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Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are bioactive lipid molecules that are ubiquitously expressed in the human body and play an important role in the immune system. S1P-S1PR signaling has been well characterized in immune trafficking and activation in both innate and adaptive immune systems. Despite this knowledge, the full scope in the pathogenesis of autoimmune disorders is not well characterized yet. From the discovery of fingolimod, the first S1P modulator, until siponimod, the new molecule recently approved for the treatment of secondary progressive multiple sclerosis (SPMS), there has been a great advance in understanding the S1P functions and their involvement in immune diseases, including multiple sclerosis (MS). Modulation on S1P is an interesting target for the treatment of various autoimmune disorders. Improved understanding of the mechanism of action of fingolimod has allowed the development of the more selective second-generation S1PR modulators. Subtype 1 of the S1PR (S1PR1) is expressed on the cell surface of lymphocytes, which are known to play a major role in MS pathogenesis. The understanding of S1PR1’s role facilitated the development of pharmacological strategies directed to this target, and theoretically reduced the safety concerns derived from the use of fingolimod. A great advance in the MS treatment was achieved in March 2019 when the Food and Drug Association (FDA) approved Siponimod, for both active secondary progressive MS and relapsing–remitting MS. Siponimod became the first oral disease modifying therapy (DMT) specifically approved for active forms of secondary progressive MS. Additionally, for the treatment of relapsing forms of MS, ozanimod was approved by FDA in March 2020. Currently, there are ongoing trials focused on other new-generation S1PR1 modulators. This review approaches the fundamental aspects of the sphingosine phosphate modulators and their main similarities and differences.

ObjectiveThe micro RNAs (miRNAs) and their target mRNAs are differentially expressed in various immune-mediated cells. Here, we investigated the role of Mir223 and sphingosine-1-phosphate receptor 1 ( S1pr1 ) in the pathogenesis of systemic lupus erythematosus.MethodsWe analyzed miRNA and mRNA profiling data of CD4+ splenic T cells derived from MRL/MpJ- Faslpr /J mice. We performed 3′ untranslated region (UTR) luciferase reporter gene assay using human umbilical vein endothelial cells (HUVECs). We generated the B6- Mir223 −/− Faslpr/lpr mice and the lupus phenotypes were analyzed.ResultsIn CD4+ splenic T cells, we identified upregulation of miR-223-3p and downregulation of the possible target, S1pr1 by RNA sequencing of MRL/MpJ- Faslpr /J mice. The transfection with miR-223-3p mimic significantly suppressed a luciferase activity in HUVEC treated with a Lentivirus vector containing 3′ UTR of S1pr1 . The mRNA levels of S1pr1 were significantly decreased after miR-223-3p overexpression. In B6- Mir223 −/− Faslpr/lpr mice, the proportion of CD3+ T cells, CD3+CD4-CD8− cells, B cells, plasma cells, and S1PR1+CD4+ T cells in the spleen was significantly increased compared with that in B6- Mir223 +/+ Faslpr/lpr mice by flow cytometry. B6- Mir223 −/− Faslpr/lpr mice demonstrated the elevation of glomerular and renal vascular scores associated with enhanced intraglomerular infiltration of S1PR1+CD4+ T cells.ConclusionUnexpectedly, the deletion of Mir223 exacerbated the lupus phenotypes associated with increased population of S1PR1+CD4+ T in spleen and the enhanced infiltration of S1PR1+CD4+ T cells in inflamed kidney tissues, suggesting compensatory role of Mir223 in the pathogenesis of lupus nephritis.

