The molecular mechanisms of signal pathway activating effect of E2F-1/NF-κB/GSK-3β on cognitive dysfunction of Alzheimer rats

Abstract Background Dysfunctional osteogenesis of bone marrow mesenchymal stem cells (BMSCs) plays an important role in osteoporosis occurrence and development. However, the molecular mechanisms of osteogenic differentiation remain unclear. This study explored whether microfibrillar-associated protein 5 (MFAP5) regulated BMSCs osteogenic differentiation. Methods We used shRNA or cDNA to knock down or overexpress MFAP5 in C3H10 and MC3T3-E1 cells. AR-S- and ALP-staining were performed to quantify cellular osteogenic differentiation. The mRNA levels of the classical osteogenic differentiation biomarkers Runx2, Col1α1, and OCN were quantified by qRT-PCR. Finally, we employed Western blotting to measure the levels of Wnt/β-catenin and AMPK signaling proteins. Results At days 0, 3, 7, and 14 after osteogenic induction, AR-S- and ALP-staining was lighter in MFAP5 knockdown compared to control cells, as were the levels of Runx2, Col1α1 and OCN. During osteogenesis, the levels of β-catenin, p-GSK-3β, AMPK, and p-AMPK were upregulated, while that of GSK-3β was downregulated, indicating that Wnt/β-catenin and AMPK signaling were activated. The relevant molecules were expressed at lower levels in the knockdown than control group; the opposite was seen for overexpressing cell lines. Conclusions MFAP5 regulates osteogenesis via Wnt/β‑catenin- and AMPK-signaling; MFAP5 may serve as a therapeutic target in patients with osteoporosis.

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Molecular mechanisms of cognitive dysfunction following traumatic brain injury

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2013.00029 ◽

2013 ◽

Vol 5 ◽

Cited By ~ 130

Author(s):

Kendall R. Walker ◽

Giuseppina Tesco

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cognitive Dysfunction ◽

Molecular Mechanisms

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Glycogen Synthase Kinase 3β Promotes Postoperative Cognitive Dysfunction by Inducing the M1 Polarization and Migration of Microglia

Mediators of Inflammation ◽

10.1155/2020/7860829 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Jingjin Li ◽

Chonglong Shi ◽

Zhengnian Ding ◽

Wenjie Jin

Keyword(s):

Cognitive Dysfunction ◽

Lithium Chloride ◽

Glycogen Synthase ◽

Postoperative Cognitive Dysfunction ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β ◽

Central Nervous System Complication ◽

Proinflammatory Mediators ◽

M1 Polarization ◽

Gsk 3Β

Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system complication, especially in the elderly. It has been consistently reported that the pathological process of this clinical syndrome is related to neuroinflammation and microglial proliferation. Glycogen synthase kinase 3β (GSK-3β) is a widely expressed kinase with distinct functions in different types of cells. The role of GSK-3β in regulating innate immune activation has been well documented, but as far as we know, its role in POCD has not been fully elucidated. Lithium chloride (LiCl) is a widely used inhibitor of GSK-3β, and it is also the main drug for the treatment of bipolar disorder. Prophylactic administration of lithium chloride (2 mM/kg) can inhibit the expression of proinflammatory mediators in the hippocampus, reduce the hippocampal expression of NF-κB, and increase both the downregulation of M1 microglial-related genes (inducible nitric oxide synthase and CD86) and upregulation of M2 microglial-related genes (IL-10 and CD206), to alleviate the cognitive impairment caused by orthopedic surgery. In vitro, LiCl reversed LPS-induced production of proinflammatory mediators and M1 polarization of microglia. To sum up these results, GSK-3β is a key contributor to POCD and a potential target of neuroprotective strategies.

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Associations between prolactin, diabetes and cognitive impairment: a literature review

Neuroendocrinology ◽

10.1159/000521653 ◽

2021 ◽

Author(s):

Hai Duc Nguyen ◽

Hojin Oh ◽

Byung Pal Yu ◽

Ngoc Minh Hong Hoang ◽

Won Hee Jo ◽

...

Keyword(s):

Cognitive Impairment ◽

Literature Review ◽

Cognitive Dysfunction ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Akt Pathway ◽

Molecular Aspects

Background: Converging evidence indicates prolactin (PRL) and diabetes play an important role in the pathophysiology of cognitive impairment. However, little is known about the mechanisms responsible for the effects of PRL and diabetes on cognitive impairment. Summary: We summarize and review the available literature and current knowledge of the association between PRL and diabetes on aspects of cognitive impairment. Key Messages: The PI3K/AKT pathway is central to the molecular mechanisms underlying how PRL and diabetes interact in cognitive impairment. Further work is needed to identify the interaction between PRL and diabetes, especially in the molecular aspects of cognitive impairment, which can suggest novel strategies for cognitive dysfunction treatment.

