Identification of FTY720 and COH29 as novel topoisomerase I catalytic inhibitors by experimental and computational studies.

The development of novel topoisomerase I (TOP1) inhibitors is crucial for overcoming the drawbacks and limitations of current TOP1 poisons. Here, we identified two potential TOP1 inhibitors, namely, FTY720 (a sphingosine 1-phosphate antagonist) and COH29 (a ribonucleotide reductase inhibitor), through experimental screening of known active compounds. Biological experiments verified that FTY720 and COH29 were nonintercalative TOP1 catalytic inhibitors that did not induce the formation of DNA-TOP1 covalent complexes. Molecular docking revealed that FTY720 and COH29 interacted favorably with TOP1. Molecular dynamics simulations revealed that FTY720 and COH29 could affect the catalytic domain of TOP1, thus resulting in altered DNA-binding cavity size. The alanine scanning and interaction entropy identified Arg536 as a hotspot residue. In addition, the bioinformatics analysis predicted that FTY720 and COH29 could be effective in treating malignant breast tumors. Biological experiments verified their antitumor activities using MCF-7 breast cancer cells. Their combinatory effects with TOP1 poisons were also investigated. Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1.

Myeloid Cells and Sphingosine-1-Phosphate Are Required for TCRαß Intraepithelial Lymphocyte Recruitment to the Colon Epithelium.

Intraepithelial lymphocytes (IELs) are T cells important for the maintenance of barrier integrity in the intestine. Colon IELs are significantly reduced in both MyD88-deficient mice and those lacking an intact microbiota, suggesting that MyD88-mediated detection of bacterial products is important for the recruitment and/or retention of these cells. Here, using conditionally deficient MyD88 mice, we show that myeloid cells are the key mediators of TCRαß+ IEL recruitment to the colon. Upon exposure to luminal bacteria, myeloid cells produce sphingosine-1-phosphate (S1P) in a MyD88-dependent fashion. TCRαß+ IEL recruitment may be blocked using the S1P receptor antagonist FTY720, confirming the importance of S1P in the recruitment of TCRαß+ IELs to the colon epithelium. Finally, using the TNFΔARE/+ model of Crohn's-like bowel inflammation, we show that disruption of colon IEL recruitment through myeloid-specific MyD88 deficiency results in reduced pathology. Our results illustrate one mechanism for recruitment of a subset of IELs to the colon.

Neutrophil Membrane-Camouflaged Polyprodrug Nanomedicine for Inflammation Suppression in Ischemic Stroke Therapy.

Neuroinflammation has emerged as a major concern in ischemic stroke therapy because it exacebates neurological dysfunction and suppresses neurological recovery after ischemia/reperfusion. Fingolimod hydrochloride (FTY720) is an FDA-approved anti-inflammatory drug which exhibits potential neuroprotective effects in ischemic brain parenchyma. However, delivering a sufficient amount of FTY720 through the blood-brain barrier into brain lesions without inducing severe cardiovascular side effects remains challenging. Here, a neutrophil membrane-camouflaged polyprodrug nanomedicine that can migrate into ischemic brain tissues and in situ release FTY720 in response to elevated levels of reactive oxygen species. This nanomedicine delivers 15.2-fold more FTY720 into the ischemic brain and significantly reduces the risk of cardiotoxicity and infection compared with intravenously administered free drug. In addition, single-cell RNA-sequencing analysis identifies that the nanomedicine attenuates poststroke inflammation by reprogramming microglia toward anti-inflammatory phenotypes, which is realized via modulating Cebpb-regulated activation of NLRP3 inflammasomes and secretion of CXCL2 chemokine. This study offers new insights into the design and fabrication of polyprodrug nanomedicines for effective suppression of inflammation in ischemic stroke therapy.

Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries.

BACKGROUND: High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. METHODS: Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. FINDINGS: A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated. INTERPRETATION: Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. FUNDING: National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship.

