Search Results (498)

This review explores the dual role of reactive oxygen species (ROS) and free radicals in the pathogenesis of endometriosis, aiming to deepen our understanding of these processes through a systematic literature review. To assess the induction and involvement of ROS in endometriosis, we conducted a comprehensive literature review using Cochrane Libraries, EMBASE, Google Scholar, PubMed, and SCOPUS databases. Of 30 qualifying papers ultimately reviewed, 28 reported a significant contribution of ROS to the pathogenesis of endometriosis, while two found no association. The presence of ROS in endometriosis is associated with infertility, irregular menstrual cycles, painful menstruation, and chronic pelvic discomfort. Among individual ROS types studied, hydrogen peroxide was most frequently investigated, followed by lipid peroxides and superoxide radicals. Notable polymorphisms associated with ROS in endometriosis include those for AT-rich interactive domain 1A (ARID1A) and quinone oxidoreductase 1 (NQO1) isoforms. Key enzymes for ROS scavenging and detoxification include superoxide dismutase, glutathione, and glutathione peroxidase. Effective inhibitors of ROS related to endometriosis are vitamins C and E, astaxanthin, fatty acid-binding protein 4, cerium oxide nanoparticles (nanoceria), osteopontin, sphingosine 1-phosphate, N-acetyl-L-cysteine, catalase, and a high-antioxidant diet. Elevated levels of ROS and free radicals are involved in the pathogenesis of endometriosis, suggesting that targeting these molecules could offer potential therapeutic strategies. Full article

This review aimed to provide a comprehensive overview of the current landscape of etrasimod. Etrasimod is an oral, once-daily selective modulator of sphingosine 1-phosphate receptors (S1PR), developed for the treatment of moderately to severely active ulcerative colitis and currently being explored for its potential in other immune-mediated inflammatory diseases. It selectively targets the S1PR subtypes S1PR₁, S1PR₄, and S1PR₅, with limited activity on S1PR₃ and no activity on S1PR₂. Clinical trials have demonstrated that etrasimod significantly reduces symptoms and induces endoscopic improvement in patients with moderate to severe ulcerative colitis who are refractory or intolerant to at least one conventional therapy, biologic agent, or Janus kinase inhibitor, while maintaining a favourable safety profile. At the end of 2023, etrasimod was approved in the United States and Europe, and it is currently under review for ulcerative colitis in several other regions. Etrasimod offers a novel therapeutic option with unique characteristics that may help address the persistent unmet needs of real-world patients with moderately to severely active ulcerative colitis. Full article

Glioblastoma, classified as a grade IV astrocytoma, is an aggressive and malignant primary brain tumor with no known cure. Despite the implementation of standard medical and surgical treatment protocols, the disease often progresses with unsatisfactory outcomes. This study aimed to evaluate the cytotoxic, proapoptotic, and antimetastatic effects of anti-angiogenic monoclonal antibody bevacizumab combined with the sphingosine-1-phosphate receptor modulator fingolimod on rat glioma C6 cells. The cytotoxicity of bevacizumab and fingolimod was evaluated using the MTT assay. Proapoptotic activity was assessed through flow cytometric analyses, including Annexin V–FITC staining, caspase 3/7 activation, and mitochondrial membrane potential measurements. Morphological changes were examined using confocal microscopy. Antimetastatic effects were evaluated via anti-migration and colony formation assays. The combination of bevacizumab and fingolimod exhibited antiproliferative, cytotoxic, proapoptotic, and antimetastatic effects on C6 glioma cells at low IC₅₀ concentrations. Based on growth inhibitory, proapoptotic, and antimetastatic activities on C6 glioma cells, the combination of bevacizumab and fingolimod demonstrates significant growth-inhibitory, proapoptotic, and antimetastatic activities against C6 glioma cells, suggesting its potential as a promising pharmacotherapeutic approach for the treatment of glioblastoma. Full article

