Disruption of the Na+/K+-ATPase-purinergic P2X7 receptor complex in microglia promotes stress-induced anxiety.

Na+/K+-ATPase (NKA) plays an important role in the central nervous system. However, little is known about its function in the microglia. Here, we found that NKAα1 forms a complex with the purinergic P2X7 receptor (P2X7R), an adenosine 5'-triphosphate (ATP)-gated ion channel, under physiological conditions. Chronic stress or treatment with lipopolysaccharide plus ATP decreased the membrane expression of NKAα1 in microglia, facilitated P2X7R function, and promoted microglia inflammatory activation via activation of the NLRP3 inflammasome. Accordingly, global deletion or conditional deletion of NKAα1 in microglia under chronic stress-induced aggravated anxiety-like behavior and neuronal hyperexcitability. DR5-12D, a monoclonal antibody that stabilizes membrane NKAα1, improved stress-induced anxiety-like behavior and ameliorated neuronal hyperexcitability and neurogenesis deficits in the ventral hippocampus of mice. Our results reveal that NKAα1 limits microglia inflammation and may provide a target for the treatment of stress-related neuroinflammation and diseases.

Prenatal dexamethasone exposure induces anxiety- and depressive-like behavior of male offspring rats through intrauterine programming of the activation of NRG1-ErbB4 signaling in hippocampal PV interneurons.

Dexamethasone is a commonly used synthetic glucocorticoid in the clinic. As a compound that can cross the placental barrier to promote fetal lung maturation, dexamethasone is extensively used in pregnant women at risk of premature delivery. However, the use of glucocorticoids during pregnancy increases the risk of neurodevelopmental disorders. In the present study, we observed anxiety- and depressive-like behavior changes and hyperexcitability of hippocampal neurons in adult rat offspring with previous prenatal dexamethasone exposure (PDE); the observed changes were related to in utero damage of parvalbumin interneurons. A programmed change in neuregulin 1 (NRG1)-Erb-b2 receptor tyrosine kinase 4 (ErbB4) signaling was the key to the damage of parvalbumin interneurons in the hippocampus of PDE offspring. Anxiety- and depressive-like behavior, NRG1-ErbB4 signaling activation, and damage of parvalbumin interneurons in PDE offspring were aggravated after chronic stress. The intervention of NRG1-ErbB4 signaling contributed to the improvement in dexamethasone-mediated injury to parvalbumin interneurons. These results suggested that PDE might cause anxiety- and depressive-like behavior changes in male rat offspring through the programmed activation of NRG1-ErbB4 signaling, resulting in damage to parvalbumin interneurons and hyperactivity of the hippocampus. Intrauterine programming of neuregulin 1 (NRG1)-Erb-b2 receptor tyrosine kinase 4 (ERBB4) overactivation by dexamethasone mediates anxiety- and depressive-like behavior in male rat offspring.

Regulation of brain drug metabolizing enzymes and transporters by nuclear receptors.

Nuclear receptors (NRs) belong to a family of ligand-dependent transcription factors. The target genes of NRs include many drug metabolizing enzymes and transporters. The central nervous system (CNS) bears the expression of NRs, drug metabolizing enzymes and transporters. NRs that express in the brain can be divided into three groups according to their characteristics of ligand binding: steroid hormone receptors, non-steroid hormone receptors, and orphan receptors. The NR-mediated regulation of drug metabolizing enzymes and transporters plays important roles in the metabolism and disposition of drugs in the CNS and the penetration of endogenous and exogenous substances through the blood-brain barrier (BBB). NR-mediated regulation of drug metabolizing enzymes and transporters can cause the toxicological effects of xenobiotics in the CNS and also lead to drug resistance in the centrum. The regulatory pathways of drug metabolizing enzymes and transporters can provide new strategies for selective regulation of the BBB permeability and drug metabolism in the brain. This review focuses on the importance of NR-mediated regulation of drug metabolizing enzymes and transporters in the CNS and the implications of this regulation in the therapeutic effect of CNS drugs and CNS side effects of drugs and other xenotoxicants.

Na+/K+-ATPase: ion pump, signal transducer, or cytoprotective protein, and novel biological functions.

Na+/K+-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na+ out of and two K+ into cells. Additionally, Na+/K+-ATPase participates in Ca2+-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane. Na+/K+-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells. Therefore, it is not surprising that Na+/K+-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases. However, published studies have so far only elucidated the important roles of Na+/K+-ATPase dysfunction in disease development, and we are lacking detailed mechanisms to clarify how Na+/K+-ATPase affects cell function. Our recent studies revealed that membrane loss of Na+/K+-ATPase is a key mechanism in many neurological disorders, particularly stroke and Parkinson's disease. Stabilization of plasma membrane Na+/K+-ATPase with an antibody is a novel strategy to treat these diseases. For this reason, Na+/K+-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein, participating in signal transduction such as neuronal autophagy and apoptosis, and glial cell migration. Thus, the present review attempts to summarize the novel biological functions of Na+/K+-ATPase and Na+/K+-ATPase-related pathogenesis. The potential for novel strategies to treat Na+/K+-ATPase-related brain diseases will also be discussed.

Human adipose and synovial-derived MSCs synergistically attenuate osteoarthritis by promoting chondrocyte autophagy through FoxO1 signaling.

