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Background: Esophageal squamous cell carcinoma (ESCC) stands as a significant global health challenge, distinguished by its aggressive progression from the esophageal epithelium. Central to this malignancy is sphingolipid metabolism, a critical pathway that governs key cellular processes, including apoptosis and immune regulation, thereby influencing tumor behavior. The advent of single-cell and transcriptome sequencing technologies has catalyzed significant advancements in oncology research, offering unprecedented insights into the molecular underpinnings of cancer. Methods: We explored sphingolipid metabolism-related genes in ESCC using scRNA-seq data from GEO and transcriptome data from TCGA. We assessed 97 genes in epithelial cells with AUCell, UCell, and singscore algorithms, followed by bulk RNA-seq and differential analysis to identify prognosis-related genes. Immune infiltration and potential immunotherapeutic strategies were also investigated, and tumor gene mutations and drug treatment strategies were analyzed. Result: Our study identified distinct gene expression patterns, highlighting ARSD, CTSA, DEGS1, and PPTQ's roles in later cellular stages. We identified seven independent prognostic genes and created a precise nomogram for prognosis. Conclusion: This study integrates single-cell and transcriptomic data to provide a reliable prognostic model associated with sphingolipid metabolism and to inform immunotherapy and pharmacotherapy for ESCC at the genetic level. The findings have significant implications for precision therapy in esophageal cancer. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a complex multisystem neurodegenerative disease, and cognitive impairment is a common symptom in the trajectory of PD. Duzhong Fang (DZF) consists of Eucommia ulmoides, Dendrobium, Rehmanniae Radix, and Dried Ginger. Our previous study showed that DZF improves motor deficits in mice. However, whether DZF can ameliorate cognitive impairment in PD has not been reported. In this study, we established mice models of PD induced by rotenone and examined the effect of DZF on cognitive impairment in Parkinson's disease (PD-CI). The results confirmed that DZF treatment not only significantly improved the motor deficits in PD mice and decreased the loss of dopaminergic neurons, but also had significant effects in improving cognitive impairment. We further integrate serum metabolome and network pharmacology to explore the mechanisms by which DZF improves PD-CI. The results revealed that DZF can treat PD-CI by regulating sphingolipid metabolism to inhibit neuronal apoptotic pathway. In conclusion, preliminary studies confirmed that DZF contributes to the improvement of cognitive ability in PD, and our results provide a potential drug for the clinical treatment of PD and a theoretical foundation for DZF in clinical application. [ABSTRACT FROM AUTHOR]

Exposure to heavy metals (HMs) is often associated with inflammation and cell death, exacerbating respiratory diseases including asthma. Most inhaled particulate HM exposures result in the deposition of HM-bound fine particulate matter, PM2.5, in pulmonary cell populations. While localized high concentrations of HMs may be a causative factor, existing studies have mostly evaluated the effects of systemic or low-dose chronic HM exposures. This report investigates the impact of local high concentrations of specific HMs (NaAsO2, MnCl2, and CdCl2) on sphingolipid homeostasis and oxidative stress, as both play a role in mediating responses to HM exposure and have been implicated in asthma. Utilizing an in vitro model system and three-dimensional ex vivo human tissue models, we evaluated the expression of enzymatic regulators of the salvage, recycling, and de novo synthesis pathways of sphingolipid metabolism, and observed differential modulation in these enzymes between HM exposures. Sphingolipidomic analyses of specific HM-exposed cells showed increased levels of anti-apoptotic sphingolipids and reduced pro-apoptotic sphingolipids, suggesting activation of the salvage and de novo synthesis pathways. Differential sphingolipid regulation was observed within HM-exposed lung tissues, with CdCl2 exposure and NaAsO2 exposure activating the salvage and de novo synthesis pathway, respectively. Additionally, using spatial transcriptomics and quantitative real-time PCR, we identified HM exposure-induced transcriptomic signatures of oxidative stress in epithelial cells and human lung tissues. [ABSTRACT FROM AUTHOR]

Abstract Background Esophageal squamous cell carcinoma (ESCC) stands as a significant global health challenge, distinguished by its aggressive progression from the esophageal epithelium. Central to this malignancy is sphingolipid metabolism, a critical pathway that governs key cellular processes, including apoptosis and immune regulation, thereby influencing tumor behavior. The advent of single-cell and transcriptome sequencing technologies has catalyzed significant advancements in oncology research, offering unprecedented insights into the molecular underpinnings of cancer. Methods We explored sphingolipid metabolism-related genes in ESCC using scRNA-seq data from GEO and transcriptome data from TCGA. We assessed 97 genes in epithelial cells with AUCell, UCell, and singscore algorithms, followed by bulk RNA-seq and differential analysis to identify prognosis-related genes. Immune infiltration and potential immunotherapeutic strategies were also investigated, and tumor gene mutations and drug treatment strategies were analyzed. Result Our study identified distinct gene expression patterns, highlighting ARSD, CTSA, DEGS1, and PPTQ's roles in later cellular stages. We identified seven independent prognostic genes and created a precise nomogram for prognosis. Conclusion This study integrates single-cell and transcriptomic data to provide a reliable prognostic model associated with sphingolipid metabolism and to inform immunotherapy and pharmacotherapy for ESCC at the genetic level. The findings have significant implications for precision therapy in esophageal cancer.

