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Update on treatment in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In recent years, many disease-modifying therapies (DMT) have been approved for MS treatment. For this reason, a profound knowledge of the characteristics and indications of the available compounds is required to tailor the therapeutic strategy to the individual patient characteristics. This should include the mechanism of action and pharmacokinetic of the drug, the safety and efficacy profile provided by clinical trials, as well as the understanding of possible side effects. Moreover, the evolving knowledg

The Sphingolipid Balance and Endothelial Dysfunction in Lysosomal Storage Diseases: Shared Mechanisms in Gaucher, Niemann-Pick and Fabry Disease.

Endothelial dysfunction underlies many cardiovascular and metabolic diseases. Lysosomal storage disorders, particularly sphingolipidoses, ca … lial phenotypes. We summarize current knowledge on how substrate accumulation disrupts the ceramide/sphingosine-1-phosphate (S1P) rheostat, affecting NO synthase, vascular permeability, inflammation, angiogenesis, autophagy and cell death. Common and disease-specific changes in endothelial morphology and barrier function are discussed. Importantly, direct exp …

Transcriptional signature of rapidly responding NK cells reveals S1P5 and CXCR4 as anti-tumor response disruptors.

Natural killer (NK) cells are prototypic cytotoxic innate lymphocytes that can kill target cells, such as tumor cells, in the absence of antigen-restriction. Peripheral NK cells exhibit a high degree of heterogeneity. Here, we set out to broadly assess intrinsic modulators of NK cell degranulation in an unbiased manner. We stimulated human primary blood-borne NK cells pre-treated with different cytokine regimens with the HCT116 human colon cancer cell line and used detection of lysosome-associated membrane glycoprotein 1 (LAMP1) as an identifier of rapid NK cell degranulation. RNA sequencing o

Phytosphingosine alleviates Staphylococcus aureus-induced mastitis by inhibiting inflammatory responses and improving the blood-milk barrier in mice.

Mastitis is one of the common diseases in dairy cows which threatens the health of cows and impacts on economic benefits seriously. Recent studies have been showed that Subacute Ruminal Acidosis (SARA) increased the susceptibility of cow mastitis. SARA leads the disturbance of the rumen microbiota, and the rumen bacterial disordered community is an important endogenous factor of cow mastitis. That is to say, cows which suffer from SARA have a disordered rumen microbiota, a prolonged decline in ruminal PH and a high level of lipopolysaccharide (LPS) in the rumen, blood. Therefore, ruminal metab

CERS6-derived ceramides aggravate kidney fibrosis by inhibiting PINK1-mediated mitophagy in diabetic kidney disease.

During diabetic kidney disease (DKD), ectopic ceramide (CER) accumulation in renal tubular epithelial cells (RTECs) is associated with interstitial fibrosis and albuminuria. As RTECs are primarily responsible for renal energy metabolism, their function is intimately linked to mitochondrial quality control. The role of CER synthesis in the progression of diabetic renal fibrosis has not been thoroughly investigated. In this study, we observed a significant upregulation of ceramide synthase 6 (Cers6) expression in the renal cortex of db/db mice, coinciding with increased production of CER (d18:1/

Sphingosylphosphorylcholine ameliorates experimental sjögren's syndrome by regulating salivary gland inflammation and hypofunction, and regulatory B cells.

Sjögren syndrome (SS) is an autoimmune disease in which immune cells infiltrate the exocrine gland. Since SS is caused by a disorder of the immune system, treatments should regulate the immune response. Sphingosylphosphorylcholine (SPC) is a sphingolipid that mediates cellular signaling. In immune cells, SPC has several immunomodulatory functions. Accordingly, this study verifies the immunomodulatory ability and therapeutic effect of SPC in SS. To understand the function of SPC in SS, we treated SPC in female NOD/ShiJcl (NOD) mice. The mice were monitored for 10 weeks, and inflammation in the

High-Density Lipoprotein Regulation of Mitochondrial Function.

Lipoproteins play a key role in regulating plasma and tissue levels of cholesterol. Apolipoprotein B (apoB)-containing lipoproteins, including chylomicrons, very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL), serve as carriers of triglycerides and cholesterol and deliver these metabolites to peripheral tissues. In contrast, high-density lipoprotein (HDL) mediates Reverse Cholesterol Transport (RCT), a process by which excess cholesterol is removed from the periphery and taken up by hepatocytes where it is metabolized and excreted. Anti-atherogenic properties of HDL have been

A new turning point in glycosphingolipid research.