Measles, hepatitis C, and COVID-19 are significant human diseases caused by RNA viruses. While vaccines exist to prevent infections, there are a small number of currently available therapeutic agents that can effectively treat these diseases after infection occurs. This study explores a new therapeutic strategy using a small molecule designated polyprenyl immunostimulant (PI) to increase innate immune responses and combat viral infections. Using a multi-disciplinary approach, this study quantifies the effects of PI in mice and THP-1 cells using flow cytometry to identify immune phenotypic markers and mass spectroscopy to monitor the metabolomic profiles of immune cells perturbed by PI treatment. The metabolomic studies identified that sphinganine and ceramide, which are precursors of sphingosine-1-phosphate (S1P), were the common metabolites upregulated in THP-1 and mice blood. Sphingosine-1-phosphate can mediate the trafficking of T cells, whereas ceramide can signal the activation and proliferation of T cells, thereby modulating the mammalian host’s immunity. To demonstrate proof-of-principle, a case study was conducted to examine the benefit of administering PI to improve the outcomes of a feline co-infected with two distinct RNA viruses—feline leukemia virus and feline infectious peritonitis virus. Both viruses produce deadly symptoms that closely resemble RNA viruses that infect humans. The results identify quantifiable cellular and metabolic markers arising from PI treatment that can be used to establish a platform measuring the efficacy of PI in modulating the innate immune system. Full article

Introduction: The introduction of biologic therapies and small molecule drugs has revolutionized the management of inflammatory bowel disease (IBD), providing targeted control of inflammation. However, concerns remain regarding their long-term safety profiles, particularly in relation to cancer risk. Chronic inflammation and immunosuppressive therapies contribute to malignancy risk, including skin cancers, such as melanoma and non-melanoma skin cancer (NMSC). This review examines the evidence on skin cancer risks associated with these therapies, focusing on specific drug classes and their mechanisms. Results: Tumor necrosis factor (TNF) inhibitors have shown conflicting evidence regarding melanoma risk, with some studies reporting a modest increase and others finding no significant association. Anti-integrin agents, such as vedolizumab, and interleukin (IL)-12/23 inhibitors, including ustekinumab, have demonstrated favorable safety profiles with minimal skin cancer risks. Selective IL-23 inhibitors and sphingosine-1-phosphate (S1P) receptor modulators have limited long-term data, but early findings indicate a low incidence of skin malignancies. Janus kinase (JAK) inhibitors do not show an increased risk of skin cancers in IBD. Conclusions: Current evidence suggests that skin cancer risk in IBD patients treated with biologics and small molecule drugs varies by drug class. TNF inhibitors and JAK inhibitors are associated with higher risks, while other therapies show lower malignancy risks. Regular skin cancer screening and protective measures remain critical, particularly for patients with additional risk factors. Further long-term studies are essential to refine safety profiles and inform clinical practice in this evolving therapeutic landscape. Full article

Sphingosine 1 phosphate receptor (S1PR) modulators are the latest drug class to have received approval for the treatment of ulcerative colitis, and have brought a new mechanism of action to this landscape. They target immune cell trafficking, specifically the egress of lymphocytes from lymph nodes to the bloodstream, and have proven to be an efficacious and safe anti-inflammatory mechanism. This narrative review aims to distil the key trial data on the efficacy and safety of ozanimod and etrasimod, the two S1PR modulators currently licensed for use in UC. We discuss the higher response rates in the advanced therapy naive versus exposed subgroups. We summarise their safety profiles, taking into consideration open label extension data. Finally, we consider where this class of drugs may be best placed in the treatment landscape and also provide a practical guide for their use in clinical practice. Full article

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder that predominantly affects the Purkinje cells (PCs) of the cerebellum, leading to cerebellar degeneration, motor dysfunction, and cognitive impairment. Sphingosine-1-phosphate (S1P) signaling, known to modulate neuroinflammation, has been identified as a potential therapeutic target in SCA1. To investigate the therapeutic efficacy of the S1P modulator fingolimod, we treated a mouse model for SCA1, ATXN1[82Q]/+ mice during three different periods with fingolimod and assessed the effects. Potential therapeutic effects were monitored by tracking locomotion during the treatment period and examining PC morphology, connectivity, and markers for neuroinflammation post-mortem. Fingolimod treatment reduced astrocyte and microglial activation during all three treatment periods. We found no effect on calbindin levels or the thickness of the molecular layer, but fingolimod did improve the extent of the synaptic input of climbing fibers to PCs. While fingolimod improved important aspects of cellular pathology, we could only detect signs of improvement in the locomotion phenotype when treatment started at a later stage of the disease. In conclusion, fingolimod is able to mitigate neuroinflammation, preserve aspects of PC function in SCA1, and remediate part of the ataxia phenotype when treatment is appropriately timed. Although behavioral benefits were limited, targeting S1P pathways represents a potential therapeutic strategy for SCA1. Further studies are needed to optimize treatment regimens and assess long-term outcomes. Full article

