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M2-like cells from the macrophage lineage might play a central role in closure of the embryonic neural tube.

Herein it is hypothesized that M2-like macrophages or pre-macrophages of fetal origin might play a central role in development and closure o … tes mellitus, one carbon metabolism (including folic acid deficit), inositol, arachidonic acid, and sphingosine-1-phosphate, as well as in the teratogenicity of nitric acid, valproic acid, and fumonisin. The influence of each of these factors is interpreted in light of potential interactions with M2-like macrophages or macrophage progenitors on the developing …

Metabolic pathways modulate the neuronal toxicity associated with fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects premutation carriers (55-200 C … t enhanced neuronal toxicity associated with CGG repeats, such as Schlank (ceramide synthase), Sk2 (sphingosine kinase) and Ras (IMP dehydrogenase). By combining metabolic profiling with a Drosophila genetic screen to identify genetic modifiers of FXTAS, we demonstrate an effective method for functional validation of high-throughput metabolic data and show th …

SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency.

CONTEXT: Multiple autosomal recessive genes have been etiologically linked to primary adrenal insufficiency (PAI). Recently, sphingosine-1-phosphate lyase 1 (SGPL1) gene mutations were recognized as a cause of steroid-resistant nephrotic syndrome type 14 (NPHS14), a sphingolipidosis with multisystemic manifestations, including PAI. OBJECTIVE: To check if SGPL1 mutations are involved in the pathogenesis of PAI in patients who do not exhibit nephrotic syndrome. METHODS: Sequencing of the SGPL1 gene in 21 patients with familial glucocorticoid disease or triple A syndrome. RESULTS: We identifie…

Распространение хламидии от репродуктивного тракта до желудочно-кишечного тракта происходит поэтапно и зависит от переноса хламидии в ячейках хостинга.

Хламидийный трахоматис — бактериальный патоген, являющийся главной причиной заболеваний, передаваемых половым путем, и предотвратимой слепоты. У женщин инфекция с помощью трахоматиса может привести к воспалительным заболеваниям таза (PID), эктической беременности, хронической боли таза и бесплодию. Помимо заражения женского репродуктивного тракта (FRT), хламидийные спа обычно встречаются в желудочно-кишечном (GI) тракте животных и людей и могут служить резервуаром для реинфекции FRT. Остается неизвестным, распространяет ли Хламидия от FRT до трассы GI по внутренним маршрутам. С помощью мыши C.

Совпадение в аннотации оригинала
Chlamydia trachomatis is a Gram-negative bacterial pathogen and a major cause of sexually transmitted disease and preventable blindness. In … pleen, also relies on cell transport. However, this step is dependent on cell migration mediated by sphingosine 1-phosphate (S1P) signaling. Finally, spleen to GI tract Chlamydia spread is the third critical step, and is significantly hindered in splenectomized mice. Inhibition of Chlamydia dissemination significantly reduces or precludes the induction of Chl …

Induction of hemangiosarcoma in mice after chronic treatment with S1P-modulator siponimod and its lack of relevance to rat and human.

A high incidence of hemangiosarcoma (HSA) was observed in mice treated for 2 years with siponimod, a sphingosine-1-phosphate receptor 1 (S1P1) functional antagonist, while no such tumors were observed in rats under the same treatment conditions. In 3-month rat (90 mg/kg/day) and 9-month mouse (25 and 75 mg/kg/day) in vivo mechanistic studies, vascular endothelial cell (VEC) activation was observed in both species, but VEC proliferation and persistent increases in circulating placental growth factor 2 (PLGF2) were only seen in the mouse. In mice, these effects were sustained over the 9-month st…

Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus.

Ozanimod (RPC1063) is a specific and potent small molecule modulator of the sphingosine 1-phosphate receptor 1 (S1PR1) and receptor 5 (S1PR5), which has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis. Ozanimod and its active metabolite, RP-101075, exhibit a similar specificity profile at the S1P receptor family in vitro and pharmacodynamic profile in vivo. The NZBWF1 mouse model was used in therapeutic dosing mode to assess the potential benefit of ozanimod and RP-101075 in an established animal model of systemic lupus erythematosus. Compare…

Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy.

