scholarly journals The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1515
Author(s):  
Alexandra Lucaciu ◽  
Robert Brunkhorst ◽  
Josef Pfeilschifter ◽  
Waltraud Pfeilschifter ◽  
Julien Subburayalu
Keyword(s):  
Neurological Disorders ◽  
Intracellular Signaling ◽  
Cerebrovascular Disorders ◽  
Current Evidence ◽  
Lipid Mediator ◽  
Molecular Signaling ◽  
Sphingosine 1 Phosphate ◽  
Clinical Conditions ◽  
Immune Phenomena ◽  
Receptor Ligation

Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a pleiotropic bioactive lipid mediator capable of evoking complex immune phenomena. Studies have highlighted its importance regarding intracellular signaling cascades as well as membrane-bound S1P receptor (S1PR) engagement in various clinical conditions. In neurological disorders, the S1P–S1PR axis is acknowledged in neurodegenerative, neuroinflammatory, and cerebrovascular disorders. Modulators of S1P signaling have enabled an immense insight into fundamental pathological pathways, which were pivotal in identifying and improving the treatment of human diseases. However, its intricate molecular signaling pathways initiated upon receptor ligation are still poorly elucidated. In this review, the authors highlight the current evidence for S1P signaling in neurodegenerative and neuroinflammatory disorders as well as stroke and present an array of drugs targeting the S1P signaling pathway, which are being tested in clinical trials. Further insights on how the S1P–S1PR axis orchestrates disease initiation, progression, and recovery may hold a remarkable potential regarding therapeutic options in these neurological disorders.

scholarly journals Speech Processing Disorder in Neural Hearing Loss

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Joseph P. Pillion
Keyword(s):  
Speech Processing ◽  
Auditory Processing ◽  
Neurological Disorders ◽  
Auditory Neuropathy ◽  
Central Auditory Processing ◽  
Temporal Lobes ◽  
Electrophysiological Tests ◽  
Bilateral Lesions ◽  
Clinical Conditions ◽  
Inferior Colliculi

Deficits in central auditory processing may occur in a variety of clinical conditions including traumatic brain injury, neurodegenerative disease, auditory neuropathy/dyssynchrony syndrome, neurological disorders associated with aging, and aphasia. Deficits in central auditory processing of a more subtle nature have also been studied extensively in neurodevelopmental disorders in children with learning disabilities, ADD, and developmental language disorders. Illustrative cases are reviewed demonstrating the use of an audiological test battery in patients with auditory neuropathy/dyssynchrony syndrome, bilateral lesions to the inferior colliculi, and bilateral lesions to the temporal lobes. Electrophysiological tests of auditory function were utilized to define the locus of dysfunction at neural levels ranging from the auditory nerve, midbrain, and cortical levels.

scholarly journals The Hallmarks of Flavonoids in Cancer

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 2029
Author(s):  
Luis Gustavo Saboia Ponte ◽  
Isadora Carolina Betim Pavan ◽  
Mariana Camargo Silva Mancini ◽  
Luiz Guilherme Salvino da Silva ◽  
Ana Paula Morelli ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Biological Activity ◽  
Neurological Disorders ◽  
Mechanisms Of Action ◽  
Molecular Signaling ◽  
Hallmarks Of Cancer ◽  
Redox Metabolism ◽  
Important Group ◽  
Cellular Context

Flavonoids represent an important group of bioactive compounds derived from plant-based foods and beverages with known biological activity in cells. From the modulation of inflammation to the inhibition of cell proliferation, flavonoids have been described as important therapeutic adjuvants against several diseases, including diabetes, arteriosclerosis, neurological disorders, and cancer. Cancer is a complex and multifactor disease that has been studied for years however, its prevention is still one of the best known and efficient factors impacting the epidemiology of the disease. In the molecular and cellular context, some of the mechanisms underlying the oncogenesis and the progression of the disease are understood, known as the hallmarks of cancer. In this text, we review important molecular signaling pathways, including inflammation, immunity, redox metabolism, cell growth, autophagy, apoptosis, and cell cycle, and analyze the known mechanisms of action of flavonoids in cancer. The current literature provides enough evidence supporting that flavonoids may be important adjuvants in cancer therapy, highlighting the importance of healthy and balanced diets to prevent the onset and progression of the disease.