Endometrial cancer (EC) is classified into two main subtypes with distinct molecular profiles. Sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), are crucial regulators of cell survival, apoptosis, and oxidative stress. This study examined the impact of sphingolipid metabolism in Ishikawa (type 1) and HEC-1A (type 2) EC cells following the silencing of Sptlc1 and Sptlc2, which encode subunits of serine palmitoyltransferase (SPT), a key enzyme in de novo sphingolipid synthesis. Gene silencing was confirmed by RT-PCR and Western blot, while sphingolipid levels were quantified using UHPLC/MS/MS and the sphingolipid rheostat (S1P/ceramide ratio) was calculated. Cell viability (MTT assay), cell death, ROS levels (ELISA), total antioxidant capacity (TAC), catalase and caspase-3 activity, and mitochondrial membrane potential were also assessed. The obtained data showed higher ceramide levels in Ishikawa_(CON) cells and higher S1P levels in HEC-1A_(CON) cells, resulting in a higher sphingolipid rheostat in HEC-1A cells. SPT knockdown reduced sphingolipid levels, increased cell viability, elevated ROS levels, and decreased cell death, particularly in Ishikawa cells. Furthermore, after gene silencing, these cells exhibited reduced catalase activity and diminished TAC, indicating an impaired redox balance. These findings reveal subtype-specific responses to disrupted sphingolipid synthesis and highlight the importance of sphingolipid homeostasis in the behavior of EC cells. Full article

Systemic molecular responses to pathogen-associated molecular patterns and their modulation by antioxidants are poorly understood in humans. Here, we present a two-stage clinical interventional study in healthy humans challenged with lipopolysaccharide. In the first step, the kinetics of inflammatory modulators within 8 h were investigated by plasma proteomics and lipidomics. In a second step, the effects of a placebo-controlled antioxidant intervention on the individual responses prior to another lipopolysaccharide challenge were determined. Plasma proteomics revealed an early involvement of the endothelium and platelets, followed by the induction of liver-derived acute phase proteins and an innate immune cell response. Untargeted lipidomics revealed an early release of fatty acids and taurocholic acid, followed by complex regulatory events exerted by oxylipins. The consistent lipopolysaccharide-induced downregulation of lysophospholipids suggested the involvement of the Lands cycle, and the downregulation of deoxycholic acid reinforced emerging links between the inflammasome and bile acids. Groups of molecules with similar kinetics to lipopolysaccharide challenge were observed to share precursors, synthesizing enzymes or cellular origin. Dietary antioxidant supplementation prior to lipopolysaccharide challenge had no detectable effect on protein kinetics but significantly downregulated pro-inflammatory sphingosine-1-phosphate and increased levels of oxylipins, 20-HEPE, and 22-HDoHE, which have been described to facilitate the resolution of inflammation. The present study identified a complex network of lipid mediators deregulated in plasma upon lipopolysaccharide challenge and highlighted the role of platelets, endothelial cells, and erythrocytes as potential inflammatory modulators. While dietary antioxidant supplementation hardly affected the initiation of inflammation, it may exert its effects supporting the resolution of inflammation. Full article