Concurrent glioma and multiple sclerosis: A systematic review of case reports.

BACKGROUND: It is uncommon for individuals with demyelinating disease, notably multiple sclerosis (MS), to be diagnosed with intracranial gliomas. It has been debated whether or not the concurrence of these two disorders is accidental. Clinically, it may be challenging to diagnose someone who has MS and an intracranial tumor simultaneously. We conducted this systematic review to evaluate the glioma patients following MS. METHODS: We collected 63 studies from 1672 databases from January 1990 to February 2023, and our inclusion criteria involved peer-reviewed case reports/series studies reporting concurrent MS and glioma in patients, considering various types of gliomas. RESULTS: We included 145 cases, 51% were women and 49 % were men, with an average age of 47.4 years. Common symptoms of glioma at admission included seizures (31.2 %), hemiparesis (15.6 %), and headache (14.3 %). 75 % of patients had primarily with relapsing-remitting MS (RRMS). MS treatments included interferon(IFN)-ß (44.6 %), glatiramer acetate (GA) (21.4 %), fingolimod (19.6 %), and natalizumab (19.6 %). The average time between MS and glioma diagnosis was 12.1 years, with various timeframes. Among the 59 reported cases, 45.8 % led to patient fatalities, while the remaining 54.2 % managed to survive. CONCLUSION: This co-occurrence, though rare, suggests potential underlying shared mechanisms or vulnerabilities, possibly at a genetic or environmental level. An interdisciplinary approach, combining the expertise of neurologists, oncologists, radiologists, and pathologists, is vital to ensure accurate diagnosis and optimal management of affected individuals. Nonetheless, there is still a significant lack of information regarding this phenomenon, necessitating large-scale population-based studies and experimental research.

Sphingosine 1-phosphate receptor modulators in multiple sclerosis treatment: A practical review.

Four sphingosine 1-phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head-to-head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real-world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.

Pharmacological Effects of FTY720 and its Derivatives.

FTY720 is an analog of sphingosine-1-phosphate (S1P) derived from the ascomycete Cordyceps sinensis. As a new immunosuppressant, FTY720 is widely used to treat multiple sclerosis. FTY720 binds to the S1P receptor after phosphorylation, thereby exerting immunosuppressive effects. The nonphosphorylated form of FTY720 can induce cell apoptosis, enhance chemotherapy sensitivity, and inhibit tumor metastasis of multiple tumors by inhibiting SPHK1 (sphingosine kinase 1) and activating PP2A (protein phosphatase 2A) and various cell death pathways. FTY720 can induce neutrophil extracellular traps to neutralize and kill pathogens in vitro, thus exerting anti- infective effects. At present, a series of FTY720 derivatives, which have pharmacological effects such as anti-tumor and alleviating airway hyperresponsiveness, have been developed through structural modification. This article reviews the pharmacological effects of FTY720 and its derivatives.

Teaching NeuroImage: Cryptococcus in a Woman With Multiple Sclerosis on Fingolimod.

A 33-year-old woman with relapsing remitting multiple sclerosis who was on fingolimod for 5 years presented with a solitary skin lesion on her abdomen (Figure 1) for 2 months, which was unresponsive to antibiotics. The neurologic examination was normal. She denied having infectious symptoms, chest pain, shortness of breath, recent travel, trauma to the area, or animal exposure. Her most recent absolute lymphocyte count was 0.22 × 109/L (reference 1.2-4.0 109/L). The differential diagnosis included skinfold friction, dermatofibroma, pyoderma gangrenosum, and basal cell carcinoma. Although a dermatologist did not initially recommend a biopsy because the lesion was not ulcerated, she obtained one based on the recommendation of her neurologist. Shave biopsy revealed cryptococcal fungal infection (Figure 2). There was no evidence of asymptomatic disseminated cryptococcus. The proposed mechanism for the lesion involves a latent infection while immunocompetent with reactivation once immunocompromised.1 Cryptococcus infections are associated with immunosuppression, most often due to human immunodeficiency virus infection, and only 6 fingolimod-associated cutaneous infections have been reported in the literature.2 Patients with MS on immunosuppressant medication should be carefully screened for cutaneous infections.

