FTY720

Vitamin B12 (B12 ) deficiency causes neurological manifestations resembling multiple sclerosis (MS); however, a molecular explanation for the similarity is unknown. FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analog approved for MS therapy that can functionally antagonize S1P1 . Here, we report that FTY720 suppresses neuroinflammation by functionally and physically regulating the B12 pathways. Genetic and pharmacological S1P1 inhibition upregulates a transcobalamin 2 (TCN2)-B12 receptor, CD320, in immediate-early astrocytes (ieAstrocytes; a c-Fos-activated astrocyte subset that tracks with experimental autoimmune encephalomyelitis [EAE] severity)...

Extensive vascular leakage and shock is a major cause of dengue-associated mortality. At present, there are no specific treatments available. Sphingolipid pathway is a key player in the endothelial barrier integrity; and is mediated through the five sphingosine-1-phosphate receptors (S1PR1-S1PR5). Signaling through S1PR2 promotes barrier disruption; and in Dengue virus (DENV)-infection, there is overexpression of this receptor. Fingolimod (FTY720) is a specific agonist that targets the remaining barrier-protective S1P receptors, without targeting S1PR2...

The use of immune checkpoint blockade (ICB) is a promising approach for clinical cancer treatment. However, most of cancer patients do not respond to anti-PD-1/PD-L1 antibody. In this study, we proposed a novel strategy of antibody-β-glucan conjugates (AGC) to enhance the antitumor immune response to ICB therapy. The AGC were constructed by conjugating an anti-PD-L1 antibody with a β-glucan via click chemistry. This design facilitates the delivery of β-glucan into the tumor microenvironment (TME)...

BACKGROUND: Oral squamous cell carcinoma has high recurrence and cisplatin resistance. As cancer stem cells, autophagy, and sphingolipids have been appointed as associated with chemotherapy resistance, we tested combined treatments targeting autophagy and/or sphingolipid metabolism with paclitaxel using cisplatin-resistant oral squamous cell carcinoma cells. METHODS: Cisplatin-resistant oral squamous cell carcinoma cells were maintained under exposition to FTY720 and chloroquine combined with paclitaxel and submitted to viability, clonogenicity, and spheres formation assays...

TRPM7, a TRP channel with ion conductance and kinase activities, has emerged as an attractive drug target for immunomodulation. Reverse genetics and cell biological studies have already established a key role for TRPM7 in the inflammatory activation of macrophages. Advancing TRPM7 as a viable molecular target for immunomodulation requires selective TRPM7 inhibitors with in vivo tolerability and efficacy. Such inhibitors have the potential to interdict inflammatory cascades mediated by systemic and tissue-specialized macrophages...

BACKGROUND: The overexpression of P-glycoprotein (P-gp) contributes to drug resistance in patients with epilepsy, and the change of P-gp expression located at the blood-brain barrier alienates the anti-seizure effects of P-gp substrates. Thus, the present study explored the effect of fingolimod (FTY720) acting through an endothelin-sphingolipid pathway on P-gp-induced pentylenetetrazol (PTZ)-kindled phenobarbital (PB)-resistant rats. MATERIALS AND METHODS: PTZ kindling (30 mg/kg; i...

KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A-R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients...

Immunosuppressants are emerging as promising candidates for cancer therapy with lower cytotoxicity compared to traditional chemotherapy drugs; yet, the intrinsic side effects such as immunosuppression remain a critical concern. Herein, we introduce a photoactivatable antitumor immunosuppressant called dmBODIPY-FTY720 (BF) that shows no cytotoxicity but can be temporally and locally activated by deep-red light illumination to induce tumor cell apoptosis. To further reduce potential side effects, we integrate BF with another classic photosensitizer called methylene blue (MB) that is activated under the same wavelength of deep-red light (>650 nm) and successfully establish a red-light-activatable AND Boolean logic gate through a mechanism that we found to be synergetic apoptotic induction...

This study provides evidence of the existence of presynaptic inhibitory sphingosine-1-phosphate receptor 1 (S1P1R) and facilitatory S1P3R in cortical nerve endings (synaptosomes) of healthy mice. The conclusion relies on the findings that (i) the S1P1R agonist CS-2100 (0.1-30 nM) inhibits the 12 mM KCl-evoked glutamate exocytosis (quantified as the release of [3 H]D-aspartate) while the S1P3R allosteric agonist CYM-5541 potentiates it and (ii) these effects are inhibited by the S1P1R antagonist Ex 26 (30-300 nM) and the S1P3R antagonist TY-52156 (100-1000 nM), respectively...