Multiple sclerosis is a chronic autoimmune disease in which the immune system attacks the protective sheath or myelin that covers nerve fibers, impacting the brain’s ability to communicate with other areas of the body. This abnormal immune response recruits inflammatory substances, which appear as lesions on the brain and spinal cord. A stroke is characterized by a sudden impairment of neurological function resulting from the loss or restriction of blood flow due to acute damage to a localized area of the central nervous system, including the brain, retina, or spinal cord. While strokes, both ischemic and hemorrhagic, are different in terms of their pathogenesis to MS, mechanisms such as neuroinflammation and neurodegeneration are common denominators among these conditions. Recent studies highlight the involvement of the sphingosine-1-phosphate receptor in the treatment of strokes and how fingolimod, an S1P receptor modulator employed in MS treatment, may play a role in the treatment of stroke-like symptoms. This review aims to explore the potential link between stroke and MS, providing a comprehensive analysis of the existing evidence. It will also shed light on the role of S1P receptors in the pathophysiology of stroke, offering insights into their mechanistic contributions. Furthermore, the review will examine recent studies investigating the therapeutic potential of the S1P modulator, fingolimod, in acute stroke patients, highlighting its efficacy and potential clinical applications. Through this multifaceted approach, we hope to contribute to the development of a deeper understanding of these interconnected neurological conditions and their treatment strategies. Full article

A significant challenge in cancer treatment is the rising problem of drug resistance that reduces the effectiveness of therapeutic strategies. Current knowledge shows that multiple mechanisms play a role in cancer drug resistance. Another mechanism that has gained attention is the alteration in sphingolipid trafficking and the dysregulation of its metabolism, which was reported to cause cancer-associated drug resistance. Sphingolipids are lipids containing sphingosine and have multiple roles, ranging from lipid raft formation, apoptosis, and cell signaling to immune cell trafficking. Recent studies show that in developing cancer cells, altered or dysregulated sphingolipids are associated with drug efflux and promote the survival of cancer cells by bypassing apoptosis. Upregulated levels of the glucosylceramide synthase (GCS), an enzyme that functions in sphingolipid metabolism, lead to the upregulated ABCB1 gene that induces drug efflux from the cancer cells. These bypass mechanisms make drugs that induce apoptosis in tumor cells ineffective. By highlighting the current findings, this review aims to provide a mechanism of drug resistance caused by the dysregulation of glucosylceramide synthase, sphingosine kinase, and acid ceramidase enzymes as possible therapeutic targets to enhance the effectiveness of the currently used chemotherapeutic agents. Full article

Lymphocytes are central to the pathogenesis of hypersensitivity pneumonitis and a strong body of evidence supports that lymphocytes are modulated by sphingosine-1-phosphate receptor-modifying drugs. This exploratory study aimed to determine if a pharmacological sphingosine-1-phosphate receptor ligand interfered with the activation of lymphocytes obtained from fibrotic hypersensitivity pneumonitis patients. Peripheral blood mononuclear cells of 12 patients and 10 control subjects were submitted to CD3/CD28 stimulation, isolated B cells were incubated with a TLR9 ligand; and we tested how these stimulations were impacted by ozanimod, a sphingosine-1-phosphate receptor ligand. T cell and B cell subsets from patients overexpressed CD69 and cytokines such as TNF and IL-4 in response to CD3/CD28 stimulation, compared to controls. In patients with fibrotic hypersensitivity pneumonitis, ozanimod alleviated CD3/CD28 induction of CD69, IL-4, and TNF in CD8, but not CD4 T cells. In isolated B cells stimulated with a TLR9 ligand, ozanimod reduced cell surface expression of CD69, CD86, and CD40, as well as TNF and IL-6 accumulation in supernatant. We conclude that lymphocyte subsets are functionally impacted in patients with fibrotic hypersensitivity pneumonitis and that ozanimod can interfere ex vivo with the overactivation of B cells and CD8 T cells in response to specific stimuli. Full article

Ceramide is a critical molecule in both the physiology and pathology of the central nervous system. The most studied aspect is its effect on embryonic/stem cells. A salient question is whether low doses of ceramide induce neuronal differentiation without interfering with sphingolipid metabolism and whether high doses can be used in glioblastoma for their cytotoxic effect. Here, we examined the effect of a high dose of ceramide (13 µM) on HN9.10e cells. Interestingly, 13 µM ceramide induced an immediate increase in cell viability, followed by an increase in the number of mitochondria. Microscopic and morphometric analysis revealed a decrease in the number of differentiated cells with 13 µM compared to 0.1 µM but with longer neurites. Furthermore, the lipidomic study demonstrated an increase in the formation of medium–long-chain ceramide and sphingomyelin species and sphingosine 1 phosphate. Sphingolipid modification correlated with SMPD3, ASAH2, and SPHK2 gene expression coding for neutral sphingomyenase 2, ceramidase 2, and sphingosine kinase 2, respectively. Overall, our data show that the variety of responses to ceramide of the same cell type is dependent on the concentration used. Low doses do not affect sphingolipid metabolism, and high doses do so with a different cellular response. Full article