Abstract Background Sphingolipids not only serve as structural components for maintaining cell membrane fluidity but also function as bioactive molecules involved in cell signaling and the regulation of various biological processes. Their pivotal role in cancer cell development, encompassing cancer cell proliferation, migration, angiogenesis, and metastasis, has been a focal point for decades. However, the contribution of sphingolipids to the complexity of tumor microenvironment promoting cancer progression has been rarely investigated. Methods Through the integration of publicly available bulk RNA‐seq and single‐cell RNA‐seq data, we conducted a comprehensive analysis to compare the transcriptomic features between tumors and adjacent normal tissues, thus elucidating the intricacies of the tumor microenvironment (TME). Results Disparities in sphingolipid metabolism (SLM)‐associated genes were observed between normal and cancerous tissues, with the TME characterized by the enrichment of sphingolipid signaling in macrophages. Cellular interaction analysis revealed robust communication between macrophages and cancer cells exhibiting low SLM, identifying the crucial ligand‐receptor pair, macrophage inhibitory factor (MIF)‐CD74. Pseudo‐time analysis unveiled the involvement of SLM in modulating macrophage polarization towards either M1 or M2 phenotypes. Categorizing macrophages into six subclusters based on gene expression patterns and function, the SPP1+ cluster, RGS1+ cluster, and CXCL10+ cluster were likely implicated in sphingolipid‐induced M2 macrophage polarization. Additionally, the CXCL10+, AGER+, and FABP4+ clusters were likely to be involved in angiogenesis through their interaction with endothelial cells. Conclusion Based on multiple scRNA‐seq datasets, we propose that a MIF‐targeted strategy could potentially impede the polarization from M1 to M2 and impair tumor angiogenesis in low‐SLM non‐small cell lung cancer (NSCLC), demonstrating its potent antitumor efficacy.

Abstract In this study, we used the LC‐ESI‐MS/MS technique to elucidate the effects of stir‐frying on the lipidomics of oat flour before and after storage. We detected 1540 lipids in 54 subclasses; triglycerides were the most abundant, followed by diacylglycerol, ceramide (Cer), digalactosyldiacylglycerol, cardiolipin, and phosphatidylcholine. Principal component analysis and orthogonal least squares discriminant analysis analyses showed that oat flour lipids were significantly different before and after storage in stir‐fried oat flour and raw oat flour. After oat flour was stir‐fried, most of the lipid metabolites in it were significantly downregulated, and the changes in lipids during storage were reduced. Sphingolipid metabolism and ether lipid metabolism were the key metabolic pathways, and Cer, PC, and lyso‐phosphatidylcholine were the key lipid metabolites identified in the related metabolic pathways during oat flour storage. Frying inhibits lipid metabolic pathways during storage of oat flour, thereby improving lipid stability and quality during storage. This study laid the foundation for further investigating quality control and the mechanism of changes in lipids during the storage of oat flour.

Noise-induced hearing loss (NIHL) is a highly prevalent form of sensorineural hearing damage that has significant negative effects on individuals of all ages and there are no effective drugs approved by the US Food and Drug Administration. In this study, we unveil the potential of superparamagnetic iron oxide nanoparticle assembly (SPIOCA) to reshape the dysbiosis of gut microbiota for treating NIHL. This modulation inhibits intestinal inflammation and oxidative stress responses, protecting the integrity of the intestinal barrier. Consequently, it reduces the transportation of pathogens and inflammatory factors from the bloodstream to the cochlea. Additionally, gut microbiota-modulated SPIOCA-induced metabolic reprogramming in the gut–inner ear axis mainly depends on the regulation of the sphingolipid metabolic pathway, which further contributes to the restoration of hearing function. Our study confirms the role of the microbiota–gut–inner ear axis in NIHL and provides a novel alternative for the treatment of NIHL and other microbiota dysbiosis-related diseases. [ABSTRACT FROM AUTHOR]

Background: Uveal melanoma (UVM) is the most common primary intraocular malignancy in adults and is highly metastatic, resulting in a poor patient prognosis. Sphingolipid metabolism plays an important role in tumor development, diagnosis, and prognosis. This study aimed to establish a reliable signature based on sphingolipid metabolism genes (SMGs), thus providing a new perspective for assessing immunotherapy response and prognosis in patients with UVM. Methods: In this study, SMGs were used to classify UVM from the TCGA-UVM and GEO cohorts. Genes significantly associated with prognosis in UVM patients were screened using univariate cox regression analysis. The most significantly characterized genes were obtained by machine learning, and 4-SMGs prognosis signature was constructed by stepwise multifactorial cox. External validation was performed in the GSE84976 cohort. The level of immune infiltration of 4-SMGs in high- and low-risk patients was analyzed by platforms such as CIBERSORT. The prediction of 4-SMGs on immunotherapy and immune checkpoint blockade (ICB) response in UVM patients was assessed by ImmuCellAI and TIP portals. Results: 4-SMGs were considered to be strongly associated with the prognosis of UVM and were good predictors of UVM prognosis. Multivariate analysis found that the model was an independent predictor of UVM, with patients in the low-risk group having higher overall survival than those in the high-risk group. The nomogram constructed from clinical characteristics and risk scores had good prognostic power. The high-risk group showed better results when receiving immunotherapy. Conclusions: 4-SMGs signature and nomogram showed excellent predictive performance and provided a new perspective for assessing pre-immune efficacy, which will facilitate future precision immuno-oncology studies. [ABSTRACT FROM AUTHOR]

