Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

Hong

et al. 2021

Clin Exp Pharma Physio

Sphingosine 1‐phosphate (S1P) exerts its various physiological and pathological effects by interacting with G protein‐coupled receptors. In addition, S1P can induce biological dysfunction in fibroblast‐like synoviocytes (FLSs) in the development of rheumatoid arthritis (RA). However, the mechanism underlying this S1P‐induced dysfunction remains unclear. An imbalance between Gαi and Gαs can affect the level of cAMP, an important regulator of numerous cell functions. Therefore, we studied the effects of S1P receptor (S1PR) 1‐, 2‐, and 3‐associated Gαi/Gαs imbalance on the biological function of rheumatoid arthritis fibroblast‐like synoviocyte (MH7A cells). The results showed that blocking S1PR1/3 and Gαi, and activating Gαs, inhibited the proliferation, migration, invasion, and proinflammatory cytokine release of MH7A cells in a S1P‐induced inflammation model, whereas suppressing S1PR2 only affected the invasion and the release of proinflammatory cytokines of these cells. Analysis of the expression of S1PR1/2/3 and Gαi/Gαs further showed that S1PR1/2/3 could regulate the Gαi/Gαs balance. Furthermore, our data suggested that the level of cAMP was also affected. Combined, our results showed that impaired S1PR1/2/3 signalling can affect MH7A cells biological function via Gαi/Gαs‐cAMP signalling, which can provide a new idea for the treatment of RA.

Section: Discussionsupporting

confidence: 85%

Inhibition of sphingosine 1‐phosphate (S1P) receptor 1/2/3 ameliorates biological dysfunction in rheumatoid arthritis fibroblast‐like synoviocyte MH7A cells through Gαi/Gαs rebalancing

Hong

et al. 2021

Clin Exp Pharma Physio

“…Lysophosphatidic acid is a bioactive lysophospholipid that induces cellular responses via specific GPCRs (LPA1–6). LPA is produced from lysophosphatidylcholine by the action of autotaxin ( Hao et al, 2020 ). Several studies have indicated that LPA treatment of BMECs induces BBB impairment.…”

Section: Inflammatory Mediators Involved In Bbb Dysfunction and Related Intracellular Signaling Pathways In Bmecsmentioning

confidence: 99%

“…S1P is synthesized by phosphorylation of sphingosine derived from sphingolipids by sphingosine kinases 1 and 2 (Sphk1 and Sphk2). Intracellular S1P is secreted into the extracellular space via S1P transporters (e.g., Abca1 and Spns2) where it acts as an extracellular signaling molecule through GPCRs (S1PR1–5) coupled with G q , G i , G 12/13 , and Rho proteins ( Hao et al, 2020 ; Pluimer et al, 2020 ). S1P regulates a number of biological processes including vascular development and function.…”

Section: Inflammatory Mediators Involved In Bbb Dysfunction and Related Intracellular Signaling Pathways In Bmecsmentioning

confidence: 99%

Blood-Brain Barrier Dysfunction Amplifies the Development of Neuroinflammation: Understanding of Cellular Events in Brain Microvascular Endothelial Cells for Prevention and Treatment of BBB Dysfunction

Takata

Nakagawa

Matsumoto

et al. 2021

Front. Cell. Neurosci.

266

142

Neuroinflammation is involved in the onset or progression of various neurodegenerative diseases. Initiation of neuroinflammation is triggered by endogenous substances (damage-associated molecular patterns) and/or exogenous pathogens. Activation of glial cells (microglia and astrocytes) is widely recognized as a hallmark of neuroinflammation and triggers the release of proinflammatory cytokines, leading to neurotoxicity and neuronal dysfunction. Another feature associated with neuroinflammatory diseases is impairment of the blood-brain barrier (BBB). The BBB, which is composed of brain endothelial cells connected by tight junctions, maintains brain homeostasis and protects neurons. Impairment of this barrier allows trafficking of immune cells or plasma proteins into the brain parenchyma and subsequent inflammatory processes in the brain. Besides neurons, activated glial cells also affect BBB integrity. Therefore, BBB dysfunction can amplify neuroinflammation and act as a key process in the development of neuroinflammation. BBB integrity is determined by the integration of multiple signaling pathways within brain endothelial cells through intercellular communication between brain endothelial cells and brain perivascular cells (pericytes, astrocytes, microglia, and oligodendrocytes). For prevention of BBB disruption, both cellular components, such as signaling molecules in brain endothelial cells, and non-cellular components, such as inflammatory mediators released by perivascular cells, should be considered. Thus, understanding of intracellular signaling pathways that disrupt the BBB can provide novel treatments for neurological diseases associated with neuroinflammation. In this review, we discuss current knowledge regarding the underlying mechanisms involved in BBB impairment by inflammatory mediators released by perivascular cells.

“…Cognitive disorders, such as dementia with AD, raise this bar even further since disorders such as AD are multifactorial in origin. Multiple mechanisms may lead to cognitive impairment and involve cellular injury from β-amyloid (Aβ), tau, excitotoxicity, metabotropic receptors, lipid dysfunction, mitochondrial damage, acetylcholine loss, astrocytic cell injury, oxidative stress, heavy metal disease, and cellular metabolic dysfunction with diabetes mellitus (DM) [3,4,8,14,27,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. Present strategies to treat cognitive loss with AD involve therapy with cholinesterase inhibitors that may decrease some symptoms but do not alter disease progression [11,15,52,55].…”

Section: Novel Therapeutic Considerations For Cognitive Lossmentioning

confidence: 99%

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

Maiese

2021

Biomolecules

Neurodegenerative disorders affect fifteen percent of the world’s population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer’s disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.