Role of Chronic Administration of Antidepressant Drugs in the Prenatal Stress-Evoked Inflammatory Response in the Brain of Adult Offspring Rats: Involvement of the NLRP3 Inflammasome-Related Pathway

Serpins are a superfamily of proteins characterized by their common function as serine protease inhibitors. So far, 36 serpins from nine clades have been identified. These proteins are expressed in all the organs and are involved in multiple important functions such as the regulation of blood pressure, hormone transport, insulin sensitivity, and the inflammatory response. Diseases such as obesity, diabetes, cardiovascular, and kidney disorders are intensively studied to find effective therapeutic targets. Given serpins' outstanding functionality, the deficiency or overexpression of certain types of serpin have been associated with diverse pathophysiological events. In particular, we will focus on reviewing the studies evaluating the participation of serpins, and particularly SerpinA3, in diverse diseases that occur in relevant organs such as the brain, retinas, corneas, lungs, cardiac vasculature, and kidneys. In this review, we summarize the role of serpins in physiological and pathophysiological processes, as well as recent evidence on the crucial role of SerpinA3 in several pathologies. Finally, we emphasize the importance of SerpinA3 in regulating cellular processes such as angiogenesis, apoptosis, fibrosis, oxidative stress, and the inflammatory response.

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Regional difference in inflammatory response to LPS-injection in the brain: Role of microglia cell density

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2011.06.017 ◽

2011 ◽

Vol 238 (1-2) ◽

pp. 44-51 ◽

Cited By ~ 18

Author(s):

Cristina Pintado ◽

Elisa Revilla ◽

María L. Vizuete ◽

Sebastián Jiménez ◽

Luisa García-Cuervo ◽

...

Keyword(s):

Inflammatory Response ◽

Cell Density ◽

Regional Difference ◽

Microglia Cell ◽

The Brain

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Fractalkine Attenuates Microglial Cell Activation Induced by Prenatal Stress

Neural Plasticity ◽

10.1155/2016/7258201 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Joanna Ślusarczyk ◽

Ewa Trojan ◽

Katarzyna Głombik ◽

Katarzyna Chamera ◽

Adam Roman ◽

...

Keyword(s):

Prenatal Stress ◽

Cell Activation ◽

Inflammatory Factors ◽

Potential Contribution ◽

Fractalkine Receptor ◽

Neuropsychiatric Diseases ◽

Prenatally Stressed ◽

The Brain ◽

Receptor Cx3cr1

The potential contribution of inflammation to the development of neuropsychiatric diseases has recently received substantial attention. In the brain, the main immune cells are the microglia. As they are the main source of inflammatory factors, it is plausible that the regulation of their activation may be a potential therapeutic target. Fractalkine (CX3CL1) and its receptor CX3CR1 play a crucial role in the control of the biological activity of the microglia. In the present study, using microglial cultures we investigated whether fractalkine is able to reverse changes in microglia caused by a prenatal stress procedure. Our study found that the microglia do not express fractalkine. Prenatal stress decreases the expression of the fractalkine receptor, which in turn is enhanced by the administration of exogenous fractalkine. Moreover, treatment with fractalkine diminishes the prenatal stress-induced overproduction of proinflammatory factors such as IL-1β, IL-18, IL-6, TNF-α, CCL2, or NO in the microglial cells derived from prenatally stressed newborns. In conclusion, the present results revealed that the pathological activation of microglia in prenatally stressed newborns may be attenuated by fractalkine administration. Therefore, understanding of the role of the CX3CL1-CX3CR1 system may help to elucidate the mechanisms underlying the neuron-microglia interaction and its role in pathological conditions in the brain.

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Plantamajoside Ameliorates Inflammatory Response of Chondrocytes via Regulating NF-κB/NLRP3 Inflammasome Pathway

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2634 ◽

2021 ◽

Vol 11 (5) ◽

pp. 997-1002

Author(s):

Chi Zhang ◽

Yuanhe Wang ◽

Chuan Hu ◽

Kang Sun ◽

Dingzhu Yu ◽

...