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Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-β1/Smad3 and Wnt/β-Catenin Signaling Pathways

Frontiers in Pharmacology ◽

10.3389/fphar.2020.594139 ◽

2021 ◽

Vol 11 ◽

Author(s):

Fan Yang ◽

Zhen-feng Hou ◽

Hao-yue Zhu ◽

Xiao-xuan Chen ◽

Wan-yang Li ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Gene Expression Omnibus ◽

Matrix Remodeling ◽

Mesenchymal Transition ◽

Collagen Remodeling ◽

Gsk 3Β ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.

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β-Catenin Regulates Wound Healing and IL-6 Expression in Activated Human Astrocytes

Biomedicines ◽

10.3390/biomedicines8110479 ◽

2020 ◽

Vol 8 (11) ◽

pp. 479

Author(s):

Venkata Viswanadh Edara ◽

Shruthi Nooka ◽

Jessica Proulx ◽

Satomi Stacy ◽

Anuja Ghorpade ◽

...

Keyword(s):

Wound Healing ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Glycogen Synthase ◽

Reactive Astrogliosis ◽

Human Astrocytes ◽

Tnf Α ◽

Inflammatory Stimuli ◽

Chemokine Ligand ◽

Gsk 3Β

Reactive astrogliosis is prominent in most neurodegenerative disorders and is often associated with neuroinflammation. The molecular mechanisms regulating astrocyte-linked neuropathogenesis during injury, aging and human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are not fully understood. In this study, we investigated the implications of the wingless type (Wnt)/β-catenin signaling pathway in regulating astrocyte function during gliosis. First, we identified that HIV-associated inflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor (TNF)-α induced mediators of the Wnt/β-catenin pathway including β-catenin and lymphoid enhancer-binding factor (LEF)-1 expression in astrocytes. Next, we investigated the regulatory role of β-catenin on primary aspects of reactive astrogliosis, including proliferation, migration and proinflammatory responses, such as IL-6. Knockdown of β-catenin impaired astrocyte proliferation and migration as shown by reduced cyclin-D1 levels, bromodeoxyuridine incorporation and wound healing. HIV-associated cytokines, IL-1β alone and in combination with TNF-α, strongly induced the expression of proinflammatory cytokines including C-C motif chemokine ligand (CCL)2, C-X-C motif chemokine ligand (CXCL)8 and IL-6; however, only IL-6 levels were regulated by β-catenin as demonstrated by knockdown and pharmacological stabilization. In this context, IL-6 levels were negatively regulated by β-catenin. To better understand this relationship, we examined the crossroads between β-catenin and nuclear factor (NF)-κB pathways. While NF-κB expression was significantly increased by IL-1β and TNF-α, NF-κB levels were not affected by β-catenin knockdown. IL-1β treatment significantly increased glycogen synthase kinase (GSK)-3β phosphorylation, which inhibits β-catenin degradation. Further, pharmacological inhibition of GSK-3β increased nuclear translocation of both β-catenin and NF-κB p65 into the nucleus in the absence of any other inflammatory stimuli. HIV+ human astrocytes show increased IL-6, β-catenin and NF-κB expression levels and are interconnected by regulatory associations during HAND. In summary, our study demonstrates that HIV-associated inflammation increases β-catenin pathway mediators to augment activated astrocyte responses including migration and proliferation, while mitigating IL-6 expression. These findings suggest that β-catenin plays an anti-inflammatory role in activated human astrocytes during neuroinflammatory pathologies, such as HAND.

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Effect of High-Fat Diets on Oxidative Stress, Cellular Inflammatory Response and Cognitive Function

Nutrients ◽

10.3390/nu11112579 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2579 ◽

Cited By ~ 10

Author(s):

Bee Ling Tan ◽

Mohd Esa Norhaizan

Keyword(s):

Oxidative Stress ◽

Fatty Acids ◽

Free Fatty Acids ◽

Cognitive Dysfunction ◽

Molecular Mechanisms ◽

Cell Mediated Immunity ◽

Low Grade ◽

High Fat ◽

Cellular Inflammatory Response

Cognitive dysfunction is linked to chronic low-grade inflammatory stress that contributes to cell-mediated immunity in creating an oxidative environment. Food is a vitally important energy source; it affects brain function and provides direct energy. Several studies have indicated that high-fat consumption causes overproduction of circulating free fatty acids and systemic inflammation. Immune cells, free fatty acids, and circulating cytokines reach the hypothalamus and initiate local inflammation through processes such as microglial proliferation. Therefore, the role of high-fat diet (HFD) in promoting oxidative stress and neurodegeneration is worthy of further discussion. Of particular interest in this article, we highlight the associations and molecular mechanisms of HFD in the modulation of inflammation and cognitive deficits. Taken together, a better understanding of the role of oxidative stress in cognitive impairment following HFD consumption would provide a useful approach for the prevention of cognitive dysfunction.

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