Search Results (108)

Huntington’s Disease (HD) is characterized by prominent degeneration of the principal neurons of the striatum and by progressive motor and cognitive deterioration. Striatal neurons degenerate in HD due to multiple cell-autonomous and non-autonomous factors. Impaired neurotrophin signaling by brain-derived neurotrophic factor (BDNF) and its cognate receptor Tropomyosin receptor kinase B (TrkB) is an important mechanism underlying neuronal loss in HD. Fingolimod, a clinically approved oral drug for Multiple Sclerosis, was originally developed based on its anti-inflammatory properties. Recent work suggests that fingolimod can also promote BDNF expression and enhance neurotrophic support in the brain. We hypothesized that fingolimod treatment initiated during the presymptomatic phase would increase striatal BDNF levels and protect against motor dysfunction in HD. In wild-type mice, fingolimod treatment increases striatal BDNF levels and enhances BDNF-TrkB signaling. However, chronic fingolimod therapy (0.1 mg/kg, i.p., twice per week, over 7 weeks) initiated at age 4 weeks in the R6/2 mouse model of HD failed to improve behavioral locomotor deficits and exacerbated limb clasping. Furthermore, fingolimod treatment in these presymptomatic R6/2 mice acutely decreased BDNF-TrkB signaling in the striatum in a dose-dependent manner. In contrast, acute administration of fingolimod in symptomatic 7-week-old R6/2 mice increased striatal BDNF-TrkB signaling in a dose-dependent manner, consistent with previous work suggesting that chronic fingolimod can improve motor behavior when given during the symptomatic phase. Thus, the effects of fingolimod striatal BDNF-TrkB signaling and motor behavior in HD are complex and vary with disease stage. Addressing this variability is critical for the design of neuroprotective drug trials in HD, including those utilizing sphingosine-1-phosphate receptor (S1P) modulators. Full article

Background: Multiple sclerosis (MS), a debilitating chronic disease of the central nervous system, is characterized by both inflammatory and neurodegenerative processes that lead to demyelination and neuronal damage. While MS remains incurable, therapies like fingolimod can slow disease progression by modulating immune function. Fingolimod acts as a sphingosine-1-phosphate receptor modulator, limiting lymphocyte migration into the central nervous system and thereby reducing inflammation. Methods: In this study, we developed a computational model to describe fingolimod’s impact on immune dynamics in MS, focusing on CD8⁺ T-cell migration blockade. Model calibration utilized cohort data, enabling the comparison of simulated outcomes with observed clinical metrics. Results: The results indicate that our model effectively captures the timing and extent of CD8⁺ T-cell sequestration, consistent with key features in the patient data. Conclusions: These findings suggest that computational modeling can provide quantitative insight into the fingolimod’s mechanism of action and assist in predicting treatment response, offering a promising framework for exploring personalized fingolimod dosing strategies and enhancing therapeutic planning in MS. Full article

Background: Pseudomonas aeruginosa infection is a major driver of morbidity and mortality in cystic fibrosis (CF), yet disease severity varies widely among people with CF (pwCF). This clinical heterogeneity suggests the involvement of host genetic modifiers beyond CFTR. We previously identified sphingosine 1-phosphate receptor 1 (S1PR1) as a candidate gene associated with susceptibility to P. aeruginosa. Here, we investigated its role in modulating airway epithelial responses to infection. Methods: Using CRISPR/Cas9, we generated S1PR1-knockout bronchial epithelial cells with (IB3-1) and without (C38) CFTR mutations. We assessed cell viability, cytotoxicity, and interleukin-8 secretion following exposure to P. aeruginosa exoproducts. S1PR1 protein expression was evaluated in lung tissue from pwCF and non-CF individuals using immunohistochemistry. Results: S1PR1-mutant cells produced truncated, non-functional peptides. In CFTR-mutant cells, S1PR1 loss reduced viability, increased cytotoxicity, and significantly enhanced interleukin-8 production in response to P. aeruginosa exoproducts. These effects were not observed in CFTR-competent cells. Notably, S1PR1 protein levels were markedly lower in lung tissue from pwCF compared to non-CF individuals. Conclusions: S1PR1 deficiency exacerbates epithelial damage and inflammatory responses to P. aeruginosa in CF models. These findings highlight S1PR1 as a potential contributor to infection severity and a promising target for therapeutic strategies in pwCF. Full article