Research on glycosphingolipids has advanced with the finding of their involvement in sphingolipidoses, blood group- and differentiation-related antigens, and receptors for bacteria and viruses. Recently, the molecular cloning of genes for the synthesis of glycosphingolipids has been performed extensively, and mice without sugar transferase-genes have been generated. These transferase-null mice have shown that the complex carbohydrate structures of glycosphingolipids are not essential for the embryogenesis, morphogenesis or development of animals, but that the accumulation of an intermediate, s

Glucosylceramide and glucosylsphingosine modulate calcium mobilization from brain microsomes via different mechanisms.

We recently demonstrated that elevation of intracellular glucosylceramide (GlcCer) levels results in increased functional Ca2+ stores in cul … er GSLs and sphingolipids, including galactosylceramide, lactosylceramide, ceramide, sphingomyelin, sphingosine 1-phosphate, sphinganine 1-phosphate, and sphingosylphosphorylcholine had no effect on Ca2+ mobilization from rat brain microsomes, but both galactosylsphingosine (psychosine) and glucosylsphingosine stimulated Ca2+ release, although only galactosyl …

Protein kinase C enhances Ca2+ mobilization in human platelets by activating Na+/H+ exchange.

Control of cytoplasmic pH (pHi) by a Na+/H+ antiport appears a general property of most eukaryotic cells. In human platelets activation of the Na+/H+ exchanger enhances Ca2+ mobilization and aggregation induced by low concentrations of thrombin (Siffert, W., and Akkerman, J. W. N. (1987) Nature 325, 456-458). Several observations indicate that the exchanger is regulated by protein kinase C. (i) Inhibitors of protein kinase C (trifluoperazine, sphingosine) inhibit the increase in pHi seen during thrombin stimulation as well as Ca2+ mobilization; artificially increasing pHi by monensin or NH4Cl …

Muribaculaceae regulate β-muricholic acid to target S1PR2 signaling and reduce neurological injury in intracerebral hemorrhage.

BACKGROUND: Intestinal flora imbalance after intracerebral hemorrhage (ICH) aggravates neuroinflammation and secondary brain injury through the gut-brain axis, although the specific mechanism remains unclear. This study focuses on the regulatory effects of Muribaculaceae and β-muricholic acid (β-MA, a primary bile acid) on neurological injury after ICH, aiming to reveal the molecular mechanism by which it improves the prognosis of ICH through the sphingosine-1-phosphate receptor 2 (S1PR2). METHODS: A mouse ICH model was constructed by collagenase induction to evaluate the changes in gut micro…

Phytosphingosine disrupts dual-species oral biofilms and attenuates LPS-induced pro-inflammatory responses in human gingival fibroblasts.

Oral biofilms are major etiological factors in dental caries and periodontitis and are often resistant to conventional anti-microbial therapies, particularly in mixed-species communities. Phytosphingosine (PHS), a naturally occurring bioactive sphingolipid, has demonstrated anti-microbial activity against several pathogens; however, its effects on mixed-species oral biofilms and inflammatory responses remain unclear. This study investigated the in vitro anti-microbial, anti-biofilm, and immunomodulatory activities of PHS against Streptococcus mutans and Aggregatibacter actinomycetemcomitans in…

Ultrasound-gated nanobubbles for sequential pyroptosis blockade and mechanotransductive neurorepair in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a life-threatening neuroinflammatory complication of sepsis for which effective treatment remains unavailable. A major challenge is that most therapeutics cannot efficiently cross the blood-brain barrier or simultaneously address the coupled pathological processes driving disease progression, namely microglial pyroptosis and impaired neurotrophic support. Here, we report an ultrasound-gated nanobubble platform designed for SAE that enables sequential pyroptosis blockade and mechanotransduction-mediated neurorepair. The platform consists of sphingosine-…

Реальный опыт использования озанимода у взрослых с множественной скlerозом.