Background: Sphingolipids not only serve as structural components for maintaining cell membrane fluidity but also function as bioactive molecules involved in cell signaling and the regulation of various biological processes. Their pivotal role in cancer cell development, encompassing cancer cell proliferation, migration, angiogenesis, and metastasis, has been a focal point for decades. However, the contribution of sphingolipids to the complexity of tumor microenvironment promoting cancer progression has been rarely investigated. Methods: Through the integration of publicly available bulk RNA‐seq and single‐cell RNA‐seq data, we conducted a comprehensive analysis to compare the transcriptomic features between tumors and adjacent normal tissues, thus elucidating the intricacies of the tumor microenvironment (TME). Results: Disparities in sphingolipid metabolism (SLM)‐associated genes were observed between normal and cancerous tissues, with the TME characterized by the enrichment of sphingolipid signaling in macrophages. Cellular interaction analysis revealed robust communication between macrophages and cancer cells exhibiting low SLM, identifying the crucial ligand‐receptor pair, macrophage inhibitory factor (MIF)‐CD74. Pseudo‐time analysis unveiled the involvement of SLM in modulating macrophage polarization towards either M1 or M2 phenotypes. Categorizing macrophages into six subclusters based on gene expression patterns and function, the SPP1+ cluster, RGS1+ cluster, and CXCL10+ cluster were likely implicated in sphingolipid‐induced M2 macrophage polarization. Additionally, the CXCL10+, AGER+, and FABP4+ clusters were likely to be involved in angiogenesis through their interaction with endothelial cells. Conclusion: Based on multiple scRNA‐seq datasets, we propose that a MIF‐targeted strategy could potentially impede the polarization from M1 to M2 and impair tumor angiogenesis in low‐SLM non‐small cell lung cancer (NSCLC), demonstrating its potent antitumor efficacy. [ABSTRACT FROM AUTHOR]

In this study, we used the LC‐ESI‐MS/MS technique to elucidate the effects of stir‐frying on the lipidomics of oat flour before and after storage. We detected 1540 lipids in 54 subclasses; triglycerides were the most abundant, followed by diacylglycerol, ceramide (Cer), digalactosyldiacylglycerol, cardiolipin, and phosphatidylcholine. Principal component analysis and orthogonal least squares discriminant analysis analyses showed that oat flour lipids were significantly different before and after storage in stir‐fried oat flour and raw oat flour. After oat flour was stir‐fried, most of the lipid metabolites in it were significantly downregulated, and the changes in lipids during storage were reduced. Sphingolipid metabolism and ether lipid metabolism were the key metabolic pathways, and Cer, PC, and lyso‐phosphatidylcholine were the key lipid metabolites identified in the related metabolic pathways during oat flour storage. Frying inhibits lipid metabolic pathways during storage of oat flour, thereby improving lipid stability and quality during storage. This study laid the foundation for further investigating quality control and the mechanism of changes in lipids during the storage of oat flour. [ABSTRACT FROM AUTHOR]

IntroductionRed ginseng (RG), a traditional herbal remedy, has garnered attention owing to its diverse health benefits resulting from its complex composition. However, extensive research is needed to substantiate the efficacy of RG and understand the underlying mechanisms supporting these benefits. This study aimed to identify potential biomarkers and investigate the impact of RG on related metabolic pathways in horse plasma using liquid chromatography–mass spectrometry (LC–MS)-based metabolomics.MethodsTen horses were divided into control and RG groups, with the latter administered RG at a dose of 600 mg⋅kg−1⋅day−1 for 3 weeks. Subsequently, the plasma samples were collected and analyzed using LC–MS. Multivariate statistical analysis, volcano plots, and feature-based molecular networking were employed.ResultsThe analysis identified 16 metabolites that substantially decreased and 21 metabolites that substantially increased following RG consumption. Among the identified metabolites were oleanolic acid, ursolic acid, and ginsenoside Rb1, which are known for their antioxidant and anti-inflammatory properties, as well as lipid species that influence sphingolipid and glycerophospholipid metabolism. Additionally, potential biomarkers, including major RG components, demonstrated distinct group clustering in principal component analysis and partial least squares-discriminant analysis, indicating their utility in assessing the physiological effects of RG consumption.DiscussionThis study contributes to a comprehensive understanding of the effects of RG on health.

Cobalt (Co) and Nickel (Ni) are used nowadays in various industrial applications like lithium-ion batteries, raising concerns about their environmental release and public health threats. Both metals are potentially carcinogenic and may cause neurological and cardiovascular dysfunctions, though underlying toxicity mechanisms have to be further elucidated. This study employs untargeted transcriptomics to analyze downstream cellular effects of individual and combined Co and Ni toxicity in human liver carcinoma cells (HepG2). The results reveal a synergistic effect of Co and Ni, leading to significantly higher number of differentially expressed genes (DEGs) compared to individual exposure. There was a clear enrichment of Nrf2 regulated genes linked to pathways such as glycolysis, iron and glutathione metabolism, and sphingolipid metabolism, confirmed by targeted analysis. Co and Ni exposure alone and combined caused nuclear Nrf2 translocation, while only combined exposure significantly affects iron and glutathione metabolism, evidenced by upregulation of HMOX-1 and iron storage protein FTL. Both metals impact sphingolipid metabolism, increasing dihydroceramide levels and decreasing ceramides, sphingosine and lactosylceramides, along with diacylglycerol accumulation. By combining transcriptomics and analytical methods, this study provides valuable insights into molecular mechanisms of Co and Ni toxicity, paving the way for further understanding of metal stress.

