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Are Small Molecules Effective in Treating Inflammatory Pouch Disorders Following Ileal Pouch-Anal Anastomosis for Ulcerative Colitis? Here Is Where We Stand.

Ulcerative colitis (UC) management encompasses conventional and advanced treatments, including biological therapy and small molecules. Surge … nce concerning small molecules in chronic pouchitis, specifically Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor (S1P-R) modulators. According to the preliminary studies and reports, Tofacitinib shows a potential effectiveness in CARP. Upadacitinib presents variable outcomes from the case series, necessitating further evaluation. Filgotini …

New Therapeutic Options in Pulmonal Diseases: Sphingolipids and Modulation of Sphingolipid Metabolism.

Sphingolipids are crucial molecules in the respiratory airways. As in most other tissues and organs, in the lung sphingolipids play an essential role as structural constituents as they regulate barrier function and fluidity of cell membranes. A lung-specific feature is the occurrence of sphingolipids as minor structural components in the surfactant. However, sphingolipids are also key signaling molecules involved in airway cell signaling and their dynamical formation and metabolism are important for normal lung physiology. Dysregulation of sphingolipid metabolism and signaling is involved in a

Bronchoconstriction damages airway epithelia by crowding-induced excess cell extrusion.

Asthma is deemed an inflammatory disease, yet the defining diagnostic feature is mechanical bronchoconstriction. We previously discovered a conserved process called cell extrusion that drives homeostatic epithelial cell death when cells become too crowded. In this work, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion in both mice and humans. Although relaxing the airways with the rescue treatment albuterol did not affect these responses, inhibiting live cel

Lack of S1PR2 in Macrophage Ameliorates Sepsis-associated Lung Injury through Inducing IL-33-mediated Type 2 Immunity.

The function of type 2 immunity and mechanisms underlying the initiation of type 2 immunity after sepsis-induced lung injury remain unclear. Sphingosine-1-phosphate receptor 2 (S1PR2) has been demonstrated to modulate type 2 immunity in the context of asthma and pulmonary fibrosis. Thus, this study aims to investigate the role of type 2 immunity and whether and how S1PR2 regulates type 2 immunity in sepsis. Peripheral type 2 immune responses in patients with sepsis and healthy control subjects were assessed. The impact of S1PR2 on type 2 immunity in patients with sepsis and in a murine model o…

Cell-intrinsic ceramides determine T cell function during melanoma progression.

Acid sphingomyelinase (Asm) and acid ceramidase (Ac) are parts of the sphingolipid metabolism. Asm hydrolyzes sphingomyelin to ceramide, which is further metabolized to sphingosine by Ac. Ceramide generates ceramide-enriched platforms that are involved in receptor clustering within cellular membranes. However, the impact of cell-intrinsic ceramide on T cell function is not well characterized. By using T cell-specific Asm- or Ac-deficient mice, with reduced or elevated ceramide levels in T cells, we identified ceramide to play a crucial role in T cell function in vitro and in vivo. T cell-speci…

Novel biological markers of bone: from bone metabolism to bone physiology.

Biochemical markers of bone turnover have been used for decades in the management of bone diseases, to assess the prognosis of these conditi … to mechanical loading and may also play a role in chronic kidney disease bone and mineral disorder; sphingosine-1-phosphate is a lipid mediator interacting with bone resorption. Some of the bone markers are in fact hormones produced by the bone that affect various physiological and pathological functions in other organs. Thus, osteocalcin is produced by osteo …

Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder.

We report the case of a patient who developed extensive brain lesions during fingolimod (FTY720) treatment in the TRANSFORMS study. His initial diagnosis was multiple sclerosis, but after encephalopathy anti-aquaporin4 antibody (anti-AQP4 Ab) was detected, it was changed to neuromyelitis optica spectrum disorder. After treatment with fingolimod, he developed bilateral extensive brain lesions. The brain MRI showed lesions predominantly involving the right frontal and parietal lobes, with vasogenic edema and enhancement. He had residual encephalomalacia and no recurrence with steroid treatment o

Multipathway Integrated Adjustment Mechanism of Glycyrrhiza Triterpenes Curing Gastric Ulcer in Rats.