Sphingosine-1-phosphate receptor-1 (S1PR1), a G protein-coupled receptor, has been reported to be involved in lymphangiogenesis. Degradations of extracellular matrix (ECM) are recognized as dynamic modulators in regulating the formation of new lymphatic vessels. However, little research has studied the ECM on S1PR1 in the regulation of lymphatic endothelial cells (LECs) in tumor lymphangiogenesis. Here we attempt to investigate hyaluronan fragments abundant in tumor microenvironment (TME) on S1PR1 in new lymphatic vessel formation. First, we verified that low molecular weight hyaluronan (LMW-HA) derived from tumor cells could promote LECs migration and capillary-like tube formation. Then, we demonstrated that S1PR1 on LECs underwent internalization into the endoplasmic reticulum in response to LMW-HA treatments. Notably, the S1PR1 endocytosis could upregulate lymphangiogenesis. Next, we found that the ablation of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) could attenuate the S1PR1 endocytosis, implying a novel role of LMW-HA/LYVE-1 in the S1PR1 cycling pathway. Furthermore, we identified that LMW-HA/LYVE-1 interaction could activate Src kinase which in turn upregulates S1PR1 tyrosine phosphorylation, resulting in S1PR1 endocytosis. Collectively, our findings suggested that hyaluronan fragments in TME could induce S1PR1 internalization in LECs, leading to lymphangiogenesis promotion.

Oxidative stress induces granulosa cell (GC) apoptosis and subsequent follicular atresia. Since our previous studies indicate that microRNA-181a (miR-181a) expression is increased in GCs undergoing apoptosis, the present study was designed to define the relationship between exposure to oxidative stressors in GCs and changes in miR-181a expression and function. To achieve this, we employed an H2O2-induced in vitro model and a 3-nitropropionic acid-induced in vivo model of ovarian oxidative stress. We demonstrated that in vitro miR-181a overexpression promoted GC apoptosis in a dose-dependent manner; sphingosine-1-phosphate (S1P) significantly reversed both H2O2-induced and miR-181a-induced apoptosis in GCs. Moreover, we identified sphingosine-1-phosphate receptor 1 (S1PR1), a critical receptor of S1P, as a novel target of miR-181a in GCs. MicroRNA-181a induced GC apoptosis by repressing S1PR1 expression in vitro. Importantly, increased miR-181a expression and decreased S1PR1 expression were detected in the in vivo ovarian oxidative stress model by Western blot analysis and immunohistochemistry. Furthermore, we found similar expression patterns of miR-181a and S1PR1 in GCs from patients with premature ovarian insufficiency. In conclusion, our results suggest that miR-181a directly suppresses expression of S1PR1, which has critical roles in mediating oxidative stress-induced GC apoptosis both in vitro and in vivo. Summary sentence MicroRNA-181a directly suppresses expression of S1PR1, which has critical roles in mediating oxidative stress-induced GC apoptosis both in vitro and in vivo.

Aims Cardiac hypertrophy, an adaptive response of the heart to stress overload, is closely associated with heart failure and sudden cardiac death. This study aimed to investigate the therapeutic effects of chlorogenic acid (CGA) on cardiac hypertrophy and elucidate the underlying mechanisms. Methods and results To simulate cardiac hypertrophy, myocardial cells were exposed to isoproterenol (ISO, 10 μM). A rat model of ISO‐induced cardiac hypertrophy was also established. The expression levels of cardiac hypertrophy markers, endoplasmic reticulum stress (ERS) markers, and apoptosis markers were measured using quantitative reverse transcription PCR and western blotting. The apoptosis level, size of myocardial cells, and heart tissue pathological changes were determined by terminal deoxynucleotidyl transferase dUTP nick‐end labelling staining, immunofluorescence staining, haematoxylin and eosin staining, and Masson's staining. We found that CGA treatment decreased the size of ISO‐treated H9c2 cells. Moreover, CGA inhibited ISO‐induced up‐regulation of cardiac hypertrophy markers (atrial natriuretic peptide, brain natriuretic peptide, and β‐myosin heavy chain), ERS markers (C/EBP homologous protein, glucose regulatory protein 78, and protein kinase R‐like endoplasmic reticulum kinase), and apoptosis markers (bax and cleaved caspase‐12/9/3) but increased the expression of anti‐apoptosis marker bcl‐2 in a dose‐dependent way (0, 10, 50, and 100 μM). Knockdown of sphingosine‐1‐phosphate receptor 1 (S1pr1) reversed the protective effect of CGA on cardiac hypertrophy, ERS, and apoptosis in vitro (P < 0.05). CGA also restored ISO‐induced inhibition on the AMP‐activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signalling in H9c2 cells, while S1pr1 knockdown abolished these CGA‐induced effects (P < 0.05). CGA (90 mg/kg/day, for six consecutive days) protected rats against cardiac hypertrophy in vivo (P < 0.05). Conclusions CGA treatment attenuated ISO‐induced ERS and cardiac hypertrophy by activating the AMPK/SIRT1 pathway via modulation of S1pr1.