Measurements of sphingolipid metabolism are most accurately performed by LC-MS. However, this technique is expensive, not widely accessible, and without the use of specific probes, it does not provide insight into metabolic flux through the pathway. Employing the fluorescent ceramide analogue NBD-C6-ceramide as a tracer in intact cells, we developed a comprehensive HPLC-based method that simultaneously measures the main nodes of ceramide metabolism in the Golgi. Hence, by quantifying the conversion of NBD-C6-ceramide to NBD-C6-sphingomyelin, NBD-C6-hexosylceramides, and NBD-C6-ceramide-1-phosphate (NBD-C1P), the activities of Golgi resident enzymes sphingomyelin synthase 1, glucosylceramide synthase, and ceramide kinase (CERK) could be measured simultaneously. Importantly, the detection of NBD-C1P allowed us to quantify CERK activity in cells, a usually difficult task. By applying this method, we evaluated the specificity of commonly used sphingolipid inhibitors and discovered that 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, which targets glucosylceramide synthase, and fenretinide (4HPR), an inhibitor for dihydroceramide desaturase, also suppress CERK activity. This study demonstrates the benefit of an expanded analysis of ceramide metabolism in the Golgi, and it provides a qualitative and easy-to-implement method.

Abstract Background Gastric cancer (GC) is one of the most common malignant tumors worldwide. Nevertheless, GC still lacks effective diagnosed and monitoring method and treating targets. This study used multi omics data to explore novel biomarkers and immune therapy targets around sphingolipids metabolism genes (SMGs). Method LASSO regression analysis was performed to filter prognostic and differently expression SMGs among TCGA and GTEx data. Risk score model and Kaplan-Meier were built to validate the prognostic SMG signature and prognostic nomogram was further constructed. The biological functions of SMG signature were annotated via multi omics. The heterogeneity landscape of immune microenvironment in GC was explored. qRT-PCR was performed to validate the expression level of SMG signature. Competing endogenous RNA regulatory network was established to explore the molecular regulatory mechanisms. Result 3-SMGs prognostic signature (GLA, LAMC1, TRAF2) and related nomogram were constructed combing several clinical characterizes. The expression difference and diagnostic value were validated by PCR data. Multi omics data reveals 3-SMG signature affects cell cycle and death via several signaling pathways to regulate GC progression. Overexpression of 3-SMG signature influenced various immune cell infiltration in GC microenvironment. RBP-SMGs-miRNA-mRNAs/lncRNAs regulatory network was built to annotate regulatory system. Conclusion Upregulated 3-SMGs signature are excellent predictive diagnosed and prognostic biomarkers, providing a new perspective for future GC immunotherapy.

Dianming Li,1,* Weiman Shi,1,* Changfeng Hu,1,2 Chengping Wen,1,2 Lin Huang,1,2 Qiao Wang1,2 1College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China; 2Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Hangzhou City, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lin Huang; Qiao Wang, College of Basic Medical Sciences, Key Laboratory of Chinese medicine rheumatology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province, People’s Republic of China, Tel +86 571-86613587, Email huanglin@zcmu.edu.cn; wangqiao0309@163.comBackground: Gouty arthritis (GA) is a common inflammatory disease caused by deposition of monosodium urate (MSU) crystals in diarthrodial joints. GA attacks commonly involved in joint with red, swollen, heat and pain, and often happened in unilateral foot-first metatarsophalangeal. Accumulated studies have proved that lipids play critical roles in biological processes and lipids biomarkers can substitute for the diagnosis of various diseases.Methods: Herein, shotgun lipidomics was used to quantitatively analyze serum lipidomes of a gouty model which was induced by injecting MSU crystals and feeding high-fat diet with/without treatment with allopurinol. Meanwhile, ELISA kit was used to detect mouse serum levels of inflammatory cytokines (eg, tumor necrosis factor-α, interleukin 1 beta) and HE staining was used to observe the infiltration of inflammatory cells in the foot pad.Results: A total of 9 types of serum lipids were detected in lipidomics by shotguns, and the result of NMDS’ analysis demonstrated significant differences in lipids profiles between the control and model group. It is worth noting that lipid abnormality in GA (such as Ceramide (Cer), sphingomyelin (SM), 4-hydroxyalkenals (HNE), phosphatidylinositol (PI), ethanolamine glycerophospholipid (PE), etc.) is related with phospholipid and energy metabolism, and allopurinol treatment could correct the aberrant metabolism of lipid to some extent.Conclusion: Our results indicated that various aberrant lipid metabolisms were present in the established gouty model, and allopurinol treatment could relief this aberrant metabolism of lipids to some degree.Keywords: gouty arthritis, lipidomics, autoimmune reaction, glycerophospholipid metabolism, sphingolipid metabolism, inflammation