The pathogenesis of Inflammatory Bowel Disease is complex and not completely understood, resulting from multifactorial interactions between genetic predisposition, environmental triggers, and dysregulation of both innate and adaptive immune responses. Cytokines, produced by dysregulated immune cells, trigger chronic intestinal inflammation leading to tissue damage, carcinogenesis, and disease perpetuation. Current advanced therapies—including tumor necrosis factor (TNF)-α antagonists, adhesion and trafficking inhibitors (such as anti-integrin agents and sphingosine-1-phosphate receptor modulators), interleukin inhibitors, and Janus kinase inhibitors—have improved patient outcomes, but targeting a single inflammatory pathway is often insufficient for long-term disease control. To further improve therapeutic efficacy, novel approaches are under investigation, including advanced combination therapies that simultaneously inhibit multiple pro-inflammatory pathways and microbiome-based treatments to restore intestinal homeostasis. In this evolving therapeutic scenario, precision medicine and advanced combination therapies appear promising for breaking through the current therapeutic ceiling. This review highlights current knowledge on the role of cytokines in IBD pathogenesis and explores how their modulation can modify and control disease course. Full article

Inflammatory bowel disease commonly requires advanced therapies to induce and maintain durable remission. Sphingosine-1-phosphate receptor modulators are the latest class of orally administered small molecules that have been added to the therapeutic armamentarium for inflammatory bowel disease. These molecules reduce inflammation by sequestering lymphocytes in lymph nodes, thereby reducing immune cell trafficking to the gut. Etrasimod and ozanimod are both licensed for moderate-to-severe ulcerative colitis and have both shown superiority over placebo, with emerging data for their use in Crohn’s disease. By modulating immune cell distribution, without reducing overall immune function, they offer a highly favourable safety profile. This narrative review explores the pharmacology, safety and efficacy of sphingosine-1-phosphate receptor modulators based on clinical trials and real-world evidence and offers practical guidance on their initiation and monitoring. Full article

Background: Type 2 diabetes mellitus (T2DM) is a rapidly expanding worldwide health issue associated with impairments in memory and executive functions. The bioactive sphingolipid sphingosine-1-phosphate (S1P) regulates cell death/survival and the inflammatory response by acting on S1P receptors (S1PRs). Unfortunately, the role of S1PRs signaling in the T2DM brain remains elusive. Methods: The effect of fingolimod (FTY720, S1PRs modulator) on the behavior and expression profile of genes encoding S1PRs, sphingosine kinases (SPHK1 and 2), glucose transporters, proteins engaged in insulin signaling, sirtuin 1 (SIRT1), and proinflammatory cytokines in the brain cortex and hippocampus of diabetic mice was examined. Results: We observed a significant reduction in S1pr1, Sirt1, and insulin-like growth factor-1 (Igf1) gene expression that was accompanied by elevation of Sphk2, S1pr3, Il6, and Tnf in T2DM mice. Moreover, animals showed anxiety-like behavior and memory deficits. Fingolimod administration recovered downregulated S1pr1, Sirt1, and Igf1 expression and upregulated Slc2a4 (GLUT-4) and Ide (insulin-degrading enzyme). Furthermore, FTY720 reduced the elevated expression of Il6 and Tnf. Fingolimod also exerted an anxiolytic effect in T2DM. Conclusions: Results indicate an important role of S1PR modulation in T2DM. Moreover, fingolimod affected mRNA levels of proteins engaged in glucose metabolism/insulin signaling and improved the behavior of diabetic mice. Full article

Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a serious health problem worldwide. Moreover, increased systemic and cerebrovascular inflammation is one of the major pathophysiological features of T2DM, and a growing body of evidence emphasizes T2DM with memory and executive function decline. Bioactive sphingolipids regulate a cell’s survival, inflammatory response, as well as glucose and insulin signaling/metabolism. Moreover, current research on the role of sphingosine kinases (SPHKs) and sphingosine-1-phosphate receptors (S1PRs) in T2DM is not fully understood, and the results obtained often differ. The aim of the present study was to evaluate the effect of metformin (anti-diabetic agent, MET) on the brain’s sphingosine-1-phosphate-related signaling and ultrastructure in diabetic mice. Our results revealed elevated mRNA levels of genes encoding sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate receptor 3 (S1PR3), which was accompanied by downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) in the hippocampus of diabetic mice. Simultaneously, upregulation of genes encoding pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) was observed. Administration of MET significantly reversed changes in mRNA levels in the hippocampus and reduced Sphk2, Il6, and Tnf, with concomitant upregulation of S1pr1 gene expression. Ultrastructural analysis of diabetic mice hippocampus revealed morphological alterations in neurons, neuropil, and capillaries that were manifested as mitochondria swelling, blurred synaptic structure, and thickened basal membrane of capillaries. The use of MET partially reversed those changes. Our research emphasizes the important role of insulin sensitivity modulation by metformin in the regulation of SPHKs and S1PRs and inflammatory gene expression in a murine model of T2DM. Full article

Ischemic stroke remains a leading cause of mortality and disability worldwide, with current therapies such as intravenous thrombolysis and mechanical thrombectomy benefiting only a limited proportion of patients. Neuroinflammation is a key contributor to secondary brain injury, creating a strong rationale for adjunctive therapies targeting immune modulation. Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator originally approved for multiple sclerosis, has shown promising effects in both preclinical and early clinical studies of acute ischemic stroke. Methods: We conducted a structured narrative review of preclinical and clinical studies published between 2015 and 2024, using PubMed, Scopus, and Web of Science databases. Inclusion criteria were original studies evaluating fingolimod in ischemic stroke models or human patients, either as monotherapy or in combination with reperfusion therapies. Exclusion criteria included conference abstracts without peer review, studies lacking mechanistic insight, and non-English publications. Results: Preclinical evidence demonstrates that fingolimod reduces infarct size, preserves blood–brain barrier integrity, and modulates neuroinflammation through multiple mechanisms, including T cell sequestration, microglial polarization, and mitochondrial protection. Clinical trials, though limited in size, suggest improved short- and long-term outcomes when fingolimod is used in combination with intravenous thrombolysis or endovascular therapy, with a manageable safety profile. Novel nanotechnology-based delivery systems further enhance central nervous system (CNS) targeting and reduce systemic side effects. Conclusions: Fingolimod represents a promising multi-targeted adjunctive strategy for ischemic stroke, acting at the intersection of immune modulation, vascular protection, and neuroprotection. While current findings are encouraging, larger randomized controlled trials and biomarker-driven patient selection are needed to validate its clinical utility. This review highlights the translational potential of fingolimod and outlines key directions for future research. Full article

Background: Inflammatory bowel disease (IBD) represents significant health challenges on a global scale, primarily encompassing Crohn’s disease and ulcerative colitis. These conditions are characterized by cycles of relapse and remission. Current treatment options, including conventional chemical therapies and biologics such as anti-Tumor Necrosis Factor α (anti-TNFα), anti-integrin, anti-interleukins 12 (IL-12) or 23 (IL-23) agents, Janus Kinase (JAK) inhibitors, and sphingosine-1-phosphate (S1p) receptor modulators, provide symptomatic relief but do not offer a cure. These therapies are associated with both localized and systemic adverse effects, necessitating careful patient monitoring. Probiotics and prebiotics have been investigated for their potential to enhance gut microbiota diversity, which may assist in managing IBD. However, their efficacy in preventing disease flares remains limited. Recent advances in drug delivery systems, including pressure-based and pH-sensitive formulations, aim at enhancing localized treatment efficacy while minimizing adverse effects. Additionally, a pharmacogenomic approach could improve treatment personalization, optimize therapeutic outcomes, and enhance patients’ quality of life by addressing mental health needs and ensuring comprehensive follow-up care. Despite increased awareness and education among healthcare providers regarding IBD, there is still a need for clearer guidance on available treatment options. Objective: This review aims at providing deeper understanding of IBD management strategies, ultimately striving to improve the quality of care for individuals affected by this disease. Full article

