepsy could be inhibition of astrocytes and/or GS.

Signal Transduction in Astrocytes during Chronic or Acute Treatment with Drugs (SSRIs, Antibipolar Drugs, GABA-ergic Drugs, and Benzodiazepines) Ameliorating Mood Disorders.

Chronic treatment with fluoxetine or other so-called serotonin-specific reuptake inhibitor antidepressants (SSRIs) or with a lithium salt "lithium", carbamazepine, or valproic acid, the three classical antibipolar drugs, exerts a multitude of effects on astrocytes, which in turn modulate astrocyte-neuronal interactions and brain function. In the case of the SSRIs, they are to a large extent due to 5-HT2B-mediated upregulation and editing of genes. These alterations induce alteration in effects of cPLA2, GluK2, and the 5-HT2B receptor, probably including increases in both glucose metabolism and…

On-line species-unspecific isotope dilution analysis in the picomolar range reveals the time- and species-depending mercury uptake in human astrocytes.

In order to reveal the time-depending mercury species uptake by human astrocytes, a novel approach for total mercury analysis is presented, which uses an accelerated sample introduction system combined on-line with an inductively coupled plasma mass spectrometer equipped with a collision/reaction cell. Human astrocyte samples were incubated with inorganic mercury (HgCl2), methylmercury chloride (MeHgCl), and thimerosal. After 1-h incubation with Hg(2+), cellular concentrations of 3 μM were obtained, whereas for organic species, concentrations of 14-18 μM could be found. After 24 h, a cellular …

σ1 receptors activate astrocytes via p38 MAPK phosphorylation leading to the development of mechanical allodynia in a mouse model of neuropathic pain.

BACKGROUND AND PURPOSE: Spinal astrocytes have emerged as important mechanistic contributors to the genesis of mechanical allodynia (MA) in neuropathic pain. We recently demonstrated that the spinal sigma non-opioid intracellular receptor 1 (σ1 receptor) modulates p38 MAPK phosphorylation (p-p38), which plays a critical role in the induction of MA in neuropathic rats. However, the histological and physiological relationships among σ1, p-p38 and astrocyte activation is unclear. EXPERIMENTAL APPROACH: We investigated: (i) the precise location of σ1 receptors and p-p38 in spinal dorsal horn; (ii…