Search Results (131)

Emerging evidence highlights the critical role of phagocytosis-related genes in CRC progression, underscoring the need for novel phagocytosis-based prognostic models to predict clinical outcomes. In this study, a four-gene (SPHK1, VSIG4, FCGR2B and FPR2) signature associated with CRC prognosis was developed using single-sample gene set enrichment analysis (ssGSEA), least absolute shrinkage and selection operator (LASSO) regression, and univariate Cox analysis. Pathway enrichment analysis was conducted on the prognostic genes, along with evaluations of the tumor microenvironment and sensitivity to immunotherapy and chemotherapy across the high- and low-risk groups. Prognostic gene validation was performed via quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) using CRC cDNA and tissue microarrays. High-risk patients showed enhanced responsiveness to immunotherapy, while chemotherapy sensitivity varied across risk subgroups. qRT-PCR results revealed upregulation of SPHK1 and FPR2 in cancer tissues, whereas FCGR2B and VSIG4 were downregulated. IHC assays confirmed increased SPHK1 and FPR2 expression in cancer samples. Single-cell RNA sequencing analysis demonstrated a decrease in SPHK1 and FCGR2B, while VSIG4 and FPR2 progressively increased during macrophage differentiation. These findings provide a potential framework for targeted therapy. Full article

Resonance self-shielding in multi-resonant nuclide media is a dominant physical process in reactor neutronics analysis. This study proposes an improved subgroup method (ISM) based on Padé rational approximation, constructing a high-order rational function mapping between effective and background cross-sections to overcome the precision bottleneck of traditional DSMs and BIMs in nonlinear resonance interference scenarios. The method first generates cross-section relation data via ultra-fine group calculations, then solves subgroup parameters using a positive definite system, with a Spatial Homogenization (SPH) factor introduced for reaction rate conservation. Validation results show that ISM + SPH reduces k-infinity errors from −708 pcm (DSM) to +5 pcm for UO₂ fuel, and from −269 pcm to +45 pcm for MOX fuel with ²³⁹Pu, significantly enhancing neutron transport accuracy in complex fuel systems. This work provides a theoretically rigorous and practically applicable approach for efficient resonance modeling in advanced reactor fuel design. Full article

Background: Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by chronic inflammation and excessive extracellular matrix deposition, with fibrocytes playing a pivotal role in fibrotic remodeling. This study aimed to identify upstream molecular mechanisms regulating fibrocyte recruitment and activation, focusing on the SPHK1 pathway as a potential therapeutic target. Methods: We utilized Mendelian Randomization and phenome-wide association analyses on genes involved in sphingolipid metabolism to identify potential regulators of idiopathic pulmonary fibrosis (IPF). A bleomycin-induced mouse model was employed to examine the role of the SPHK1-S1P axis in fibrocyte recruitment, using SKI-349 to target SPHK1 and FTY720 to antagonize S1PR1. Results: Our analyses revealed SPHK1 as a significant genetic driver of IPF. Targeting SPHK1 and S1PR1 led to a marked reduction in fibrocyte accumulation, collagen deposition, and histopathological fibrosis. Additionally, PAXX and RBKS were identified as downstream effectors of SPHK1. Our protein–protein interaction mapping indicated potential therapeutic synergies with existing anti-fibrotic drug targets. Conclusions: Our findings establish the SPHK1-S1P-S1PR1 axis as a key regulator of fibrocyte-mediated pulmonary fibrosis and support SPHK1 as a promising therapeutic target. Full article