FTY720 increases paclitaxel efficacy in cisplatin-resistant oral squamous cell carcinoma.

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. The xenograft tumor model using cisplatin-resistant CAL27 cells was adopted to examine the drug combinations' potential antitumoral efficacy. Using an animal model, sphingolipids profiles from plasma and tissue samples were obtained by liquid chromatography coupled to mass spectrometry to identify potential lipids associated with drug response. RESULTS AND DISCUSSION: Our results showed higher autophagic flux in cisplatin-resistant Ooral squamous cell carcinoma (CAL27 and SCC9) cells than in parental cells. The combinations of an autophagy inhibitor (chloroquine) or an autophagy inducer/sphingosine kinase 1 antagonist (FTY720) with paclitaxel (PTX) had a synergistic antitumor effect. Treated CisR cells lost clonogenicity and tumor sphere abilities and reduced proteins associated with proliferation, survival, and cancer stem cells. FTY720 plus PTX had higher antitumor efficacy than PTX against CAL27 CisR xenograft tumor formation. Additionally, increases in glucosylceramide, dehydroglucosylceramide, and sphingomyelin were presented in responsive tumors. CONCLUSION: FTY720 sensitizes cisplatin-resistant oral squamous cell carcinoma cells for paclitaxel.

Purmorphamine, a Smo-Shh/Gli Activator, Promotes Sonic Hedgehog-Mediated Neurogenesis and Restores Behavioural and Neurochemical Deficits in Experimental Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a pathological condition characterized by the demyelination of nerve fibers, primarily attributed to the destruction of oligodendrocytes and subsequent motor neuron impairment. Ethidium bromide (EB) is a neurotoxic compound that induces neuronal degeneration, resulting in demyelination and symptoms resembling those observed in experimental animal models of multiple sclerosis (MS). The neurotoxic effects induced by EB in multiple sclerosis (MS) are distinguished by the death of oligodendrocytes, degradation of myelin basic protein (MBP), and deterioration of axons. Neurological complications related to MS have been linked to alterations in the signaling pathway known as smo-shh. Purmorphine (PUR) is a semi-synthetic compound that exhibits potent Smo-shh agonistic activity. It possesses various pharmacological properties, including antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory effects. Hence, the current investigation was conducted to assess the neuroprotective efficacy of PUR (at doses of 5 and 10 mg/kg, administered intraperitoneally) both individually and in conjunction with Fingolimod (FING) (at a dose of 0.5 mg/kg, administered intraperitoneally) in the experimental model of MS induced by EB. The administration of EB was conducted via the intracerebropeduncle route (ICP) over a period of seven days in the brain of rats. The Wistar rats were allocated into six groups using randomization, each consisting of eight rats (n = 8 per group). The experimental groups in this study were categorized as follows: (I) Sham Control, (II) Vehicle Control, (III) PUR per se, (IV) EB, (V) EB + PUR5, (VI) EB + PUR10, (VII) EB + FING 0.5, and (VIII) EB + PUR10 + FING 0.5. On the final day of the experimental timeline, all animal subjects were euthanized, and subsequent neurochemical estimations were conducted on cerebrospinal fluid, blood plasma, and brain tissue samples. In addition, we conducted neurofilament (NFL) analysis and histopathological examination. We utilized the luxol myelin stain to understand better the degeneration associated with MS and its associated neurological complications. The findings of our study indicate that the activation of SMO-Shh by PUR has a mitigating effect on neurobehavioral impairments induced by EB, as well as a restorative effect on cellular and neurotransmitter abnormalities in an experimental model of MS.