AIM: Ozanimod — фингозин второго поколения. 1-phosphate Модулятор рецептора (S1PR), утвержденный для лечения повторного склероза (MS). Данные об использовании озанимодов в реальной клинической практике отсутствуют. Цель этого исследования состоит в том, чтобы определить характеристики людей, у которых MS (PwMS) предписан озанимод, а также стойкость, терпимость, безопасность и эффективность по отношению к ним. one Год. МЕТОДЫ: Ретроспективно собирались данные по взрослым с синдромом MS или клинически изолированным синдромом, которые получали озанимод two Высшие центры MS. Результаты: Мы определ

Совпадение в аннотации оригинала
AIM: Ozanimod is a second-generation sphingosine 1-phosphate receptor (S1PR) modulator approved for treatment of relapsing multiple sclerosis (MS). Data are lacking for ozanimod use in real-world clinical practice. This study aims to determine characteristics of people with MS (pwMS) prescribed ozanimod as well as ozanimod persistence, tolerability, safety, …

Pinealectomy-Induced Melatonin Deficiency Exerts Age-Specific Effects on Sphingolipid Turnover in Rats.

The existing body of literature, in conjunction with our recent studies, shows that melatonin dysfunction can accelerate the aging process, with this effect depending on the specific age of the subject. The present study aims to ascertain the impact of pinealectomy on sphingolipid (SL) turnover in young adult (3-month-old), middle-aged (14-month-old), and old (18-month-old) rats. Ceramide (Cer) levels, neutral (NSMase) and acid sphingomyelinase (ASMase), acid ceramidase (ASAH1), and sphingosine-1-phosphate (S1P) levels in hippocampus and/or plasma, were evaluated by enzyme-linked immunosorbent…

S1P/S1PR2 promote pancreatic stellate cell activation and pancreatic fibrosis in chronic pancreatitis by regulating autophagy and the NLRP3 inflammasome.

Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule that governs various functions by embedding its receptor, S1PR, in different cells. Chronic pancreatitis (CP) is characterized by pancreatic fibrosis via activation of pancreatic stellate cells (PSCs). However, the effect of S1P on CP and PSC activation is still unknown. Here, we conducted a series of experiments to explore the effect of S1P on a CP rat model and primary cultured PSCs. In vivo, CP was induced by intravenous injection of dibutyltin dichloride. S1P was administered at a dosage of 200 μg/kg body weight per day by intrape…

COVID-19 infection after SARS-CoV-2 mRNA vaccination in Multiple Sclerosis, AQP4-antibody NMOSD and MOGAD patients during the Omicron subvariant BA.1/2 wave in Singapore.

BACKGROUND: The SARS-CoV-2 Omicron variant appears to cause milder infections, however, its capacity for immune evasion and high transmissib … k of infection, however, Cox proportional-hazards regression showed that patients on anti-CD20s and sphingosine-1-phosphate modulators (S1PRMs) had a shorter time to infection after V3, compared to those on other immunotherapies or not on immunotherapy. CONCLUSIONS: The Omicron subvariant BA.1/2 is highly infectious in patients with central nervous system in …

Plasma sphingolipid abnormalities in neurodegenerative diseases.

BACKGROUND: In recent years, there has been increasing evidence that several lipid metabolism abnormalities play an important role in the pa … AD, and progressive supranuclear palsy (PSP) and CNs. RESULTS: The results showed that (1) plasma sphingosine-1-phosphate (S1P) was significantly lower in all neurodegenerative disease groups (IPD, DLB, MSA, AD, and PSP) than in the CN group. (2) Plasma monohexylceramide (MonCer) and lactosylceramide (LacCer) were significantly higher in all neurodegenerati …

Quantification of lysosphingomyelin and lysosphingomyelin-509 for the screening of acid sphingomyelinase deficiency.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a lysosomal disorder caused by deficiency of acid sphingomyelinase (ASM) leading to the accumulation of sphingomyelin (SM) in a variety of cell types. Lysosphingomyelin (LysoSM) is the de-acetylated form of SM and it has been shown as a biomarker for ASMD in tissues, plasma, and dried blood spots (DBS) and lysosphingomyelin-509 (LysoSM509) is the carboxylated analogue of LysoSM. High levels of Lysosphingomyelin 509 (LysoSM509) have also been shown in ASMD patients. In this study, we report the utility of the quantification of LysoSM and Ly