Skin sensitivity is increasingly prevalent, necessitating new therapeutic agents. This study screened multifunctional peptides from Takifugu fasciatus skin for transient receptor potential vanilloid 1 (TRPV1)-inhibitory and anti-inflammatory activities and investigated their mechanisms in alleviating sensitive skin (SS). A low-molecular-weight hydrolysate was prepared through enzymatic hydrolysis of T. fasciatus skin, followed by ultrafiltration, with subsequent peptide identification performed using nano-HPLC-MS/MS and molecular docking-based virtual screening. Among 20 TRPV1-antagonistic peptides (TFTIPs), QFF (T10), LDIF (T14), and FFR (T18) exhibited potent anti-inflammatory effects in (lipopolysaccharide) LPS-induced RAW 264.7 macrophages. T14 showed the strongest TRPV1 inhibition; T14 (200 μM) inhibited Ca²⁺ in capsaicin-stimulated HaCaT cells by 73.1% and showed stable binding in molecular docking, warranting further analysis. Mechanistic studies revealed that T14 suppressed NF-κB signaling by downregulating p65 protein expression, thereby reducing pro-inflammatory cytokine secretion (G-CSF, GM-CSF, ICAM-1, IL-6, TNF-α) in RAW 264.7 cells. Additionally, T14 (400 μM) inhibited ET-1 in LPS-stimulated endothelial cells by 75.0%; ICAM-1 reached 49.0%. Network pharmacology predicted STAT3, MAPK3, SPHK1, and CTSB as key targets mediating T14’s effects. These study findings suggest that T14 may be a promising candidate for skincare applications targeting SS. Full article

FAM46C is a tumor suppressor initially identified in multiple myeloma (MM) but increasingly recognized for its role also in other cancers. Despite its significance, studies exploring the therapeutic potential of FAM46C in combination with targeted treatments remain limited. Sphingosine kinases (SphK1 and SphK2) are key regulators of sphingolipid signaling, a pathway essential for maintaining cell structure and function but frequently deregulated in tumors, making them promising targets for cancer therapy. Preliminary work from our laboratory showed that FAM46C expression synergizes with administration of SKI-I, a pan-inhibitor of sphingosine kinases. In this study, we focused specifically on SphK1, the sphingosine kinase predominantly implicated in cancer and investigated the combinatorial effect of forced FAM46C expression and treatment with PF-543, a selective SphK1 inhibitor. We found that FAM46C overexpression enhances, whereas its downregulation reduces, the cytotoxic efficacy of PF-543 in MM cell lines. Using an in vivo xenograft model, we further validated these findings, showing that FAM46C-expressing MM tumors are indeed sensitive to PF-543 while tumors harboring the D90G loss-of-function variant of FAM46C are not. Overall, our results uncover a novel synergistic interaction between FAM46C expression and SphK1 inhibition, highlighting a promising therapeutic strategy for MM treatment. Full article