Background: The specific impact of sphingolipid metabolism on developing hepatocellular Carcinoma (HCC) remains unclear. This study aims to explore the relationship between sphingolipid metabolism and HCC prognosis, immune response, and drug sensitivity. Methods: Data were obtained from The Cancer Genome Atlas (TCGA)- Hepatocellular Carcinoma (LIHC) and Gene Expression Omnibus (GEO, GSE14520 datasets). 47 sphingolipid metabolism genes were obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. After classifying HCC samples using the Non-negative Matrix Factorization (NMF) clustering method, differentially expressed genes were screened. Then, 8 risk genes were obtained by univariate analysis, survival random forest reduction and lasso analysis. The expression of 8 risk genes was verified in vitro. Results: 8 risk genes were used to construct the Sphingolipid score model. High-Sphingolipid score predicted poor prognosis of HCC patients. Sphingolipid score was associated with immune checkpoints (IL-1B, TLR4, TGFB1, and IL-10), immune cells (Th2, Treg, MDSC, Neutrophil, Fibroblasts and macrophage), and MAPK Cascade. In the High-Sphingolipid score group, a significantly higher proportion of patients with TP53 (p53) mutations was significantly higher (56%). Furthermore, patients with a high- Sphingolipid score were predicted to have a higher sensitivity to chemotherapy drugs. In vitro validation showed that compared with normal liver cells LX-2, TRIM47, and S100A9 significantly increased in liver cancer cells Hep G2, MHCC-97H, and Hep3B2.1-7, while SLC1A7, LPCAT1, and CFHR4 significantly decreased. Silencing TRIM47 reduced the proliferation and promoted apoptosis. The levels of ceramide synthesis-related indexes (CERS1, CERS6, CERS5, and SPTLC2) increased, and the ACER3 related to catalytic hydrolysis decreased. Conclusion: We constructed a sphingolipid metabolism-related prognostic signature (Sphingolipid score) based on 8 risk genes. TRIM47 may affect the development of liver cancer by regulating the relevant indicators of ceramide synthesis and catalytic hydrolysis. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is one of the most common malignant tumors worldwide. Nevertheless, GC still lacks effective diagnosed and monitoring method and treating targets. This study used multi omics data to explore novel biomarkers and immune therapy targets around sphingolipids metabolism genes (SMGs). Method: LASSO regression analysis was performed to filter prognostic and differently expression SMGs among TCGA and GTEx data. Risk score model and Kaplan-Meier were built to validate the prognostic SMG signature and prognostic nomogram was further constructed. The biological functions of SMG signature were annotated via multi omics. The heterogeneity landscape of immune microenvironment in GC was explored. qRT-PCR was performed to validate the expression level of SMG signature. Competing endogenous RNA regulatory network was established to explore the molecular regulatory mechanisms. Result: 3-SMGs prognostic signature (GLA, LAMC1, TRAF2) and related nomogram were constructed combing several clinical characterizes. The expression difference and diagnostic value were validated by PCR data. Multi omics data reveals 3-SMG signature affects cell cycle and death via several signaling pathways to regulate GC progression. Overexpression of 3-SMG signature influenced various immune cell infiltration in GC microenvironment. RBP-SMGs-miRNA-mRNAs/lncRNAs regulatory network was built to annotate regulatory system. Conclusion: Upregulated 3-SMGs signature are excellent predictive diagnosed and prognostic biomarkers, providing a new perspective for future GC immunotherapy. [ABSTRACT FROM AUTHOR]

Pain is a clinical condition that is currently of great concern and is often caused by tissue or nerve damage or occurs as a concomitant symptom of a variety of diseases such as cancer. Severe pain seriously affects the functional status of the body. However, existing pain management programs are not fully satisfactory. Therefore, there is a need to delve deeper into the pathological mechanisms underlying pain generation and to find new targets for drug therapy. Sphingolipids (SLs), as a major component of the bilayer structure of eukaryotic cell membranes, also have powerful signal transduction functions. Sphingolipids are abundant, and their intracellular metabolism constitutes a huge network. Sphingolipids and their various metabolites play significant roles in cell proliferation, differentiation, apoptosis, etc., and have powerful biological activities. The molecules related to sphingolipid metabolism, mainly the core molecule ceramide and the downstream metabolism molecule sphingosine-1-phosphate (S1P), are involved in the specific mechanisms of neurological disorders as well as the onset and progression of various types of pain, and are closely related to a variety of pain-related diseases. Therefore, sphingolipid metabolism can be the focus of research on pain regulation and provide new drug targets and ideas for pain. [ABSTRACT FROM AUTHOR]

Exposure to heavy metals (HMs) is often associated with inflammation and cell death, exacerbating respiratory diseases including asthma. Most inhaled particulate HM exposures result in the deposition of HM-bound fine particulate matter, PM2.5, in pulmonary cell populations. While localized high concentrations of HMs may be a causative factor, existing studies have mostly evaluated the effects of systemic or low-dose chronic HM exposures. This report investigates the impact of local high concentrations of specific HMs (NaAsO2, MnCl2, and CdCl2) on sphingolipid homeostasis and oxidative stress, as both play a role in mediating responses to HM exposure and have been implicated in asthma. Utilizing an in vitro model system and three-dimensional ex vivo human tissue models, we evaluated the expression of enzymatic regulators of the salvage, recycling, and de novo synthesis pathways of sphingolipid metabolism, and observed differential modulation in these enzymes between HM exposures. Sphingolipidomic analyses of specific HM-exposed cells showed increased levels of anti-apoptotic sphingolipids and reduced pro-apoptotic sphingolipids, suggesting activation of the salvage and de novo synthesis pathways. Differential sphingolipid regulation was observed within HM-exposed lung tissues, with CdCl2 exposure and NaAsO2 exposure activating the salvage and de novo synthesis pathway, respectively. Additionally, using spatial transcriptomics and quantitative real-time PCR, we identified HM exposure-induced transcriptomic signatures of oxidative stress in epithelial cells and human lung tissues.