scholarly journals Pandemics and Burden of Stroke and Epilepsy in Sub-Saharan Africa: Experience from a Longstanding Health Programme

2021 ◽  
Vol 18 (5) ◽  
pp. 2766
Author(s):  
Massimo Leone ◽  
Fausto Ciccacci ◽  
Stefano Orlando ◽  
Sandro Petrolati ◽  
Giovanni Guidotti ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Combined Treatment ◽  
Cerebrovascular Disorders ◽  
Sub Saharan Africa ◽  
Noncommunicable Diseases ◽  
People Living With Hiv ◽  
Sub Saharan ◽  
Health Programme ◽  
Excess Deaths ◽  
Hiv Aids

Eighty percent of people with stroke live in low- to middle-income nations, particularly in sub-Saharan Africa (SSA) where stroke has increased by more than 100% in the last decades. More than one-third of all epilepsy−related deaths occur in SSA. HIV infection is a risk factor for neurological disorders, including stroke and epilepsy. The vast majority of the 38 million people living with HIV/AIDS are in SSA, and the burden of neurological disorders in SSA parallels that of HIV/AIDS. Local healthcare systems are weak. Many standalone HIV health centres have become a platform with combined treatment for both HIV and noncommunicable diseases (NCDs), as advised by the United Nations. The COVID-19 pandemic is overwhelming the fragile health systems in SSA, and it is feared it will provoke an upsurge of excess deaths due to the disruption of care for chronic diseases such as HIV, TB, hypertension, diabetes, and cerebrovascular disorders. Disease Relief through Excellent and Advanced Means (DREAM) is a health programme active since 2002 to prevent and treat HIV/AIDS and related disorders in 10 SSA countries. DREAM is scaling up management of NCDs, including neurologic disorders such as stroke and epilepsy. We described challenges and solutions to address disruption and excess deaths from these diseases during the ongoing COVID-19 pandemic.

scholarly journals Melatonin in Wine and Beer: Beneficial Effects

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 343
Author(s):  
Javier Marhuenda ◽  
Débora Villaño ◽  
Raúl Arcusa ◽  
Pilar Zafrilla
Keyword(s):  
Intracellular Signaling ◽  
Plasma Concentrations ◽  
Radical Scavenging ◽  
Direct Interaction ◽  
Melatonin Receptors ◽  
Current Evidence ◽  
Sleep Cycle ◽  
Beneficial Effects ◽  
Neuroprotective Actions ◽  
Radical Scavenging Properties

Melatonin is a hormone secreted in the pineal gland with several functions, especially regulation of circadian sleep cycle and the biological processes related to it. This review evaluates the bioavailability of melatonin and resulting metabolites, the presence of melatonin in wine and beer and factors that influence it, and finally the different benefits related to treatment with melatonin. When administered orally, melatonin is mainly absorbed in the rectum and the ileum; it has a half-life of about 0.45–1 h and is extensively inactivated in the liver by phase 2 enzymes. Melatonin (MEL) concentration varies from picograms to ng/mL in fermented beverages such as wine and beer, depending on the fermentation process. These low quantities, within a dietary intake, are enough to reach significant plasma concentrations of melatonin, and are thus able to exert beneficial effects. Melatonin has demonstrated antioxidant, anticarcinogenic, immunomodulatory and neuroprotective actions. These benefits are related to its free radical scavenging properties as well and the direct interaction with melatonin receptors, which are involved in complex intracellular signaling pathways, including inhibition of angiogenesis and cell proliferation, among others. In the present review, the current evidence on the effects of melatonin on different pathophysiological conditions is also discussed.