BACKGROUND: Gastric ulcer is a common chronic disease in human digestive system, which is difficult to cure, easy to relapse, and endangers … s. CONCLUSION: G. triterpenes has a certain regulating effect on the metabolism of tryptophan, AA, sphingosine, and other endogenous metabolites, and we speculated that the antiulcer potential of G. triterpenes can be primarily attributed to its inhibiting gastric acid secretion, reducing the release of inflammatory mediators, and protecting gastric mucosa e …

Продолжительность мытья и лимфоцитов при переходе от фенголимода к atumumumab: доклад о деле и обзор литературы.

Переход от фингосина-1-фосфатных модуляторов, таких, как финголимод, к антиCD20-терапии, характерен для пациентов с множественным склерозом из-за неоптимальной борьбы с заболеваниями, прогрессии или планирования семьи. Однако оптимальный период < < промыва > > остается неясным, и случаи возобновления деятельности в связи с заболеваниями после прекращения использования финглимода документально зафиксированы. Мы представляем случай 43-летней женщины, которая заразилась тяжелыми заболеваниями после перехода от фенголимода к atumumumab, несмотря на 28-дневный период " смыва "

Совпадение в аннотации оригинала
Transitioning from sphingosine-1-phosphate modulators, such as fingolimod, to anti-CD20 therapies is common in patients with multiple sclerosis due to suboptimal disease control, progression, or family planning. However, the optimal washout period remains unclear, and cases of disease activity rebound following discontinuation of fingolimod have been documen…

Novel and Emerging Therapies for Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease are chronic, relapsing and remitting disorders of intestina … nhibitors, anti-interleukin (IL) (IL-12/IL-23), leukocyte trafficking/migrating inhibitors (such as sphingosine-1-phosphate receptor modulator) and other small molecules currently in development.

Immune thrombocytopenic purpura associated with fingolimod.

Fingolimod is an oral sphingosine-1-phosphate receptor modulator which causes lymphocyte sequestration in lymph nodes and is approved for relapsing multiple sclerosis. The Therapeutic Goods Administration of Australia is aware of only one case where fingolimod preceded immune thrombocytopenic purpura (ITP) by 5 weeks. Here we report three such cases.None were on any medications known to cause ITP and routine investigations were unremarkable. All cases were treated with immunosuppression. Case 1 successfully weaned prednisolone after fingolimod cessation whereas case 2 weaned slowly while conti…

A Microbial Lipid-ATP Synthase Axis Fuels NK Cell Antitumor Activity.

The gut microbiota influences systemic immunity and cancer through inter-organ communication, but OMV-mediated mechanisms remain unclear. Here, we uncover a previously unrecognized role of Bacteroides intestinalis in restraining extra-intestinal tumor growth via OMVs enriched in sphingosine (SP), a bioactive lipid that directly binds to ATP5F1A-a subunit of the mitochondrial ATP synthase-to enhance NK cell function. This microbial lipid-ATP synthase interaction augments mitochondrial efficiency, reduces reactive oxygen species (ROS) production, and potently upregulates IFN-γsecretion in NK cel…

CD8 T cell tolerance results from eviction of immature autoreactive cells from the thymus.

CD8 T cell tolerance is thought to result from clonal deletion of autoreactive thymocytes before they differentiate into mature CD8 T cells in the thymus. However, we report that, in mice, CD8 T cell tolerance instead results from premature thymic eviction of immature autoreactive CD8 thymocytes into the periphery, where they differentiate into self-tolerant mature CD8 T cells. Premature thymic eviction is triggered by T cell receptor (TCR)-driven down-regulation of the transcriptional repressor Gfi1, which induces expression of sphingosine-1-phosphate receptor-1 (S1P1) on negatively selected …

Vaginal microbiota transfer ameliorates cesarean-associated neurodevelopmental deficits in mice via N-bc2S1P synthesis on neonatal skin.