The aggravating role of long noncoding RNA (lncRNA) HOTAIR has been indicated in liver injury caused by hepatic ischemia/reperfusion. However, under the condition of alcoholic hepatitis (AH), its effects remain unclear. The present study aimed to examine the effect of lncRNA HOTAIR on hepatic stellate cell viability and apoptosis during liver injury caused by AH. In the liver tissues of AH rats, HOTAIR and S1PR1 were overexpressed, and microRNA (miR)-148a-3p was poorly expressed. Loss-of-function assays revealed that silencing of HOTAIR alleviated liver injury in AH by inhibiting the activated phenotype of hepatic stellate cells, inflammation, and fibrosis. Using the bioinformatics databases, dual-luciferase, RIP, and FISH assays, we observed that HOTAIR was mainly localized in the cytoplasm of hepatic stellate cells, and HOTAIR could bind specifically to miR-148a-3p. In addition, miR-148a-3p could target S1PR1 expression. Rescue experiments showed that silencing of miR-148a-3p or overexpression of S1PR1 reversed the alleviating effects of HOTAIR silencing on liver injury. Taken together, our findings revealed that HOTAIR regulates hepatic stellate cell proliferation via the miR-148a-3p/S1PR1 axis in liver injury, which may serve as the basis for developing novel therapeutic strategies to treat AH.

In this study, we investigated the potential mechanism of action of Qing Bi Yin (QBY) in psoriasis treatment via regulation of the sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptor 1 (S1PR1) pathway and Th17 cell differentiation. Network pharmacology was used to identify potential targets and elucidate the potential mechanisms of QBY in psoriasis. The predicted mechanisms were validated with in vitro Th17 cell differentiation assays using isolated mouse splenic CD4+ T cells. Molecular docking was performed to evaluate the binding affinities between active compounds and key target proteins. We identified 262 overlapping QBY psoriasis target genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed significant associations with the sphingolipid signaling pathway, Th17 cell differentiation, and IL-17 signaling pathway. Network algorithms were used to identify 10 key active compounds and five hub genes. QBY treatment suppresses S1P synthesis and expression in Th17-polarized cells. QBY inhibited Th17 cell proliferation and differentiation, reduced inflammatory cytokine secretion by Th17 cells via the S1P/S1PR1 pathway, and modulated STAT3 and SMAD2 phosphorylation. Molecular docking showed strong binding affinities between active compounds (glabridin, luteolin, licoflavone A, and isobutyrylshikonin) from QBY and key targets (STAT3, SMAD2, SPHK1, and RORγt) in Th17 cells. QBY ameliorates psoriatic inflammation by regulating Th17 cell differentiation via the S1P/S1PR1 signaling pathway. These findings underscore the clinical translational potential of QBY and its active constituent glabridin.