Background: Although the sphingolipid metabolism pathway is known to play a significant role in tumor progression, there have been few studies on how genetic variants in the sphingolipid metabolism pathway genes affect the survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods: We utilized available genotyping data to conduct multivariate Cox proportional hazards regression model analysis, examining the associations of 12,188 single nucleotide polymorphisms (SNPs) in 86 sphingolipid metabolism pathway genes on the survival of 866 HBV-HCC patients, and the model was also used in additive interaction analysis. We used bioinformatics functional prediction and expression quantitative trait locus (eQTL) analysis to explore the potential functions of SNPs and to evaluate the association of SNPs with the corresponding mRNA expression, respectively. We also used the online database TIMER2.0 (http://timer.comp-genomics.org/) to analyze the relationship between the corresponding mRNA expression levels and immune cell infiltration. Results: Our study found that GBA2 rs1570247 G>A was significantly associated with elevated survival of HBV-HCC patients [(hazards ratio (HR)=0.74, 95% confidence interval (CI)=0.64-0.86, P<0.001)]. And on an additive scale, a synergistic effect was observed between the GG genotype of rs1570247 and advanced BCLC stage. Among HBV-HCC patients with advanced BCLC stage, those carrying the GBA2 rs1570247 GG genotype exhibited a significantly elevated risk of mortality (HR=3.32, 95%CI=2.45-4.50). Further functional prediction and eQTL analysis revealed that rs1570247 were located in the 5' untranslated region of the GBA2, the A allele of SNP rs1570247 was associated with higher mRNA expression levels of GBA2 in normal liver tissues (P=0.009). Moreover, we observed a positive correlation between GBA2 mRNA expression and the infiltration level of B lymphocytes cell (R=0.331, P<0.001), while a negative correlation was noted between GBA2 mRNA expression and the infiltration level of macrophage M2 in HCC (R=-0.383, P<0.001). Conclusion: Our findings suggest that GBA2 rs1570247 G>A in sphingolipid metabolism pathway may be a key factor for survival of HBV-HCC patients by regulating the expression of corresponding genes and affecting the infiltration level of immune cells. [ABSTRACT FROM AUTHOR]

Sphingolipids are involved in cell signaling and metabolic pathways, and their metabolites play a critical role in host defense against intracellular pathogens. Here, we review the known mechanisms of sphingolipids in viral infections and discuss the potential implication of the study of sphingolipid metabolism in vaccine and therapeutic development. [ABSTRACT FROM AUTHOR]

Background: The causal relationship between lipid-lowering drug (LLD) use and lung cancer risk is controversial, and the role of sphingolipid metabolism in this effect remains unclear. Methods: Genome-wide association study data on low-density lipoprotein (LDL), apolipoprotein B (ApoB), and triglycerides (TG) were used to develop genetic instrumental variables (IVs) for LLDs. Two-step Mendelian randomization analyses were performed to examine the causal relationship between LLDs and lung cancer risk. The effects of ceramide, sphingosine-1- phosphate (S1P), and ceramidases on lung cancer risk were explored, and the proportions of the effects of LLDs on lung cancer riskmediated by sphingolipid metabolism were calculated. Results: APOB inhibition decreased the lung cancer risk in ever-smokers via ApoB (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.70--0.92, p = 0.010), LDL (OR 0.82, 95% CI 0.71--0.96, p = 0.040), and TG (OR 0.63, 95% CI 0.46--0.83, p = 0.015) reduction by 1 standard deviation (SD), decreased small-cell lung cancer (SCLC) risk via LDL reduction by 1 SD (OR 0.71, 95% CI 0.56--0.90, p = 0.016), and decreased the plasma ceramide level and increased the neutral ceramidase level. APOC3 inhibition decreased the lung adenocarcinoma (LUAD) risk (OR 0.60, 95% CI 0.43--0.84, p = 0.039) but increased SCLC risk (OR 2.18, 95% CI 1.17--4.09, p = 0.029) via ApoB reduction by 1 SD. HMGCR inhibition increased SCLC risk via ApoB reduction by 1 SD (OR 3.04, 95% CI 1.38--6.70, p = 0.014). The LPL agonist decreased SCLC risk via ApoB (OR 0.20, 95% CI 0.07--0.58, p = 0.012) and TG reduction (OR 0.58, 95% CI 0.43--0.77, p = 0.003) while increased the plasma S1P level. PCSK9 inhibition decreased the ceramide level. Neutral ceramidase mediated 8.1% and 9.5% of the reduced lung cancer risk in ever-smokers via ApoB and TG reduction by APOB inhibition, respectively, and mediated 8.7% of the reduced LUAD risk via ApoB reduction by APOC3 inhibition. Conclusion: We elucidated the intricate interplay between LLDs, sphingolipid metabolites, and lung cancer risk. Associations of APOB, APOC3, and HMGCR inhibition and LPL agonist with distinct lung cancer risks underscore the multifaceted nature of these relationships. The observed mediation effects highlight the considerable influence of neutral ceramidase on the lung cancer risk reduction achieved by APOB and APOC3 inhibition. [ABSTRACT FROM AUTHOR]