scholarly journals Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of cerebral venous sinus thrombosis

2020 ◽  
Vol 5 (2) ◽  
pp. 152-158
Author(s):  
Yuhua Fan ◽  
Jian Yu ◽  
Hongbing Chen ◽  
Jian Zhang ◽  
Jiangang Duan ◽  
...  
Keyword(s):  
Secondary Prevention ◽  
Clinical Management ◽  
Sinus Thrombosis ◽  
Cerebrovascular Disorders ◽  
Cerebral Venous Sinus Thrombosis ◽  
Venous Sinus ◽  
Current Evidence ◽  
Current Guideline ◽  
Venous Sinus Thrombosis ◽  
Venous Thromboembolic Events

AimCerebral venous sinus thrombosis (CVST) is a less common cerebrovascular disease that predominantly affects young patients. The incidence of CVST is 2–5/10 000 000/year, accounting for 0.5%–1% of all stroke. To reduce mortality and morbidity associated with CVST, Chinese Stroke Association commissioned the authors to write the current guideline on the management of CVST.MethodsPubMed (MEDLINE), CNKI and Wanfang database were searched for studies related to CVST from 1 January 1990 to 31 July 2019. Data were synthesised by evidence tables. Each recommendation was fully discussed by the writing group members and reviewed by Chinese Stroke Association Stroke Fellow Committees. Levels of evidence grading algorithm of Chinese Stroke Association was used to grade each recommendation.ResultsThis guideline mainly focuses on the diagnostic evaluation, therapeutic strategies and secondary prevention of CVST. CT/CTV and MRI/MRV are recommended in the initial imaging evaluation of patients with suspected CVST. Anticoagulation therapy with low-molecular weight heparin should be initiated in patients with CVST immediately. After the acute stage, warfarin is recommended for 3–6 months to prevent the recurrence of CVST and other venous thromboembolic events.ConclusionsThe guideline summarises the current evidence regarding the management of CVST, and provides references for diagnosis, treatment and secondary prevention of CVST in China.

scholarly journals Permissive Modulation of Sphingosine-1-Phosphate-Enhanced Intracellular Calcium on BKCa Channel of Chromaffin Cells

2021 ◽  
Vol 22 (4) ◽  
pp. 2175
Author(s):  
Adonis Z. Wu ◽  
Tzu-Lun Ohn ◽  
Ren-Jay Shei ◽  
Huei-Fang Wu ◽  
Yong-Cyuan Chen ◽  
...  
Keyword(s):  
Chromaffin Cells ◽  
Low Dose ◽  
Single Channel ◽  
Cell System ◽  
K Channel ◽  
Lipid Mediator ◽  
Bkca Channel ◽  
High Dose ◽  
Open Probability ◽  
Sphingosine 1 Phosphate

Sphingosine-1-phosphate (S1P), is a signaling sphingolipid which acts as a bioactive lipid mediator. We assessed whether S1P had multiplex effects in regulating the large-conductance Ca2+-activated K+ channel (BKCa) in catecholamine-secreting chromaffin cells. Using multiple patch-clamp modes, Ca2+ imaging, and computational modeling, we evaluated the effects of S1P on the Ca2+-activated K+ currents (IK(Ca)) in bovine adrenal chromaffin cells and in a pheochromocytoma cell line (PC12). In outside-out patches, the open probability of BKCa channel was reduced with a mean-closed time increment, but without a conductance change in response to a low-concentration S1P (1 µM). The intracellular Ca2+ concentration (Cai) was elevated in response to a high-dose (10 µM) but not low-dose of S1P. The single-channel activity of BKCa was also enhanced by S1P (10 µM) in the cell-attached recording of chromaffin cells. In the whole-cell voltage-clamp, a low-dose S1P (1 µM) suppressed IK(Ca), whereas a high-dose S1P (10 µM) produced a biphasic response in the amplitude of IK(Ca), i.e., an initial decrease followed by a sustained increase. The S1P-induced IK(Ca) enhancement was abolished by BAPTA. Current-clamp studies showed that S1P (1 µM) increased the action potential (AP) firing. Simulation data revealed that the decreased BKCa conductance leads to increased AP firings in a modeling chromaffin cell. Over a similar dosage range, S1P (1 µM) inhibited IK(Ca) and the permissive role of S1P on the BKCa activity was also effectively observed in the PC12 cell system. The S1P-mediated IK(Ca) stimulation may result from the elevated Cai, whereas the inhibition of BKCa activity by S1P appears to be direct. By the differentiated tailoring BKCa channel function, S1P can modulate stimulus-secretion coupling in chromaffin cells.