Keyword(s):

Oxidative Stress ◽

Inflammatory Response ◽

Cell Viability ◽

Nlrp3 Inflammasome ◽

Underlying Mechanism ◽

Cell Counting ◽

Enzyme Linked Immunosorbent Assay ◽

Apoptotic Cells ◽

Protein Levels

The damage of articular cartilage in osteoarthritis involves the oxidative stress and inflammation. The aim of the present study was to explore the role of plantamajoside (PM) in chondrocytes and elucidate the underlying mechanism. The cell viability following treatment with PM or lipopolysac-charide (LPS) was assessed by cell counting kit-8 (CCK-8). Enzyme-Linked Immunosorbent Assay (ELISA) was supplied to determine the levels of pro-inflammatory cytokines. Moreover, the oxidative stress-related markers were evaluated via assay kits. TUNEL assay was employed to stain the apoptotic cells. The components of nuclear factor-κB (NF-κB) pathway and NLRP3 inflammasome were estimated by western blot analysis. LPS-insulted cell viability of ATDC5 was restored by PM. PM alleviated the inflammatory response and oxidative stress of ATDC5 cells induced by LPS. Furthermore, it was found that the apoptotic cells were reduced following PM treatment. The protein levels of NF-κB, IκB kinase β (IKKβ) and NLRP3 inflammasome were decreased by PM. These results suggested that PM protected the ATDC5 cells from LPS stimulation, alleviated the inflammatory response may through regulating the NF-κB and NLRP3 inflammasome.

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Microglial phagocytosis dysfunction during stroke is prevented by rapamycin

10.1101/2021.11.12.468358 ◽

2021 ◽

Author(s):

Sol Beccari ◽

Virginia Sierra-Torre ◽

Jorge Valero ◽

Mikel Garcia-Zaballa ◽

Alejandro Carretero-Guillen ◽

...

Keyword(s):

Inflammatory Response ◽

Therapeutic Target ◽

Apoptotic Cell ◽

Knock Out ◽

Microglial Phagocytosis ◽

Cellular Debris ◽

The Brain

Microglial phagocytosis is rapidly emerging as a therapeutic target in neurodegenerative and neurological disorders. An efficient removal of cellular debris is necessary to prevent buildup damage of neighbor neurons and the development of an inflammatory response. As the brain professional phagocytes, microglia are equipped with an array of mechanisms that enable them to recognize and degrade several types of cargo, including neurons undergoing apoptotic cell death. While microglia are very competent phagocytes of apoptotic cells under physiological conditions, here we report their dysfunction in mouse and monkey (Macaca fascicularis and Callithrix jacchus) models of stroke by transient occlusion of the medial cerebral artery (tMCAo). The impairment of both engulfment and degradation was related to energy depletion triggered by oxygen and nutrients deprivation (OND), which led to reduced process motility, lysosomal depletion, and the induction of a protective autophagy response in microglia. Basal autophagy, which is in charge of removing and recycling intracellular elements, was critical to maintain microglial physiology, including survival and phagocytosis, as we determined both in vivo and in vitro using knock-out models of autophagy genes and the autophagy inhibitor MRT68921. Notably, the autophagy inducer rapamycin partially prevented the phagocytosis impairment induced by tMCAo in vivo but not by OND in vitro. These results suggest a more complex role of microglia in stroke than previously acknowledged, classically related to the inflammatory response. In contrast, here we demonstrate the impairment of apoptotic cell phagocytosis, a microglial function critical for brain recovery. We propose that phagocytosis is a therapeutic target yet to be explored and provide evidence that it can be modulated in vivo using rapamycin, setting the stage for future therapies for stroke patients.

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Entinostat Improves Motor Function and Neuronal Damage Via Downregulating NLRP3 Inflammasome Activation After Spinal Cord Injury

Frontiers in Pharmacology ◽

10.3389/fphar.2021.774539 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chen Dai ◽

Bin Liu ◽

Bibo Peng ◽

Bo Qu ◽

Jiezhi Lin ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Motor Function ◽

Nlrp3 Inflammasome ◽

Neuronal Damage ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Cord Injury

Background: Spinal cord injury (SCI), a major public health problem, has no effective treatment. A large number of studies have confirmed that histone deacetylases (HDACs) are involved in the physiologic processes that occur following SCI. We tried to uncover the potential neuroprotective role of entinostat (a class I HDAC inhibitor) in SCI.Methods: We conducted a study on a preclinical mouse model of SCI and OGD-induced neuronal damage to present the role of entinostat by the analysis of motor function, histopathologic damage, local NLRP3 inflammasome activation, and neuronal damage.Results: The results showed that entinostat suppressed HDAC activation (including HDAC1 and HDAC3 expression), improved the grip strength and BMS score, spinal edema, cell death, and local NLRP3 inflammasome activation in the spinal cord following SCI. Furthermore, entinostat significantly increased OGD-inhibited neuronal activity and decreased PI-positive cells, HDAC activation, caspase-1 activation, IL-1β and IL-18 levels, and NLRP3 expression.Conclusion: In summary, we first documented that entinostat improved the motor function, histopathologic damage, and local inflammatory response and NLRP3 inflammasome activation in the spinal cord following SCI and also presented the neuroprotective role of OGD-induced neuronal damage via the NLRP3 inflammasome. Thus, our study has the potential to reveal the interaction between the HDAC and NLRP3 inflammasome in the pathologic process as well as SCI and further promote the clinical indications of HDACi entinostat and clinical treatment for the inflammatory response after SCI.