In recent years, drugs that contain boronic acid groups, such as ixazomib (Ninlaro™) and bortezomib (Velcade™), have been used in the treatment of bone marrow cancer. The activity of compounds has been found to increase with the addition of boron atoms to the structure. In addition to these compounds, studies have found that fingolimod (FTY720) is more effective against breast cancer than cisplatin. Therefore, in this study, the first examples of boron-containing derivatives of fingolimod were designed and synthesized; in addition, their structures were confirmed by spectroscopic techniques...

RESEARCH QUESTION: Do sphingosine 1-phosphate (S1P) modulators have therapeutic effects on endometriosis in mice and, if they do, which receptor is responsible for these effects? DESIGN: A surgically induced endometriosis mouse model was established. In the pilot experiment, lesions were harvested to assess fibrosis and inflammation and determine the optimal concentration of a broad-spectrum S1P modulator, FTY720. Subsequently, FTY720 was compared with a selective S1P receptor 1 modulator, SEW2871 to evaluate their effects on endometriotic lesion growth, fibrosis, inflammation and immune cell infiltration...

Invasion and metastasis are important hallmarks of breast cancer and are the leading cause of patient mortality. Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer characterized by a poor prognosis and a lack of effective targeted therapies. The present study investigated the inhibitory effect of a novel FTY720 derivative on the invasive phenotype of TNBC cells. Here, we showed that a novel compound with an isoxazole ring, 4-(3-Decylisoxazol-5-yl)-1-hydroxy-2-(hydroxymethyl)butan-2-aminium chloride (CM2-II-173), significantly inhibited invasiveness of MDA-MB-231 TNBC cells...

BACKGROUND: Intervertebral disc degeneration (IVDD) is considered one of the main reasons for low back pain (LBP). To date, the specific pathology of IVDD remains unclear. The annulus fibrosus (AF) is an important part of the intervertebral disc, and AF cell oxidative stress, apoptosis plays a vital role in disc degeneration. Protein phosphatase 2 A (PP2A), a serine/threonine phosphatase, has regulatory functions in various processes, including apoptosis and autophagy. However, thus far, the effect of PP2A on IVDD is not clear...

UNLABELLED: CD4 T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4 T cells resembling lymph node central memory (T CM ) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of T CM . Brain CCR7+ CD4 T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence...

TRPM7, a TRP channel with ion conductance and kinase activities, has emerged as an attractive drug target for immunomodulation. Reverse genetics and cell biological studies have already established a key role for TRPM7 in the inflammatory activation of macrophages. Advancing TRPM7 as a viable molecular target for immunomodulation requires selective TRPM7 inhibitors with in vivo tolerability and efficacy. Such inhibitors have the potential to interdict inflammatory cascades mediated by systemic and tissue-specialized macrophages...

BACKGROUND: Peripheral nerve injury to dorsal root ganglion (DRG) neurons develops intractable neuropathic pain via induction of neuroinflammation. However, neuropathic pain is rare in the early life of rodents. Here, we aimed to identify a novel therapeutic target for neuropathic pain in adults by comprehensively analyzing the difference of gene expression changes between infant and adult rats after nerve injury. METHODS: A neuropathic pain model was produced in neonatal and young adult rats by spared nerve injury...

BACKGROUND/AIM: Fingolimod is a sphingosine-1-phosphate receptor modulator that prevents lymphocytes egress from lymphoid organs. It has been used as a disease-modifying drug for human multiple sclerosis and has shown better therapeutic effects than other conventional therapies. Therefore, this study was performed to obtain preclinical data of fingolimod in dogs. MATERIALS AND METHODS: Nine laboratory Beagle dogs were used and randomized into three groups for pharmacokinetics (PK) and pharmacodynamics (PD)...

To investigate the effect of the AGEs-RAGE-PP2A axis on cognitive impairment (CI) after chronic heart failure (CHF). Mice were divided into six groups: Sham, TAC, Sham+RAGE-/-, TAC+RAGE-/-, AG, and FTY720 group. AG mice and FTY720 mice were treated with AGEs inhibitor (aminoguanidine, AG) and PP2A activator (FTY720) respectively after TAC surgery. The cardiac function of AG and TAC+RAGE-/- mice was significantly better than that of TAC mice (P<0.05). However, the heart function of FTY720 mice were just improved a part of that...

Ulcerative colitis (UC) is a complex multifactorial disease, of which the exact etiology is not fully understood. The inappropriate aggressive inflammatory response is closely related to the disease progression of UC. FTY720 is a sphingosine-1-phosphate receptor agonist and acts as a key immunomodulator in inflammation. This study aims to investigate the protective influence of FTY720 on inflammation in the DSS-induced colitis model. In the present study, the C57BL/6 mice and the CCR2-/- mice were exposed to 5% Dextran Sodium Sulfate (DSS) drinking water for 6 days followed by an injection of FTY720 (1 mg/kg/d) or vehicle (PBS) 6 times starting on the next day...

Bruton's tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent...