The efficacy of prevention for colon cancer based on the microbiota therapy and the antitumor mechanisms with intervention of dietary Lactobacillus.

Gut microbiota and their secreted metabolites have an influence on the initiation and progression of colon cancer. Probiotics are extensively perceived as a potential microbiota-modulation strategy to promote the health of the host, while the effectiveness of preventing colon cancer based on microbiota therapy has not been confirmed, and antitumor mechanisms influenced by microbiota and their metabolites with the intervention of probiotics remain to be further investigated. In vitro, Lactobacillus (JY300-8 and JMR-01) significantly inhibited the proliferation of CT26, HT29, and HCT116 cells. Moreover, we studied the prevention and therapy efficiency of Lactobacillus and its underlying antitumor mechanism through the alteration of gut microbiota and their metabolites regulated by Lactobacillus in colon cancer models in mice. We demonstrated that the pre-administration of Lactobacillus (JY300-8 and JMR-01) for 20 days before establishing tumor models resulted in an 86.21% reduction in tumor formation rate compared to tumor control group. Subsequently, continuous oral administration of living Lactobacillus significantly suppresses tumor growth, and tumor volumes decrease by 65.2%. Microbiome and metabolome analyses reveal that Lactobacillus suppresses colonic tumorigenesis and progression through the modulation of gut microbiota homeostasis and metabolites, including the down-regulation of secondary bile acids, sphingosine 1-phosphate (S1P), and pyrimidine metabolism, as well as the production of anticarcinogenic compounds in tumor-bearing mice. Additionally, metabolome analyses of Lactobacillus (JY300-8 and JMR-01) indicate that living Lactobacillus could reduce the relative abundance of alanine and L-serine to suppress tumor progression by regulating the tumor microenvironment, including down-regulation of pyrimidine metabolism and S1P signaling in cancer. These findings provide a potential prevention strategy and therapeutic target for colon cancer through the intervention of dietary Lactobacillus. IMPORTANCE The modulation of gut microbiota and metabolites has a significant influence on the progression of colon cancer. Our research indicated that the intervention of probiotics is a potentially feasible strategy for preventing colon cancer. We have also revealed the underlying antitumor mechanism through the alteration of gut microbiota and their metabolites, which could lead to broader biomedical impacts on the prevention and therapy of colon cancer with microbiota-based therapy regulated by probiotics.

Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages.

Radiotherapy for head-and-neck cancers frequently causes long-term hypofunction of salivary glands that severely compromises quality of life and is difficult to treat. Here, we studied effects and mechanisms of Sphingosine-1-phosphate (S1P), a versatile signaling sphingolipid, in preventing irreversible dry mouth caused by radiotherapy. Mouse submandibular glands (SMGs) were irradiated with or without intra-SMG S1P pretreatment. The saliva flow rate was measured following pilocarpine stimulation. The expression of genes related to S1P signaling and radiation damage was examined by flow cytometry, immunohistochemistry, quantitative RT-PCR, Western blotting, and/or single-cell RNA-sequencing. S1P pretreatment ameliorated irradiation-induced salivary dysfunction in mice through a decrease in irradiation-induced oxidative stress and consequent apoptosis and cellular senescence, which is related to the enhancement of Nrf2-regulated anti-oxidative response. In mouse SMGs, endothelial cells and resident macrophages are the major cells capable of producing S1P and expressing the pro-regenerative S1P receptor S1pr1. Both mouse SMGs and human endothelial cells are protected from irradiation damage by S1P pretreatment, likely through the S1pr1/Akt/eNOS axis. Moreover, intra-SMG-injected S1P did not affect the growth and radiosensitivity of head-and-neck cancer in a mouse model. These data indicate that S1P signaling pathway is a promising target for alleviating irradiation-induced salivary gland hypofunction.

Sphingosine-1-Phosphate and Its Signal Modulators Alleviate Psoriasis-Like Dermatitis: Preclinical and Clinical Evidence and Possible Mechanisms.