BACKGROUND: The majority of patients with Alzheimer's disease (AD) exhibit amyloid-β (Aβ) deposits at the brain vasculature, a process refer … s performed to assess the expression and localization of ceramide, acid sphingomyelinase (ASM), and sphingosine-1-phosphate receptors (S1P1, S1P3). In addition, we determined the concentrations of S1P as well as different chain-lengths of ceramides using HPLC-MS/MS. RESULTS: Immunohistochemical analysis revealed an altered expression of ceramide, ASM, and S1 …

Analysis of sphingolipids in human corneal fibroblasts from normal and keratoconus patients.

The pathophysiology of human keratoconus (KC), a bilateral progressive corneal disease leading to protrusion of the cornea, stromal thinning … al-time PCR. Our data showed that HKCs have increased levels of signaling SPLs, ceramide (Cer), and sphingosine 1-phosphate (S1P). Treatment with T1 reversed the increase in Cer in HKCs and treatment with T3 reversed the increase in S1P. S1P3 receptor mRNA levels were also significantly upregulated in HKCs, but were reduced to normal levels following T3 treat …

Ageing adversely affects the migration and function of marginal zone B cells.

Marginal zone (MZ) B cells are positioned within the spleen to capture blood-borne antigen and immune complexes and deliver them to follicular dendritic cells in the B-cell follicles. We show that within the spleens of aged mice antigen capture by MZ B cells, and their ability to shuttle between the follicle and MZ, were impaired. The ability of aged MZ B cells to migrate towards the MZ chemoattractant sphingosine-1-phosphate was increased, suggesting that aged MZ B cells had a greater propensity to be retained within the MZ. An extrinsic impairment in aged B-cell migration towards the MZ was …

Selective coupling of the S1P3 receptor subtype to S1P-mediated RhoA activation and cardioprotection.

Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is generated and released at sites of tissue injury in the heart and can act on S1P1, S1P2, and S1P3 receptor subtypes to affect cardiovascular responses. We established that S1P causes little phosphoinositide hydrolysis and does not induce hypertrophy indicating that it does not cause receptor coupling to Gq. We previously demonstrated that S1P confers cardioprotection against ischemia/reperfusion by activating RhoA and its downstream effector PKD. The S1P receptor subtypes and G proteins that regulate RhoA activation and downstream…

Central effects of fingolimod.

INTRODUCTION: Fingolimod, a sphingosine-1-phosphate receptor modulator, was the first oral therapy approved for relapsing-remitting multiple sclerosis, and shows a novel mechanism of action. Upon binding to S1P1 receptors in lymphocytes, the selective retention of naive and central memory T cells in secondary lymphoid tissues is promoted, preventing their egress to the central nervous system (CNS). In addition, fingolimod readily crosses the blood brain barrier, and several reports suggest a direct neuroprotective effect in the CNS. AIM: To review the available data on the central effects of …

FTY720 preserved islet β-cell mass by inhibiting apoptosis and increasing survival of β-cells in db/db mice.

BACKGROUND: FTY720, an analogue of sphingosine-1-phosphate, has shown potential in the treatment of several autoimmune diseases, such as multiple sclerosis, type 1 diabetes and systemic lupus erythematosus. It prevents development or cure of autoimmune diabetes in animal models. Recently, we reported that FTY720 also prevents development of diabetes in db/db mice by β-cell regeneration in vivo. This study investigated the effect of FTY720 on apoptosis in β-cells in db/db mice treated with FTY720 16 weeks. METHODS: Six week old female db/db mice were divided into control and FTY720 groups. FTY7…

Cancer and sphingolipid storage disease therapy using novel synthetic analogs of sphingolipids.

Sphingolipid metabolites have become recognized for their participation in cell functions and signaling events that control a wide array of cellular activities. Two main sphingolipids, ceramide and sphingosine-1-phosphate, are involved in signaling pathways that regulate cell proliferation, apoptosis, motility, differentiation, angiogenesis, stress responses, protein synthesis, carbohydrate metabolism, and intracellular trafficking. Ceramide and S1P often exert opposing effects on cell survival, ceramide being pro-apoptotic and S1P generally promoting cell survival. Therefore, the conversion o…

FTY720 reduces inflammation and promotes functional recovery after spinal cord injury.