This study explores the damage behavior of typical titanium alloy aircraft panel structures under high-speed fragment impacts via ballistic experiments and FEM-SPH simulations. Using a ballistic gun and two-stage light gas gun, tests were conducted with spherical, rhombic, and rod-shaped fragments at 1100–2100 m/s to analyze damage morphology. The FEM-SPH method effectively modeled dynamic impacts, capturing primary penetration and debris cloud-induced secondary damage. Residual strength under tension was evaluated via multiple restart analysis, linking impact dynamics to post-damage mechanics. Experimental results revealed fragment-dependent damage modes: spherical fragments caused circular shear holes with conical/jet-like debris clouds; rhombic fragments induced irregular tearing and triangular perforations due to unstable flight; rod-shaped fragments produced elongated breaches with extensive plastic deformation in stringers. Numerical simulations accurately reproduced debris cloud diffusion and secondary effects like spallation. Residual strength analysis showed tensile capacity was governed by breach geometry and location: rhombic breaches (34.6 kN) had lower strength than circular/square ones (38.1–38.3 kN) due to tip stress concentration, while stringer-located damage increased ultimate load by 8–12% via structural redundancy. In conclusion, high-speed fragment impacts dominate shear/tensile tearing, with morphology dependent on fragment characteristics and impact conditions. Debris cloud-induced secondary damage must be considered in structural assessments. The FEM-SPH method is effective for complex damage simulation, while breach geometry and damage location are critical for residual strength. Stringer involvement enhances load-bearing capacity, highlighting component-level design importance for aircraft survivability. The study results and methodologies presented herein can serve as references for aircraft structural damage analysis, residual strength evaluation of battle-damaged structures, and survivability design. 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: Sphingosine kinase (SphK) overexpression is observed in many cancers, including breast, renal and leukaemia, which leads to increased cellular proliferation, survival and growth. SphK inhibition has been an attractive target for anticancer drug development for the past decade, with SphK inhibitors such as PF-543 and opaganib exhibiting clinical antitumour effects. By exploiting both CB5468139 and PF-543 as structural leads, we hereby report on the first quinoline-5,8-dione-based SphK inhibitor using a fragment-based approach. Methods: The quinoline-5,8-dione framework was developed to incorporate two defined regions, namely a polar quinoline core, which links to an aryl lipophilic chain. All synthetic molecules were characterized by NMR and HRMS and assayed against SphK 1 and 2, and molecular docking studies were performed. A subset of compounds was screened for anticancer activity. Results: As the binding site of SphK accommodates the lipophilic tail of sphingosine, we initially set out to explore the substitution of the C(7) aryl moiety to attain eight novel C(7) ether-linked quinoline-5,8-diones, which were screened for SphK1 and SphK2 activity with good potency identified. To improve SphK binding, structural fragments were adapted from PF-543 to participate in hydrogen bonding within the binding site of SphK1. A model study was performed to yield novel compounds through activated C(2) formyl intermediates. Two pyrrolidine-based quinoline-5,8-diones were assayed for SphK activity, with 21 revealing an improvement of SphK1 binding efficacy relative to the parent compound and 20 (and its precursor 4). Molecular modelling on the pyrrolidine quinoline-5,8-dione construct revealed favourable docking, low binding energies and opportunities for further improvement. Conclusions: Although the screening of anticancer activity was inconclusive, low micromolar dual SphK1/2 inhibition with the quinoline-5,8-dione framework has been identified for the first time, and a plausible new binding mode has been identified. Full article

Background: Cannabidiol, which is one of the main cannabinoids present in Cannabis sativa plants, has been shown to have therapeutic properties, including anti-inflammatory and antioxidant effects that may be useful for treatment of various kidney conditions. Objectives: This article investigates the effect of long-term cannabidiol (CBD) treatment on changes in the renal transcriptome in a mouse model. The main hypothesis was that systematic CBD treatment would affect gene expression associated with those processes in the kidney. Methods: The study was conducted on male C57BL/6J mice. Mice in the experimental groups received daily intraperitoneal injections of CBD at doses of 10 mg/kg or 20 mg/kg body weight (b.w.) for 28 days. After the experiment, kidney tissues were collected, RNA was isolated, and RNA-Seq sequencing was performed. Results: The results show CBD’s effects on changes in gene expression, including the regulation of genes related to circadian rhythm (e.g., Ciart, Nr1d1, Nr1d2, Per2, and Per3), glucocorticoid receptor function (e.g., Cyp1b1, Ddit4, Foxo3, Gjb2, and Pck1), lipid metabolism (e.g., Cyp2d22, Cyp2d9, Decr2 Hacl1, and Sphk1), and inflammatory response (e.g., Cxcr4 and Ccl28). Conclusions: The obtained results suggest that CBD may be beneficial for therapeutic purposes in treating kidney disease, and its effects should be further analyzed in clinical trials. Full article