Background In infant bronchiolitis, recent evidence indicates that respiratory viruses (eg, respiratory syncytial virus [RSV], rhinovirus [RV]) contribute to the heterogeneity of disease severity. Of the potential pathobiological molecules, lipids serve as signaling molecules in airway inflammation. However, little is known about the role of the airway lipidome in between-virus heterogeneity and disease severity. Methods In this multicenter prospective study of 800 infants hospitalized for RSV or RV bronchiolitis, we analyzed nasopharyngeal lipidome data. We examined discriminatory lipids between RSV and RV infection and the association of the discriminatory lipids with bronchiolitis severity, defined by positive pressure ventilation (PPV) use. Results We identified 30 discriminatory nasopharyngeal lipid species and 8 fatty acids between RSV and RV infection. In the multivariable models adjusting for patient-level confounders, 8 lipid species—for example, phosphatidylcholine (18:2/18:2) (adjusted odds ratio [aOR], 0.23 [95% confidence interval {CI},.11–.44]; false discovery rate [FDR] = 0.0004) and dihydroceramide (16:0) (aOR, 2.17 [95% CI, 1.12–3.96]; FDR = 0.04)—were significantly associated with the risk of PPV use. Additionally, 6 fatty acids—for example, eicosapentaenoic acid (aOR, 0.27 [95% CI,.11–.57]; FDR = 0.01)—were also significantly associated with the risk of PPV use. Conclusions In infants hospitalized for bronchiolitis, the nasopharyngeal lipidome plays an important role in the pathophysiology of between-virus heterogeneity and disease severity. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are considered to play a key role in the development and progression of pancreatic ductal adenocarcinoma (PDAC). However, little is known about lipid metabolism reprogramming in PDAC CSCs. Here, we assigned stemness indices, which were used to describe and quantify CSCs, to every patient from the Cancer Genome Atlas (TCGA-PAAD) database and observed differences in lipid metabolism between patients with high and low stemness indices. Then, tumor-repopulating cells (TRCs) cultured in soft 3D (three-dimensional) fibrin gels were demonstrated to be an available PDAC cancer stem-like cell (CSLCs) model. Comprehensive transcriptome and lipidomic analysis results suggested that fatty acid metabolism, glycerophospholipid metabolism, and, especially, the sphingolipid metabolism pathway were mostly associated with CSLCs properties. SPHK1 (sphingosine kinases 1), one of the genes involved in sphingolipid metabolism and encoding the key enzyme to catalyze sphingosine to generate S1P (sphingosine-1-phosphate), was identified to be the key gene in promoting the stemness of PDAC. In summary, we explored the characteristics of lipid metabolism both in patients with high stemness indices and in novel CSLCs models, and unraveled a molecular mechanism via which sphingolipid metabolism maintained tumor stemness. These findings may contribute to the development of a strategy for targeting lipid metabolism to inhibit CSCs in PDAC treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Modern dairy diets have shifted from being forage-based to grain and energy dense. However, feeding high-starch diets can lead to a metabolic disturbance that is linked to dysregulation of the gastrointestinal microbiome and systemic inflammatory response. Plant flavonoids have recently attracted extensive interest due to their anti-inflammatory effects in humans and ruminants. Here, multi-omics analysis was conducted to characterize the biological function and mechanisms of citrus flavonoids in modulating the hindgut microbiome of dairy cows fed a high-starch diet. Results Citrus flavonoid extract (CFE) significantly lowered serum concentrations of lipopolysaccharide (LPS) proinflammatory cytokines (TNF-α and IL-6), acute phase proteins (LPS-binding protein and haptoglobin) in dairy cows fed a high-starch diet. Dietary CFE supplementation increased fecal butyrate production and decreased fecal LPS. In addition, dietary CFE influenced the overall hindgut microbiota’s structure and composition. Notably, potentially beneficial bacteria, including Bacteroides, Bifidobacterium, Alistipes, and Akkermansia, were enriched in CFE and were found to be positively correlated with fecal metabolites and host metabolites. Fecal and serum untargeted metabolomics indicated that CFE supplementation mainly emphasized the metabolic feature “sphingolipid metabolism.” Metabolites associated with the sphingolipid metabolism pathway were positively associated with increased microorganisms in dairy cows fed CFE, particularly Bacteroides. Serum lipidomics analysis showed that the total contents of ceramide and sphingomyelin were decreased by CFE addition. Some differentially abundant sphingolipid species were markedly associated with serum IL-6, TNF-α, LPS, and fecal Bacteroides. Metaproteomics revealed that dietary supplementation with CFE strongly impacted the overall fecal bacterial protein profile and function. In CFE cows, enzymes involved in carbon metabolism, sphingolipid metabolism, and valine, leucine, and isoleucine biosynthesis were upregulated. Conclusions Our research indicates the importance of bacterial sphingolipids in maintaining hindgut symbiosis and homeostasis. Dietary supplementation with CFE can decrease systemic inflammation by maintaining hindgut microbiota homeostasis and regulating sphingolipid metabolism in dairy cows fed a high-starch diet. Video Abstract

Abstract Background Up-regulation of ceramides in pulmonary hypertension (PH), contributing to perturbations in sphingolipid homeostasis and the transition of cells to a senescence state. We assessed the safety, feasibility, and efficiency of acid ceramidase gene transfer in a rodent PH model. Methods A model of PH was established by the combination of left pneumonectomy and injection of Sugen toxin. Magnetic resonance imaging and right heart catheterization confirmed development of PH. Animals were subjected to intratracheal administration of synthetic adeno-associated viral vector (Anc80L65) carrying the acid ceramidase (Anc80L65.AC), an empty capsid vector, or saline. Therapeutic efficacy was evaluated 8 weeks after gene delivery. Results Hemodynamic assessment 4 weeks after PH model the development demonstrated an increase in the mean pulmonary artery pressure to 30.4 ± 2.13 mmHg versus 10.4 ± 1.65 mmHg in sham (p

Provoked vestibulodynia (PVD) is a chronic pain disorder characterized by local hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Despite decades of study, the lack of identified biomarkers has slowed the development of effective therapies. The primary aim of this study was to use metabolomics to identify novel biochemical mechanisms in vagina and blood underlying brain biomarkers and symptoms in PVD, thereby closing this knowledge gap. Using a cross-sectional case-control observational study design, untargeted and unbiased metabolomic profiling of vaginal fluid and plasma was performed in women with PVD compared to healthy controls. In women with PVD, we also obtained assessments of vulvar pain, vestibular and vaginal muscle tenderness, and 24-hour symptom intensity alongside resting-state brain functional connectivity of brain regions involved in pain processing and modulation. Compared to healthy controls, women with PVD demonstrated differences primarily in vaginal (but not plasma) concentrations of metabolites of the sphingolipid signaling pathways, suggesting localized effects in vagina and vulvar vestibule rather than systemic effects. Our findings reveal that dysregulation of sphingolipid metabolism in PVD is associated with increased vulvar pain and muscle tenderness, sexual dysfunction, and decreased functional connectivity strength in pain processing/modulatory brain regions. This data collectively suggests that alterations in sphingolipid signaling pathways are likely an important molecular biomarker in PVD that could lead to new targets for therapeutic intervention. PERSPECTIVE: This manuscript presents the results of a robust, unbiased molecular assessment of plasma and vaginal fluid samples in women with provoked vestibulodynia compared to healthy controls. The findings suggest that alterations in sphingolipid signaling pathways are associated with symptoms and brain biomarkers and may be an important molecular marker that could provide new targets for therapeutic intervention.