A robust and complex inflammatory cascade is known to be a prominent component of secondary injury following spinal cord injury (SCI). Specifically, the concept of trauma-induced autoimmunity has linked the lymphocyte population with neural tissue injury and neurologic deficit. FTY720, a sphingosine receptor modulator that sequesters lymphocytes in secondary lymphoid organs, has been shown to be effective in the treatment of a variety of experimental autoimmune disorders. Accordingly, by reducing lymphocyte infiltration into the spinal cord following SCI, this novel immunomodulator may enhance…

S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells.

Epithelial ovarian cancer (EOC) arises from the epithelial layer covering the surface of ovaries and i.p. metastasis is commonly observed at diagnosis. Sphingosine-1-phosphate (S1P), a bioactive lipid signaling molecule, is potentially involved in EOC tumorigenesis. We have found that S1P is elevated in human EOC ascites. We show that physiologically relevant concentrations of S1P stimulate migration and invasion of EOC cells but inhibit migration of human ovarian surface epithelial (HOSE) cells. In addition, S1P inhibits lysophosphatidic acid (LPA)-induced cell migration in HOSE but not in EO…

CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs.

Naive lymphocytes continually enter and exit lymphoid organs in a recirculation process that is essential for immune surveillance. During im … ent with poly(I:C) or infection with lymphocytic choriomeningitis virus. Lymphocyte egress requires sphingosine 1-phosphate receptor-1 (S1P1), and IFN-alpha/beta was found to inhibit lymphocyte responsiveness to S1P. By contrast, CD69-/- cells retained S1P1 function after exposure to IFN-alpha/beta. In coexpression experiments, CD69 inhibited S1P1 chemotactic …

Modulation of platelet function through adhesion receptors. A dual role for glycoprotein IIb-IIIa (integrin alpha IIb beta 3) mediated by fibrinogen and glycoprotein Ib-von Willebrand factor.

We have found that the form of glycoprotein (GP) IIb-IIIa (integrin alpha IIb beta 3) expressed on nonstimulated platelets is a functional receptor that mediates selective and irreversible adhesion to immobilized fibrinogen. This occurs even in the presence of the elevated intracellular cAMP levels induced by prostaglandin E1 or after inhibition of protein kinase C activity by sphingosine. In the absence of inhibitors, platelets adhering to fibrinogen through GP IIb-IIIa become fully activated and aggregate with one another. Immobilized von Willebrand factor (vWF), in contrast, is recognized b…

GM2-ganglioside metabolism in cultured human skin fibroblasts: unambiguous diagnosis of GM2-gangliosidosis.

The metabolism of GM2-ganglioside was studied in situ using cultured skin fibroblasts from normal individuals and patients with different forms of GM2-gangliosidosis. [3H]Sphingosine-labeled GM2 was provided in the culture medium to confluent cells in 6-cm petri dishes. After 10 days, the cells were washed free of radioactivity and harvested by trypsinization. The cellular lipids were extracted and analyzed for radioactivity in GM2 and its metabolic products. In fibroblasts from healthy subjects, 50-60% of the total cellular radioactivity was found in the neutral glycosphingolipids, ceramide, …

Active components Alignment of Gegen Qinlian Decoction for inflammatory bowel disease: exploring the possible role of the SphK1/S1P/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Gegenqinlian Decoction (GQD) has been used as a folk remedy for gastrointestinal diseases in China over thou … s aligned active components against IBD, with a focus on microbiota-involved regulation of the host sphingosine kinase 1 (SphK1) /sphingosine-1-phosphate (S1P) / NF-κB signaling pathway, using both 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced rat colitis and dextran sulfate sodium salt (DSS)-induced mouse colitis models and cultured cells. MATERIAL AND …

Emerging Therapeutic Protein Targets of Inflammation: A Comprehensive Review.

Conventional anti-inflammatory therapies, including nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, remain the mainstay o … gut microbiota, epigenetic regulators, microRNAs, microglial activation, astrocyte dysfunction, the sphingosine-1- phosphate (S1P) signalling pathway, gasdermins, transient receptor potential (TRP) channels, and the complement system. Current therapeutic strategies targeting these pathways include smallmolecule inhibitors, monoclonal antibodies, and other eme …