Background: Psoriasis is an autoimmune skin disease associated with lipid metabolism. Sphingosine-1-phosphate (S1P) is a bioactive lipid that plays a key role in the development of autoimmune diseases. However, there is currently a lack of comprehensive evidence of the effectiveness of S1P on psoriasis. Objective: To assess the efficacy and possible mechanism of S1P and its signal modulators in the treatment of psoriasis-like dermatitis. Methods: Six databases were searched through May 8, 2021, for studies reporting S1P and its signal modulators. Two reviewers independently extracted information from the enrolled studies. Methodological quality was assessed using SYRCLE's risk of bias tool. RevMan 5.3 software was used to analyze the data. For clinical studies, the Psoriasis Area and Severity Index score were the main outcomes. For preclinical studies, we clarified the role of S1P and its regulators in psoriasis in terms of phenotype and mechanism. Results: One randomized double-blind placebo-controlled trial and nine animal studies were included in this study. The pooled results showed that compared with control treatment, S1P receptor agonists [mean difference (MD): -6.80; 95% confidence interval (CI): -8.23 to -5.38; p<0.00001], and sphingosine kinase 2 inhibitors (MD: -0.95; 95% CI: -1.26 to -0.65; p<0.00001) alleviated psoriasis-like dermatitis in mice. The mechanism of S1P receptor agonists in treating psoriasis might be related to a decrease in the number of white blood cells, topical lymph node weight, interleukin-23 mRNA levels, and percentage of CD3+ T cells (p<0.05). Sphingosine kinase 2 inhibitors ameliorated psoriasis in mice, possibly by reducing spleen weight and cell numbers (p<0.05). Conclusions: S1P receptor agonists and sphingosine kinase 2 inhibitors could be potential methods for treating psoriasis by decreasing immune responses and inflammatory factors.

The S1P-S1PR Axis in Neurological Disorders-Insights into Current and Future Therapeutic Perspectives.

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.

Experimental research of pregnancy immune tolerance induced by a novel immunosuppressive agent FTY720 via blocking the S1P signaling pathway / 上海交通大学学报（医学版）

Objective · To investigate the effects and mechanisms of pregnancy immune tolerance induced by a novel immunosuppressive agent FTY720 and to provide experimental basis for the clinical treatment of unexplained recurrent spontaneous abortion. Methods · The mice of spontaneous abortion model were used as subjects. The effects of intraperitoneal injection of FTY720 on the embryo loss rate in mice of spontaneous abortion model and on the expression of sphingosine-1-phosphate (S1P) in the decidual tissue were observed. S1P-siRNA lentiviral vectors and S1P-overexpression gene lentiviral vectors were constructed and transfected into dendritic cells (DCs) from mouse bone marrow. The effects of FTY720 on the embryo loss rate in mice of spontaneous abortion model after adoptive transferring of these two types of lentiviral vectors were observed. Results · FTY720 had no significant effect on the embryo loss rate in normal pregnant mice. Intraperitoneal injection of FTY720 significantly reduced the embryo loss rate in mice of spontaneous abortion model. The expression of S1P in the decidual tissue in mice of spontaneous abortion model was low. After adoptive transferring of S1P-siRNA lentiviral vector transfected DCs, FTY720 could slightly reduce the embryo loss rate in mice of abortion mouse model, but the effect was far less than that of before adoptive transferring of S1P-siRNA lentivirus transfected DCs. After adoptive transferring of the S1P-overexpression gene lentiviral vector transfected DCs, FTY720 could significantly reduce the rate of embryo loss in mice of spontaneous abortion model and the effect was more significant than that of before adoptive transfecting of S1P-overexpression lentiviral vector transfected DCs. Conclusion · FTY720 is safe. The induction of pregnancy immune tolerance may be related to the blockage of S1P signaling pathway.

Experimental research of pregnancy immune tolerance induced by a novel immunosuppressive agent FTY720 via blocking the S1P signaling pathway / 上海交通大学学报（医学版）

Objective · To investigate the effects and mechanisms of pregnancy immune tolerance induced by a novel immunosuppressive agent FTY720 and to provide experimental basis for the clinical treatment of unexplained recurrent spontaneous abortion. Methods · The mice of spontaneous abortion model were used as subjects. The effects of intraperitoneal injection of FTY720 on the embryo loss rate in mice of spontaneous abortion model and on the expression of sphingosine-1-phosphate (S1P) in the decidual tissue were observed. S1P-siRNA lentiviral vectors and S1P-overexpression gene lentiviral vectors were constructed and transfected into dendritic cells (DCs) from mouse bone marrow. The effects of FTY720 on the embryo loss rate in mice of spontaneous abortion model after adoptive transferring of these two types of lentiviral vectors were observed. Results · FTY720 had no significant effect on the embryo loss rate in normal pregnant mice. Intraperitoneal injection of FTY720 significantly reduced the embryo loss rate in mice of spontaneous abortion model. The expression of S1P in the decidual tissue in mice of spontaneous abortion model was low. After adoptive transferring of S1P-siRNA lentiviral vector transfected DCs, FTY720 could slightly reduce the embryo loss rate in mice of abortion mouse model, but the effect was far less than that of before adoptive transferring of S1P-siRNA lentivirus transfected DCs. After adoptive transferring of the S1P-overexpression gene lentiviral vector transfected DCs, FTY720 could significantly reduce the rate of embryo loss in mice of spontaneous abortion model and the effect was more significant than that of before adoptive transfecting of S1P-overexpression lentiviral vector transfected DCs. Conclusion · FTY720 is safe. The induction of pregnancy immune tolerance may be related to the blockage of S1P signaling pathway.