Biological activities of novel lipid mediator sphingosine 1-phosphate in rat hepatic stellate cells

2000 ◽  
Vol 279 (2) ◽  
pp. G304-G310 ◽  
Author(s):  
Hitoshi Ikeda ◽  
Yutaka Yatomi ◽  
Mikio Yanase ◽  
Hiroaki Satoh ◽  
Hisato Maekawa ◽  
...  
Keyword(s):  
Wound Healing ◽  
Hepatic Stellate Cells ◽  
Biological Activities ◽  
Healing Process ◽  
Stellate Cells ◽  
Mitogen Activated Protein Kinase ◽  
Lipid Mediator ◽  
Wound Healing Process ◽  
Mrna Levels ◽  
Sphingosine 1 Phosphate

Sphingosine 1-phosphate (S-1-P), a lipid mediator shown to be a ligand for G protein-coupled receptors (AGRs), endothelial differentiation gene (EDG)1, EDG3, and AGR16/EDG5, is stored in platelets and released on their activation. Platelet consumption occurs in acute liver injury. Hepatic stellate cells (HSCs) play an important role in wound healing. Effects of S-1-P on HSCs were investigated. S-1-P enhanced proliferation of culture-activated HSCs. The mitogenic effect was pertussis toxin sensitive, mitogen-activated protein kinase dependent, and more prominent at lower cell density. S-1-P increased contraction of collagen lattices containing HSCs, irrespective of activation state, in a C3 exotoxin-sensitive manner. mRNAs of EDG1 and AGR16, but not of EDG3, were detected in HSCs. In HSC activation, EDG1 mRNA levels were downregulated, whereas AGR16 mRNA levels were unchanged. Considering that HSCs are capable of production of extracellular matrices and modulation of blood flow in sinusoids, our results suggest that S-1-P may play a role in wound healing process in the liver.

scholarly journals Heterotypic inter-GPCR ß-arrestin coupling regulates lymphatic endothelial junctional architecture in murine lymph nodes

2018 ◽  
Author(s):  
Yu Hisano ◽  
Mari Kono ◽  
Eric Engelbrecht ◽  
Koki Kawakami ◽  
Keisuke Yanagida ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymph Nodes ◽  
Cross Talk ◽  
Transcriptional Activation ◽  
Endothelial Permeability ◽  
Lipid Mediator ◽  
Protein Signaling ◽  
A Genome ◽  
Sphingosine 1 Phosphate ◽  
A Site

AbstractLysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) activate G protein-coupled receptors (GPCRs) to regulate key pathobiological processes. Here we report a novel lipid mediator GPCR cross-talk mechanism that modulates lymphatic endothelial junctional architecture in lymph nodes. LPAR1 was identified as an inducer of S1PR1/ ß-arrestin coupling from a genome-wide CRISPR/ Cas9 transcriptional activation screen. LPAR1 activation induced S1PR1 ß-arrestin recruitment while suppressing Gαi protein signaling. Lymphatic endothelial cells from cortical and medullary sinuses of lymph nodes which express LPAR1 and S1PR1, exhibit porous junctional architecture and constitutive S1PR1 coupling to ß-arrestin which was suppressed by the LPAR1 antagonist AM095. In endothelial cells, LPAR1-activation increased trans-endothelial permeability and junctional remodeling from zipper-like structures to puncta of adhesion plaques that terminate at actin-rich stress fibers with abundant intercellular gaps. Cross-talk between LPA and S1P receptors regulates complex junctional architecture of lymphatic sinus endothelial cells, a site of high lymphocyte traffic and lymph flow.