Pleiotropic effect of intramucosal injection of FTY720 on angiogenesis and tissue healing after free gingival graft surgery: a comparative experimental study in rabbits.

OBJECTIVES: Free gingival graft surgery is the gold standard for increasing the size of keratinized tissue. Blood supply in the recipient site is critical for healing. Therefore, in this study, the effect of FTY720 on angiogenesis, healing, and scar tissue presence following free gingival graft surgery is investigated. MATERIALS AND METHODS: Surgeries were performed on 10 New Zealand white rabbits. Rabbits were randomly assigned to two groups. In the experimental group, immediately after surgery, 2 and 4 days later, FTY-720 was injected into the tissue surrounding the recipient site. In the control group, the same frequency of placebo vehicle was injected. After 30 days, tissue samples were assessed histologically and histomorphometrically. RESULTS: The blood vessel count (P < 0.000) and rete ridge formation (P < 0.05) in the experimental group were significantly higher, while the epithelial thickness was lower in this group (P < 0.000). There was no significant difference in the percentage of regions occupied by collagen fibres between the groups (P = 0.987). Furthermore, a significant and negative relationship between epithelial thickness and blood vessel count was shown (Pearson correlation coefficient = - 0.917). CONCLUSIONS: The findings indicate that the angiogenic effects of FTY-720 in the recipient site of free gingival graft can be employed to promote tissue healing and reduce scar tissue presence. CLINICAL RELEVANCE: A significant decrease in epithelial thickness and increase in angiogenesis as well as rete ridge formation score in the FTY-720 group were shown, which can be translated into improved tissue healing and less presence of scar tissue.

Cryptococcal meningoencephalitis in multiple sclerosis treated with fingolimod.

A 21-year-old woman with multiple sclerosis (taking regular fingolimod) developed sudden-onset severe headache with nausea and malaise. Neurological examination was normal and she was afebrile. Blood results showed lymphocytes 0.53 x 109/L and C reactive protein 19 mg/L. CT scan of head and venogram were normal. CSF showed an opening pressure of 33 cm H2O and an incidental light growth of Cryptococcus neoformans, confirmed with positive India Ink stain and a positive cryptococcal antigen (1:100). She was treated for cryptococcal meningoencephalitis with amphotericin and flucytosine. Her presenting symptoms had closely mimicked subarachnoid haemorrhage. This atypical presentation of cryptococcal CNS infection highlights the need for vigilance in immunosuppressed patients.

SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML.

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. Silencing SET specifically abolished the clonogenic ability of KMT2A-R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10. Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A-R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3ß, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A-R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.

A novel isoxazole compound CM2-II-173 inhibits the invasive phenotype of triple-negative breast cancer cells.

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. Expression of matrix metalloproteinase (MMP)-9 and invasiveness of MCF10A normal breast cells induced by sphingosine-1-phosphate (S1P) were reduced by CM2-II-173 treatment. Activations of pMEK1, pAkt, pERK, and p38 MAPK by S1P were inhibited by treatment with CM2-II-173. Proliferation and anchorage-independent growth of MDA-MB-231 TNBC cells were significantly decreased by CM2-II-173. CM2-II-173 efficiently induced apoptosis in MDA-MB-231 TNBC cells. CM2-II-173 significantly inhibited invasive phenotypes of breast, liver, prostate, and ovarian cancer cells. CM2-II-173 exhibited a more potent effect on the invasiveness of MDA-MB-231 TNBC cells compared to FTY720. Taken together, this study demonstrated that CM2-II-173 has the potential to be a lead compound that can inhibit cancer progression of not only TNBC cells, but also of liver, prostate, and ovarian cancer cells.

Molecular docking, synthesis, anticancer activity, and metabolomics study of boronic acid ester-containing fingolimod derivatives.