Background/Objectives: Ιnflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is increasingly associated with cardiovascular (CV) complications, such as heart failure (HF), arrhythmias, and acute coronary syndromes (ACSs). As the therapeutic landscape of IBD evolves, with the introduction of newer biologics and small molecules, their CV safety warrants critical evaluation. The objective of this review is to provide an update on the current evidence of CV risks associated with IBD treatments. Methods: A comprehensive literature search from inception to April 2025 was conducted using PubMed and Medline to identify randomized controlled trials, observational studies, systematic reviews, as well as pharmacovigilance data reporting CV safety outcomes of biologic and small-molecule drugs approved for IBD. Additionally, analysis of the European Summary of Product Characteristics for each agent was also performed. Results: Anti-TNF agents, particularly infliximab, have been associated with increased reporting of HF and arrhythmias, particularly in patients with pre-existing cardiac disease. Ustekinumab and vedolizumab show consistently favorable CV safety profiles across trials and real-world studies. IL-23p19 inhibitors demonstrate low CV event rates overall, although signals for atrial fibrillation have emerged with risankizumab. Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators carry class-specific CV warnings, due to signals mainly on non-IBD populations, and require careful use in high-risk individuals. Conclusions: Although most IBD therapies are generally safe from a CV perspective, certain agents may pose risks in vulnerable patients. Individualized CV risk assessment and ongoing post-marketing surveillance are essential to guide therapeutic choices and ensure patient safety. Full article

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder characterized by immune dysregulation and epidermal barrier dysfunction. Advances in understanding the interplay of genetic predisposition, cytokine signaling, and environmental triggers have led to the emergence of targeted therapies. Although biologic agents such as dupilumab, tralokinumab, and lebrikizumab have revolutionized AD management, their high costs, injectable administration, and limited global accessibility highlight the need for alternative options. Small molecule therapies are gaining momentum as they target intracellular pathways central to AD pathogenesis and offer oral or topical administration routes. This review provides a comprehensive analysis of key agents including Janus kinase (JAK) inhibitors (upadacitinib, abrocitinib, baricitinib, ruxolitinib, delgocitinib), phosphodiesterase 4 (PDE4) inhibitors (crisaborole, difamilast, roflumilast, apremilast), as well as STAT6 degraders (KT621, NX3911), aryl hydrocarbon receptor modulators, histamine H4 receptor antagonists (adriforant, izuforant), and sphingosine-1-phosphate receptor modulators (etrasimod, BMS-986166). We summarize their mechanisms of action, pharmacological profiles, and pivotal clinical trial data, emphasizing their potential to address unmet therapeutic needs. Finally, we discuss safety concerns, long-term tolerability, and future directions for integrating small molecule therapies into precision treatment strategies for moderate-to-severe AD. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS) characterized by inflammation, demyelination, axonal degeneration, and gliosis. Its pathophysiology involves a complex interplay of genetic susceptibility, environmental triggers, and immune dysregulation, ultimately leading to progressive neurodegeneration and functional decline. Although significant advances have been made in disease-modifying therapies (DMTs), many patients continue to experience disease progression and unmet therapeutic needs. Drug repurposing—the identification of new indications for existing drugs—has emerged as a promising strategy in MS research, offering a cost-effective and time-efficient alternative to traditional drug development. Several compounds originally developed for other diseases, including immunomodulatory, anti-inflammatory, and neuroprotective agents, are currently under investigation for their efficacy in MS. Repurposed agents, such as selective sphingosine-1-phosphate (S1P) receptor modulators, kinase inhibitors, and metabolic regulators, have demonstrated potential in promoting neuroprotection, modulating immune responses, and supporting remyelination in both preclinical and clinical settings. Simultaneously, artificial intelligence (AI) is transforming drug discovery and precision medicine in MS. Machine learning and deep learning models are being employed to analyze high-dimensional biomedical data, predict drug–target interactions, streamline drug repurposing workflows, and enhance therapeutic candidate selection. By integrating multiomics and neuroimaging data, AI tools facilitate the identification of novel targets and support patient stratification for individualized treatment. This review highlights recent advances in drug repurposing and discovery for MS, with a particular emphasis on the emerging role of AI in accelerating therapeutic innovation and optimizing treatment 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

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