Background/Objectives: The objective of this study was to analyze the profiles of sphingosine (Sph), sphinganine (SPA), sphingosine-1-phosphate (S1P), and ceramides (C14 Cer, C16 Cer, C18:1 Cer, C18 Cer, C20 Cer, C22 Cer, C24:1 Cer, and C24 Cer), along with caspases (CAS-3, CAS-6, and CAS-9), in serum and in the periosteum of the maxilla and mandible in patients with dentofacial deformities undergoing treatment with titanium fixations (miniplates and miniscrews). Methods: The study group comprised 20 patients who underwent bilateral jaw osteotomy due to dentofacial deformities. The osteotomy segments were stabilized with titanium alloy miniplates and screws. The control group consisted of 20 patients who had not yet received surgical treatment for maxillofacial defects. Results: Sphinganine (SPA) and ceramide C22 (C22 Cer) were the only compounds found to be significantly elevated in the serum of the study group compared to the control group. The concentrations of Sph, SPA, C14 Cer, C16 Cer, C18 1 Cer, C18 Cer, C22 Cer, C24 1 Cer, C24 Cer, and S1P were significantly lower in the maxillary periosteum of patients in the study group compared to those in the control group. The concentration of C20 Cer was significantly higher in the maxillary periosteum of patients in the study group compared to the control group. In contrast, the concentrations of Sph, SPA, C14 Cer, C16 Cer, C18 1 Cer, C22 Cer, C24 1 Cer, and C24 Cer were significantly lower in the mandibular periosteum of the study group compared to the control group. The concentrations of C20 Cer and S1P were significantly elevated in the mandibular periosteum of patients in the study group compared with the control group. The activity of CAS-3 was significantly higher in the mandibular periosteum of patients in the study group compared to those in the control group. Conclusions: Titanium fixations induce local changes in the sphingolipid profile within the periosteum of the maxilla and mandible, while no systemic impact on this metabolism was observed. Full article

Background: Angiogenesis, the process of new blood vessel formation, is critically regulated by a balance of pro- and anti-angiogenic factors. This process plays a central role in tumor progression and is modulated by tumor cells. Sphingosine-1-phosphate (S1P), a bioactive lipid signaling molecule acting via G-protein-coupled receptors (S1PR1–5), has emerged as a key mediator of vascular development and pathological angiogenesis in cancer. Consequently, targeting the S1P-S1PRs axis represents a promising strategy for antiangiogenic therapies. This study explores S1PR3 as a potential therapeutic target in osteosarcoma, the most common primary bone malignancy, which we have previously demonstrated to secrete S1P within the acidic tumor microenvironment. Methods: The effects of KRX-725-II and its derivatives, Tic-4-KRX-725-II and [D-Tic]4-KRX-725-II—pepducins acting as S1PR3 antagonists as allosteric modulators of GPCR activity—were tested on metastatic osteosarcoma cells (143B) for proliferation and migration inhibition. Anti-angiogenic activity was assessed using endothelial cells (HUVEC) through proliferation and tubulogenesis assays in 2D, alongside sprouting and migration analyses in a 3D passively perfused microfluidic chip. Results: S1PR3 inhibition did not alter osteosarcoma cell growth or migration. However, it impaired endothelial cell tubulogenesis up to 75% and sprouting up to 30% in respect to controls. Conventional 2D assays revealed reduced tubule nodes and length, while 3D microfluidic models demonstrated diminished sprouting area and maximum migration distance, indicating S1PR3’s role in driving endothelial cell differentiation. Conclusions: These findings highlight S1PR3 as a critical regulator of angiogenesis and posit its targeting as a novel anti-angiogenic strategy, particularly for aggressive, S1P-secreting tumors with pronounced metastatic potential and an acidic microenvironment. Full article