Background: MicroRNAs (miRNAs) have been extensively studied over the decades and have been identified as potential molecular targets for cancer therapy. To date, many miRNAs have been found participating in the tumorigenesis of non-small cell lung cancer (NSCLC). The present study was designed to evaluate the functions of miR-125b-1-3p in NSCLC cells. Methods: MiR-125b-1-3p expression was detected in tissue samples from 21 NSCLC patients and in NSCLC cell lines using the real-time polymerase chain reaction. A549 cell lines were transfected with a miR-125b-1-3p mimic or miR-125b-1-3p antisense. Cell counting kit-8, wound healing, Matrigel invasion assays, and flow cytometry were used to assess the effects of these transfections on cell growth, migration, invasion, and apoptosis, respectively. Western blotting was used to detect apoptosis-related proteins, expression of S1PR1, and the phosphorylation status of STAT3. Significant differences between groups were estimated using Student's t-test or a one-way analysis of variance. Results: MiR-125b-1-3p was downregulated in NSCLC samples and cell lines. Overexpression of miR-125b-1-3p inhibited NSCLC cell proliferation (37.8 ± 9.1%, t = 3.191, P = 0.013), migration (42.3 ± 6.7%, t = 6.321, P = 0.003), and invasion (57.6 ± 11.3%, t = 4.112, P = 0.001) and simultaneously induced more NSCLC cell apoptosis (2.76 ± 0.78 folds, t = 3.772, P = 0.001). MiR-125b-1-3p antisense resulted in completely opposite results. S1PR1 was found as the target gene of miR-125b-1-3p. Overexpression of miR-125b-1-3p inhibited S1PR1 protein expression (27.4 ± 6.1% of control, t = 4.083, P = 0.007). In addition, S1PR1 siRNA decreased STAT3 phosphorylation (16.4 ± 0.14% of control, t = 3.023, P = 0.015), as in cells overexpressing miR-125b-1-3p (16.7 ± 0.17% of control, t = 4.162, P = 0.026). Conclusion: Our results suggest that miR-125b-1-3p exerts antitumor functions in NSCLC cells by targeting S1PR1.

The signaling pathway activated by sphingosine-1-phosphate (S1P) through S1P receptor 1 (S1PR1) plays specific roles in regulating vascular integrity and preventing vascular leakage during inflammatory response. Endothelial cell barrier dysfunction has been implicated in cerebral malaria (CM) pathology. To explore the S1P/S1PR1 signaling pathway in CM, the study investigated the expression of S1PR1 in the brain of fatal malaria and correlated with the level of S1P and malaria severity. Localisation of S1PR1 in brain tissues was evaluated using immunohistochemistry technique in archived brain tissues of fatal P. falciparum malaria. S1P level was determined using enzyme-linked immunosorbent assay (ELISA). S1PR1 expression was intense in cerebral blood vessels and neurons of fatal CM patients compared to brain tissues from control group and non-CM patients (all p  < 0.001). S1P level in the blood decreased significantly in CM group and was negatively correlated with S1PR1 expression in blood vessels and neurons. The expression of S1PR1 in cerebral blood vessels and neurons indicates that S1P/S1PR1 signaling pathway is involved in malaria pathogenesis and represents potential targets for S1P/S1PR1 modulators to treat CM. The outcomes can serve as a basis to explore measures to block the expression of S1PR1 which could reduce sequestration.

Opioids such as morphine are frequently used for chronic pain management despite their many adverse effects. Ongoing research aims at either finding new treatments to replace opioids or reducing its heavy adverse effects due to long-term use: opioid-induced hyperalgesia and antinociceptive tolerance. In a recent study, Doyle et al. (2020) demonstrate that the activation of sphingosine-1-phosphate receptor subtype 1 (S1PR1) in the central nervous system contributes to morphine-induced hyperalgesia and antinociceptive tolerance in a rodent model of chronic pain. By targeting S1PR1 with molecules with functional antagonistic properties (some of which are FDA-approved for multiple sclerosis treatment), hyperalgesia and tolerance were significantly reduced without modifying morphine pharmacokinetics or efficacy. Les opioïdes tels que la morphine sont des traitements de première intention prescrits pour soulager la douleur chronique mais induisent des effets adverses qui limitent sévèrement leur utilisation. En recherche, les stratégies rencontrées consistent à développer de nouveaux traitements pour remplacer les opioïdes ou à en atténuer efficacement les effets indésirables importants : l’hyperalgésie et la tolérance. Dans une étude récente, Doyle et al., en 2020, démontrent que l’activation du sous-type 1 du récepteur de la sphingosine-1-phosphate (S1PR1) dans le système nerveux central contribue à l’hyperalgésie induite par la morphine et à la tolérance antinociceptive dans un modèle de rongeur de douleur chronique. En ciblant S1PR1 avec des molécules aux propriétés d’antagonistes fonctionnels (dont certaines sont approuvées par la FDA pour le traitement de la sclérose en plaques), l’hyperalgésie et la tolérance ont été significativement réduites sans modifier la pharmacocinétique de la morphine ou son efficacité.