Sphingosine kinases (SPHKs) are essential enzymes that catalyze the phosphorylation of sphingosine to produce sphingosine-1-phosphate (S1P), which plays pivotal roles in inflammation and immune regulation. In this study, genome-wide association analysis (GWAS) identified the Ydsphk1 gene as closely associated with the resistance of yellow drum (Nibea albiflora) to Vibrio harveyi. Structural prediction showed that YDSPHK1 contains a typical diacylglycerol kinase catalytic (DAGKc) domain (154–291 aa). By constructing and transfecting Ydsphk1 expression plasmids into yellow drum kidney cells, we found that YDSPHK1 is localized in the cytoplasm. Subsequent RNA-Seq analysis of an overexpression plasmid identified 25 differentially expressed genes (DEGs), including 13 upregulated and 12 downregulated. Notably, nsun5 and hsp90aa1 were significantly upregulated, while Nfkbia and hmox1 were downregulated. Promoter analysis indicated that the core regulatory regions of Ydsphk1 are located between −1931~−1679 bp and −419~+92 bp, with two predicted TFAP2A binding sites in the −419~+92 bp region. Further studies demonstrated that varying concentrations of TFAP2A significantly reduced Ydsphk1 promoter activity. These findings underscore the pivotal role of Ydsphk1 in regulating immune responses in yellow drum, particularly through its impact on key immune-related genes and pathways such as NF-κB signaling and ferroptosis. The identification of Ydsphk1 as a mediator of immune regulation provides valuable insights into the molecular mechanisms of immune defense and highlights its potential as a target for enhancing pathogen resistance in aquaculture practices. This study lays a strong foundation for future research aimed at developing innovative strategies for disease management in aquaculture species. Full article

Background: The aim of our study was to determine the role of sphingolipids, which control proliferation and apoptosis, in the placenta of pregnant women with pregnancy-associated breast cancer (PABC) after chemotherapy compared with healthy patients. Methods: We analyzed (by the PCR method) the gene expression of key sphingolipid metabolism enzymes (sphingomyelinases (SMPD1 and SMPD3), acid ceramidase (ASAH1), ceramide synthases (CERS 1–6), sphingosine kinase1 (SPHK1), sphingosine-1-phosphate lyase 1 (SGPL1), and sphingosine-1-phosphate receptors (S1PR1, S1PR2, and S1PR3)) and the content of subspecies of ceramides, sphingosine, and sphingosine-1-phosphate in seven patients with PABC after chemotherapy and eight healthy pregnant women as a control group. Results: We found a significant increase in the expression of genes of acid ceramidase (ASAH1), sphingosine-1-phosphate lyase 1 (SGPL1), sphingosine kinase (SPHK1), and ceramide synthases (CERS 1-3, 5, 6) in the samples of patients with PABC during their treatment with cytostatic chemotherapy. The increase in the expression of the enzymes’ genes was not accompanied by changes in the content of the studied sphingolipids. Such significant changes in the expression of genes controlling the level of CER, sphingosine, and S1P may indicate their ability to initiate the metabolism of pro-apoptotic and anti-apoptotic sphingolipids in the placenta of pregnant women with cancer undergoing chemotherapy in order to maintain levels typical of the placenta of healthy women. Conclusions: Our results may indicate the promising mechanism of placenta protection during chemotherapy for pregnant women with breast cancer and, consequently, of the newborn. This protective effect of the placenta and especially for the newborn has been discovered for the first time and requires more careful study. Full article

Background: Our recent studies have identified a link between sphingolipid metabolites and the induction of a specialized form of regulated cell death termed immunogenic cell death (ICD). We have recently demonstrated that the synthetic cannabinoid (±) 5-epi CP 55,940 (5-epi) stimulates the accumulation of ceramide (Cer), and that inhibition of sphingosine kinase 1 (SphK1) enhances Cer accumulation and ICD-induction in human colorectal cancer (CRC) cell lines. Methods: We employed flow-cytometric, western blot analyses, pharmacological inhibitors of the sphingolipid metabolic pathway and small molecule agonists and antagonists of the CB receptors to further analyze the mechanism by which 5-epi induces Cer accumulation. Results: Herein, and report that 5-epi induces de novo synthesis of Cer primarily through engagement of the cannabinoid receptor 2 (CB2) and depletion of intracellular calcium levels. Moreover, we report that 5-epi stimulates Cer synthesis through dysregulation of the endogenous inhibitor of the de novo Cer pathway, ORMDL3. We also observed a remarkable and specific accumulation of one Cer species, C20:4 Cer, generated predominantly by ceramide synthase 4, as a key factor required for 5-epi-induced ICD. Conclusions: Together, these data indicate that engagement of CB2, by 5-epi, alters regulation of the de novo ceramide synthesis pathway to generate Cer species that mediate ICD. Full article