Cesarean section (CS) bypasses neonatal exposure to maternal vaginal microbiota, leaving the metabolic contribution of skin microbiota to neurodevelopment unclear. In CS neonates receiving vaginal microbiota transfer, skin multi-omics at 24 h identified restoration of β-carboline-sphingosine-1-phosphate (N-bc2S1P), whose levels correlated with ASQ-3 scores at 3 and 6 months. In mice, N-bc2S1P assembled on neonatal skin by Lactobacillus crispatus and Bacteroides fragilis reaches the brain and selectively triggers β-arrestin1-biased S1PR2 signaling in forebrain excitatory neurons. This pathway p…

Autotaxin Induces S1P/S1PR1 Signaling to Affect Th17/Treg Cell Balance and Exacerbate Intestinal Inflammation in Colitis.

Abnormal intestinal mucosal immunity plays a crucial role in ulcerative colitis (UC). Autotaxin (ATX) can promote T cell migration and was reported to have a regulatory effect on Th17 cells, while sphingosine-1-phosphate (S1P) and its receptors (S1PRs) modulate Th17/Treg balance and inflammation, with S1PR modulators approved for UC. ATX can catalyze sphingosylphosphorylcholine (SPC) to produce S1P; however, the relationship between ATX and S1P/S1PRs in UC is unclear. Understanding the role of ATX-S1P/S1PRs in intestinal immunity can provide new treatment strategies for intestinal inflammatory…

Liquiritigenin attenuates alcohol-induced liver inflammation by regulating the SphK1/S1P/SPNS2 signaling pathway.

BACKGROUND: Alcohol-associated hepatitis (AH) is both a chronic and acute condition, representing the most prevalent manifestation of alcohol-associated liver disease (ALD), characterized by high morbidity and mortality rates. Licorice, known for its hepatoprotective properties, has garnered considerable attention in this context. Liquiritigenin (LQ), a prominent flavonoid derived from licorice roots, exhibits a range of pharmacological properties, including anti-inflammatory, antioxidant, and anticancer effects. This study aims to investigate the potential of LQ to ameliorate AH by exerting a

Mediators of the stimulatory effect of S1P on colonic Na+/K+ ATPase.

The Na ⁺ /K ⁺ ATPase, commonly known as the Na ⁺ /K⁺ pump, plays a crucial role in colonic sodium and water transport, inducing diarrhea or constipation. Inflammatory bowel disease is often associated with diarrhea and elevated levels of sphingosine-1-phosphate (S1P), suggesting a potential relationship between the pump and S1P. This study investigated the effects of S1P on colonic Na ⁺ /K ⁺ ATPase using Caco-2 cells as a model and the S1P analogue used in the treatment of multiple sclerosis, FTY720P. The pump activity was assessed by measuring the amount of inorganic phosphate released in the…

Sphingolipid Metabolism in Oral Diseases: Pathogenic Mechanisms, Biomarkers, and Therapeutic Opportunities.

Sphingolipids, essential structural components of biological membranes, form a framework that maintains their stability and fluidity. In add … e structural characteristics and principal metabolic pathways of key sphingolipids (e.g., ceramide, sphingosine-1-phosphate [S1P], and glucosylceramide [GlcCer]), discusses their diverse roles in oral diseases, and summarizes recent advances in pharmacological approaches targeting enzymes involved in sphingolipid metabolism.

Multiple sphingolipid-metabolizing enzymes modulate influenza virus replication.

The sphingolipid network is sustained principally by the balance of bioactive sphingolipid molecules and their regulation by sphingolipid-metabolizing enzymes. The components in the lipid system display key functions in numerous cellular and disease conditions including virus infections. During the COVID-19 pandemic, there was a fruitful effort to use an inhibitor that blocks the activity of sphingosine kinase (SphK) 2 to cure the devastating disease. Support for the inhibitor came from pre-clinical research on influenza where the inhibitor demonstrated effective protection of mice from influe…

[Translated article] Risk of Skin Cancer Associated with Disease-Modifying Therapies in Multiple Sclerosis: A Comprehensive Evidence Review.

The use of disease-modifying therapies (DMT) has led to a paradigm shift in the management of multiple sclerosis. A comprehensive narrative review was conducted through an extensive literature search including Medline and Google Scholar to elucidate the link between DMT and the propensity of cutaneous malignancies. Sphingosine-1-phosphate receptor modulators, such as fingolimod and siponimod are associated with a higher risk of basal cell carcinoma (BCC), but not squamous cell carcinoma, or melanoma. The associated physiopathological mechanisms are not fully understood. Alemtuzumab and cladrib…