BACKGROUND: Human adipose-derived stem cells (ADSCs) exert a strong anti-inflammatory effect, and synovium-derived stem cells (SDSCs) have high chondrogenic potential. Thus, this study aims to investigate whether a combination of human ADSCs and SDSCs will have a synergistic effect that will increase the chondrogenic potential of osteoarthritis (OA) chondrocytes in vitro and attenuate the cartilage degeneration of early and advanced OA in vitro. METHODS: ADSCs, SDSCs, and chondrocytes were isolated from OA patients who underwent total knee arthroplasty. The ADSCs-SDSCs mixed cell ratios were 1:0 (ADSCs only), 8:2, 5:5 (5A5S), 2:8, and 0:1 (SDSCs only). The chondrogenic potential of the OA chondrocytes was evaluated in vitro with a transwell assay or pellet culture with various mixed cell groups. The mixed cell group with the highest chondrogenic potential was then selected and injected into the knee joints of nude rats of early and advanced OA stages in vivo. The animals were then evaluated 12 and 20 weeks after surgery through gait analysis, von frey test, microcomputed tomography, MRI, and immunohistochemical and histological analyses. Finally, the mechanisms underlying these findings were investigated through the RNA sequencing of tissue samples in vivo and Western blot of the OA chondrocyte autophagy pathway. RESULTS: Among the MSCs treatment groups, 5A5S had the greatest synergistic effect that increased the chondrogenic potential of OA chondrocytes in vitro and inhibited early and advanced OA in vivo. The 5A5S group significantly reduced cartilage degeneration, synovial inflammation, pain sensation, and nerve invasion in subchondral nude rat OA, outperforming both single-cell treatments. The underlying mechanism was the activation of chondrocyte autophagy via the FoxO1 signaling pathway. CONCLUSION: A combination of human ADSCs and SDSCs demonstrated higher potential than a single type of stem cell, demonstrating potential as a novel treatment for OA.

Gestational dexamethasone exposure impacts hippocampal excitatory synaptic transmission and learning and memory function with transgenerational effects.

The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons. Here we explored how gestational exposure to dexamethasone, a synthetic glucocorticoid commonly used in clinical practice, has lasting effects on offspring's learning and memory. Adult offspring rats of prenatal dexamethasone exposure (PDE) displayed significant impairments in novelty recognition and spatial learning memory, with some phenotypes maintained transgenerationally. PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations, and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory, but these changes failed to carry over to offspring of F5 and F7 generations. Mechanistically, altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission, which might be related to oocyte-specific high expression and transmission of miR-133a-3p. Together, PDE affects hippocampal excitatory synaptic transmission, with lasting consequences across generations, and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.

Prenatal Dexamethasone Exposure Induced Alterations in Neurobehavior and Hippocampal Glutamatergic System Balance in Female Rat Offspring.

Epidemiological investigations have suggested that periodic use of dexamethasone during pregnancy is a risk factor for abnormal behavior in offspring, but the potential mechanism remains unclear. In this study, we investigated the changes in the glutamatergic system and neurobehavior in female offspring with prenatal dexamethasone exposure (PDE) to explore intrauterine programing mechanisms. Compared with the control group, rat offspring with PDE exhibited spatial memory deficits and anxiety-like behavior. The expression of hippocampal glucocorticoid receptors (GR) and histone deacetylase 2 (HDAC2) increased, whereas histone H3 lysine 14 acetylation (H3K14ac) of brain-derived neurotrophic factor (BDNF) exon IV (BDNF IV) and expression of BDNF decreased. The glutamatergic system also changed. We further observed that changes in the fetal hippocampus were consistent with those in adult offspring. In vitro, the administration of 0.5 µM dexamethasone to the H19-7 fetal hippocampal neuron cells directly led to a cascade of changes in the GR/HDAC2/BDNF pathway, whereas the GR antagonist RU486 and the HDAC2 inhibitor romidepsin (Rom) reversed changes caused by dexamethasone to the H3K14ac level of BDNF IV and to the expression of BDNF. The increase in HDAC2 can be reversed by RU486, and the changes in the glutamatergic system can be partially reversed after supplementation with BDNF. It is suggested that PDE increases the expression of HDAC2 by activating GR, reducing the H3K14ac level of BDNF IV, inducing alterations in neurobehavior and hippocampal glutamatergic system balance. The findings suggest that BDNF supplementation and glutamatergic system improvement are potential therapeutic targets for the fetal origins of abnormal neurobehavior.

Serum metabolic profile characteristics of offspring rats before and after birth caused by prenatal caffeine exposure.

Epidemiological investigations have confirmed that prenatal caffeine intake could increase the incidence rate of intrauterine growth retardation (IUGR) and multiple diseases after birth. Based on liquid chromatography-mass spectrometry, we analyzed serum metabolic profiles of offspring rats before and after birth in IUGR model induced by prenatal caffeine exposure (PCE). We discovered that differential metabolites in PCE fetuses mainly manifested as amino acids and lipid metabolism. In adulthood, PCE offspring showed less and inconsistent types of differential metabolites compared to those in utero, which still exhibited gender differences. The main differential metabolites induced by PCE, including phospholipids, platelet-activating factor, arachidonic acid, bile acid, sphingosine-1-phosphoric acid, indoxyl sulfuric acid, and cortexolone, may participate in the pathological and physiological processes of organ toxicities. This study demonstrated the short- and long-term developmental toxicity and gender differences of caffeine, providing new ideas for exploring the early warning and drug intervention targets of IUGR offspring.