Although dysregulated sphingolipid metabolism was observed in many malignant tumors, bladder cancer has not yet been examined in this regard. This study aims to investigate the metabolism of bioactive sphingolipids across different stages of urothelial urinary bladder cancer (UBC). Forty-eight patients with UBC were included in this study. The neoplasms were classified as either non-muscle-invasive (NMIBC, n = 24) or muscle-invasive (MIBC, n = 24). Samples of the healthy bladder tissue were taken from the patients who underwent radical cystectomy. The content of sphingolipids was measured using an HPLC method, and the mRNA expression of sphingolipid transporters and metabolizing enzymes was evaluated using RT-PCR. Compared to the healthy bladder tissue, the UBC, regardless of the stage, showed an elevated expression of SphK1, Spns2, and ABCC1. The changes in the level of bioactive sphingolipids were strongly stage-dependent. MIBC showed accumulation of sphingosine-1-phosphate (S1P) and ceramide, whereas the content of these sphingolipids in the NMIBC tumor was not different from that of healthy tissue. Moreover, MIBC, compared to NMIBC, was characterized by higher levels of sphingosine and dihydroceramide. We conclude that profound alterations in sphingolipid metabolism develop upon UBC transition from non-muscle-invasive to muscle-invasive. They include the accumulation of S1P, resulting from the increased availability of sphingosine generated from ceramide, which also builds up due to a further activation of its de novo synthesis. We hypothesize that the dysregulation of S1P metabolism leading to the accumulation of this tumor-promoting sphingolipid contributes to the progression of UBC. Full article

Adenomyosis is a benign gynecological condition characterized by the proliferation of the endometrial stroma and glands into the myometrium, uterine volume enlargement, and peripheral smooth muscle hypertrophy. The typical clinical symptoms include chronic pelvic pain, abnormal uterine bleeding, and subfertility, all of which significantly impact quality of life. There are no effective prevention or treatment strategies for adenomyosis, partly due to a limited understanding of the pathological mechanisms underlying the initiation and progression of the disease. Given that signaling pathways play a crucial role in the development of adenomyosis, a better understanding of these signaling pathways is essential for identifying therapeutic targets and advancing drug development. The occurrence and progression of adenomyosis are closely linked to various underlying pathophysiological mechanisms, including proliferation, migration, invasion, fibrosis, angiogenesis, inflammation, oxidative stress, immune response, and epigenetic changes. This review summarizes the signaling pathways and targets associated with the pathogenesis of adenomyosis, including CXCL/CXCR, NLRP3, NF-κB, TGF-β/smad, VEGF, Hippo/YAP, PI3K/Akt/mTOR, JAK/STAT, and other relevant pathways. In addition, it identifies promising future targets for the development of adenomyosis treatment, such as m6A, GSK3β, sphks, etc. Full article

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolic product produced via the phosphorylation of sphingosine by sphingosine kinases (SPHKs), serving as a powerful modulator of various cellular processes through its interaction with S1P receptors (S1PRs). Currently, this incompletely understood mechanism in pancreatic diseases including pancreatitis and pancreatic cancer, largely limits therapeutic options for these disorders. Recent evidence indicates that S1P significantly contributes to pancreatic diseases by modulating inflammation, promoting pyroptosis in pancreatic acinar cells, regulating the activation of pancreatic stellate cells, and affecting organelle functions in pancreatic cancer cells. Nevertheless, no review has encapsulated these advancements. Thus, this review compiles information about the involvement of S1P signaling in exocrine pancreatic disorders, including acute pancreatitis, chronic pancreatitis, and pancreatic cancer, as well as prospective treatment strategies to target S1P signaling for these conditions. The insights presented here possess the potential to offer valuable guidance for the implementation of therapies targeting S1P signaling in various pancreatic diseases. Full article