scholarly journals Clinical Impact of Sphingosine-1-Phosphate in Breast Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Junko Tsuchida ◽  
Masayuki Nagahashi ◽  
Kazuaki Takabe ◽  
Toshifumi Wakai
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Metastasis ◽  
Clinical Importance ◽  
Breast Cancer Metastasis ◽  
Lipid Mediator ◽  
Breast Cancer Patients ◽  
Cellular Functions ◽  
Sphingosine 1 Phosphate ◽  
Underlying Mechanisms

Breast cancer metastasizes to lymph nodes or other organs, which determine the prognosis of patients. It is difficult to cure the breast cancer patients with distant metastasis due to resistance to drug therapies. Elucidating the underlying mechanisms of breast cancer metastasis and drug resistance is expected to provide new therapeutic targets. Sphingosine-1-phosphate (S1P) is a pleiotropic, bioactive lipid mediator that regulates many cellular functions, including proliferation, migration, survival, angiogenesis/lymphangiogenesis, and immune responses. S1P is formed in cells by sphingosine kinases and released from them, which acts in an autocrine, paracrine, and/or endocrine manner. S1P in extracellular space, such as interstitial fluid, interacts with components in the tumor microenvironment, which may be important for metastasis. Importantly, recent translational research has demonstrated an association between S1P levels in breast cancer patients and clinical outcomes, highlighting the clinical importance of S1P in breast cancer. We suggest that S1P is one of the key molecules to overcome the resistance to the drug therapies, such as hormonal therapy, anti-HER2 therapy, or chemotherapy, all of which are crucial aspects of a breast cancer treatment.

scholarly journals Sphingosine Kinase as a Regulator of Calcium Entry through Autocrine Sphingosine 1-Phosphate Signaling in Thyroid FRTL-5 Cells

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 5125-5134 ◽  
Author(s):  
Dan Gratschev ◽  
Christoffer Löf ◽  
Jari Heikkilä ◽  
Anders Björkbom ◽  
Pramod Sukumaran ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Sphingosine Kinase ◽  
Calcium Entry ◽  
Dominant Negative ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Entry Pathway ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
In Cells

Calcium entry is one of the main regulators of intracellular signaling. Here, we have described the importance of sphingosine, sphingosine kinase 1 (SK1), and sphingosine 1-phosphate (S1P) in regulating calcium entry in thyroid FRTL-5 cells. In cells incubated with the phosphatase inhibitor calyculin A, which evokes calcium entry without mobilizing sequestered intracellular calcium, sphingosine inhibited calcium entry in a concentration-dependent manner. Furthermore, inhibiting SK1 or the ATP-binding cassette ABCC1 multidrug transporter attenuated calcium entry. The addition of exogenous S1P restored calcium entry. Neither sphingosine nor inhibition of SK1 attenuated thapsigargin-evoked calcium entry. Blocking S1P receptor 2 or phospholipase C attenuated calcium entry, whereas blocking S1P receptor 3 did not. Overexpression of wild-type SK1, but not SK2, enhanced calyculin-evoked calcium entry compared with mock-transfected cells, whereas calcium entry was decreased in cells transfected with the dominant-negative G82D SK1 mutant. Exogenous S1P restored calcium entry in G82D cells. Our results suggest that the calcium entry pathway is blocked by sphingosine and that activation of SK1 and the production of S1P, through an autocrine mechanism, facilitate calcium entry through activation of S1P receptor 2. This is a novel mechanism by which the sphingosine-S1P rheostat regulates cellular calcium homeostasis.

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