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. The synthesized boron-containing drug candidates were found to significantly inhibit cell proliferation and induce apoptosis-mediated cell death in HT-29 (colorectal cells), SaOs-2 (osteosarcoma cells), and U87-MG (glioblastoma cells). Moreover, we revealed that the anticancer effects of boron-containing fingolimod compounds were found to be significantly enhanced over boron-free control groups and, strikingly, over the widely used anticancer drug 5-fluorouracil. The metabolomic analysis confirmed that administration of the boron-containing drug candidates induces significant changes in the metabolite profiles in HT-29, SaOs-2, and U87-MG cells. Altogether, our results showed that boron-containing fingolimod compounds can be further examined to reveal their potential as anticancer drug candidates.

Inhibitory Effect of Fingolimod on Head and Neck Squamous Cell Carcinoma and Its Mechanism: Gene Set Enrichment Analysis.

This study aimed to clarify the therapeutic effect of Fingolimod on head and neck squamous cell carcinoma (HNSC) and initially explore its mechanism through data mining, clinical sample analysis and basic experiments. The normalized Enrichment Score (NES) of Fingolimod in tumor tissues was obtained by SwissTargetPrediction and The Cancer Genome Atlas (TCGA) database. IC50 (50% inhibitory concentration) of Fingolimod for HNSC was verified based on the Genomics of Drug Sensitivity in Cancer (GDSC) database. SCC9 cells were cultured in vitro for the application of Fingolimod. Cell proliferation was determined by the Cell Counting Kit-8 (CCK-8). The expression levels of genes were determined by reverse transcription-polymerase chain reaction (RT-PCR). The molecular regulatory mechanism of Fingolimod acting on HNSC was analyzed with WebGestalt. Cyclin expression was determined by Western blot assay. The key targeted genes for Fingolimod against HNSC were screened with the TCGA database and verified in clinical samples. Gene Set Enrichment Analysis (GSEA) showed the highest NES score in HNSC (NES=1.53, P<0.05). GDSC showed the lowest IC50 in Fingolimod SSC9 cells. IC50 calculated by the cell activity detected by CCK8 was 4.34 µmol/L, and RT-PCR showed significantly suppressed expression of proliferation-related gene Ki-67 after adding Fingolimod (P<0.05). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the targeted genes for Fingolimod were mainly enriched in cell cycle-related pathways. Western blot showed significantly decreased cyclin expression in SSC9 cells after the treatment with Fingolimod (P<0.05). TCGA analysis revealed that PLK1 is a key targeted gene for Fingolimod in the treatment of HNSC. RT-PCR showed the significantly increased activity of SCC9 after over-expressing PLK1, and the increased proliferation and anti-apoptosis abilities (P<0.05), as well as the significantly inhibited expression of Ki-67 and Bcl-2 after adding Fingolimod. Fingolimod can promote the arrest in G0/G1 of SCC9 cells, and PLK1 is a key targeted gene for the treatment of HNSC. Fingolimod can inhibit cell proliferation caused by PLK1 over-expression.

FTY720 attenuates acute colitis via colonic T cells reduction and inhibition of M1 macrophages polarization independent of CCR2-mediated monocytes input.

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. The body weight, stool consistency, and occult blood were assessed daily. The inflammatory cytokines level in colon tissues and serum were assessed. Leukocyte subsets of bone marrow (BM), spleen, and colon were analyzed by flow cytometry. Our results demonstrated that FTY720 ameliorated the aberrant immune responses by trapping T cells and inhibiting the polarization of M1 macrophages in colitis mice. The effect of FTY720 on the increased number of colonic macrophages did not dependent on CCR2-mediated monocyte influx, despite most monocytes being reduced after DSS administration in the inflamed colon of CCR2-/- mice. Rather, depletion of CCR2 did not impact the protective influence of FTY720 on colonic injury in acute colitis. All these findings unravel a beneficial function of FTY720 in the inflammatory response to DSS-induced acute colitis, provided further insights into monocyte migration and might provide potential opportunities for UC therapeutic intervention.