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A Role of BDNF in the Depression Pathogenesis and a Potential Target as Antidepressant: The Modulator of Stress Sensitivity “Shati/Nat8l-BDNF System” in the Dorsal Striatum

Pharmaceuticals ◽

10.3390/ph14090889 ◽

2021 ◽

Vol 14 (9) ◽

pp. 889

Author(s):

Hajime Miyanishi ◽

Atsumi Nitta

Keyword(s):

Social Stress ◽

Molecular Mechanisms ◽

Antidepressant Drugs ◽

Dorsal Striatum ◽

Stress Sensitivity ◽

Research Progress ◽

Treatment Of Depression ◽

Mental Diseases ◽

The Brain

Depression is one of the most common mental diseases, with increasing numbers of patients globally each year. In addition, approximately 30% of patients with depression are resistant to any treatment and do not show an expected response to first-line antidepressant drugs. Therefore, novel antidepressant agents and strategies are required. Although depression is triggered by post-birth stress, while some individuals show the pathology of depression, others remain resilient. The molecular mechanisms underlying stress sensitivity remain unknown. Brain-derived neurotrophic factor (BDNF) has both pro- and anti-depressant effects, dependent on brain region. Considering the strong region-specific contribution of BDNF to depression pathogenesis, the regulation of BDNF in the whole brain is not a beneficial strategy for the treatment of depression. We reviewed a novel finding of BDNF function in the dorsal striatum, which induces vulnerability to social stress, in addition to recent research progress regarding the brain regional functions of BDNF, including the prefrontal cortex, hippocampus, and nucleus accumbens. Striatal BDNF is regulated by Shati/Nat8l, an N-acetyltransferase through epigenetic regulation. Targeting of Shati/Nat8l would allow BDNF to be striatum-specifically regulated, and the striatal Shati/Nat8l-BDNF pathway could be a promising novel therapeutic agent for the treatment of depression by modulating sensitivity to stress.

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Brucella-Induced Downregulation of lncRNA Gm28309 Triggers Macrophages Inflammatory Response Through the miR-3068-5p/NF-κB Pathway

Frontiers in Immunology ◽

10.3389/fimmu.2020.581517 ◽

2020 ◽

Vol 11 ◽

Author(s):

Xingmei Deng ◽

Jia Guo ◽

Zhihua Sun ◽

Laizhen Liu ◽

Tianyi Zhao ◽

...

Keyword(s):

Inflammatory Response ◽

Immune Responses ◽

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Underlying Mechanism ◽

Bioinformatic Analysis ◽

Luciferase Reporter ◽

Non Coding Rnas ◽

First Time

ObjectivesThe underlying mechanism of the inflammatory response against Brucellosis caused by Brucella remains poorly understood. This study aimed to determine the role of long non-coding RNAs (lncRNAs) in regulating of inflammatory and anti-Brucella responses.Materials and methodsMicroarray analysis was performed to detect differentially expressed lncRNAs in THP-1 cells infected with an S2308 Brucella strain. The candidate lncRNAs were screened using bioinformatic analysis and siRNAs; bioinformatic prediction and luciferase reporter assay were also conducted, while inflammatory responses was assessed using RT‐qPCR, western blot, immunofluorescence, ELISA, HE, and immunohistochemistry.ResultsThe lncRNA Gm28309 was identified to be involved in regulating inflammation induced by Brucella. Gm28309, localized in the cytoplasm, was down-expressed in RAW264.7 cells infected with S2308. Overexpression of Gm28309 or inhibition of miR-3068-5p repressed p65 phosphorylation and reduced NLRP3 inflammasome and IL-1β and IL-18 secretion. Mechanistically, Gm28309 acted as a ceRNA of miR-3068-5p to activate NF-κB pathway by targeting κB-Ras2, an inhibitor of NF-κB signaling. Moreover, the number of intracellular Brucella was higher when Gm28309 was overexpressed or when miR-3068-5p or p65 was inhibited. However, these effects were reversed by the miR-3068-5p mimic.ConclusionsOur study demonstrates, for the first time, that LncRNAs are involved in regulating immune responses during Brucella infection, and Gm28309, an lncRNA, plays a crucial role in activating NF-κB/NLRP3 inflammasome signaling pathway.

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