The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.

Alisol B 23-acetate (AB23A) is an important pharmacodynamic compound found in Alismatis Rhizoma. In this study, response surface methodology (RSM) and Box- Behnken design (BBD) were used to optimize the extraction parameters of the AB23A. The optimal conditions included a solid–liquid ratio of 1:13, a reflux extraction of 70% ethanol, an extraction time of 2 h, and an extraction cycle of 3 cycles. Furthermore, a rat model of acute liver injury was established using carbon tetrachloride (CCl4), and a comprehensive analysis combining histopathology, lipidomics, and metabolomics was conducted to elucidate the hepatoprotective effect of AB23A. The findings revealed that AB23A significantly reduced the levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), and restored the abnormal morphology of hepatocytes. Furthermore, AB23A exhibited the ability to attenuate CCl4-induced lipid peroxidation, as evidenced by the upregulation of glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels, along with a reduction in malondialdehyde (MDA) content in the liver. Omics results and immunohistochemistry analyses demonstrated a decrease in inflammatory reaction and oxidized phospholipid levels following AB23A administration, indicating an enhanced anti-inflammatory and antioxidant capacities of hepatocytes. Differential metabolite analysis revealed that AB23A improved anti-inflammatory and antioxidant capacities by modulating liver sphingolipid metabolism and purine metabolism, thereby enhancing hepatocyte recovery and counteracting acute liver injury induced by CCl4.

Sphingolipid metabolism affects prognosis and resistance to immunotherapy in patients with cancer and is an emerging target in cancer therapy with promising diagnostic and prognostic value. Long noncoding ribonucleic acids (lncRNAs) broadly regulate tumour-associated metabolic reprogramming. However, the potential of sphingolipid metabolism-related lncRNAs in pancreatic adenocarcinoma (PAAD) is poorly understood. In this study, coexpression algorithms were employed to identify sphingolipid metabolism-related lncRNAs. The least absolute shrinkage and selection operator (LASSO) algorithm was used to develop a sphingolipid metabolism-related lncRNA signature (SMLs). The prognostic predictive stability of the SMLs was validated using Kaplan–Meier. Univariate and multivariate Cox, receiver operating characteristic (ROC) and clinical stratification analyses were used to comprehensively assess the SMLs. Gene set variation analysis (GSVE), gene ontology (GO) and tumor mutation burden (TMB) analysis explored the potential mechanisms. Additionally, single sample gene set enrichment analysis (ssGSEA), ESTIMATE, immune checkpoints and drug sensitivity analysis were used to investigate the potential predictive function of the SMLs. Finally, an SMLs-based consensus clustering algorithm was utilized to differentiate patients and determine the suitable population for immunotherapy. The results showed that the SMLs consists of seven sphingolipid metabolism-related lncRNAs, which can well determine the clinical outcome of individuals with PAAD, with high stability and general applicability. In addition, the SMLs-based consensus clustering algorithm divided the TCGA-PAAD cohort into two clusters, with Cluster 1 showing better survival than Cluster 2. Additionally, Cluster 1 had a higher level of immune cell infiltration than Cluster 2, which combined with the higher levels of immune checkpoints in Cluster 1 suggests that Cluster 1 is more consistent with an immune ‘hot tumor’ profile and may respond better to immune checkpoint inhibitors (ICIs). This study offers new insights regarding the potential role of sphingolipid metabolism-related lncRNAs as biomarkers in PAAD. The constructed SMLs and the SMLs-based clustering are valuable tools for predicting clinical outcomes in PAAD and provide a basis for clinical selection of individualized treatments.

Background: Modern dairy diets have shifted from being forage-based to grain and energy dense. However, feeding high-starch diets can lead to a metabolic disturbance that is linked to dysregulation of the gastrointestinal microbiome and systemic inflammatory response. Plant flavonoids have recently attracted extensive interest due to their anti-inflammatory effects in humans and ruminants. Here, multi-omics analysis was conducted to characterize the biological function and mechanisms of citrus flavonoids in modulating the hindgut microbiome of dairy cows fed a high-starch diet. Results: Citrus flavonoid extract (CFE) significantly lowered serum concentrations of lipopolysaccharide (LPS) proinflammatory cytokines (TNF-α and IL-6), acute phase proteins (LPS-binding protein and haptoglobin) in dairy cows fed a high-starch diet. Dietary CFE supplementation increased fecal butyrate production and decreased fecal LPS. In addition, dietary CFE influenced the overall hindgut microbiota's structure and composition. Notably, potentially beneficial bacteria, including Bacteroides, Bifidobacterium, Alistipes, and Akkermansia, were enriched in CFE and were found to be positively correlated with fecal metabolites and host metabolites. Fecal and serum untargeted metabolomics indicated that CFE supplementation mainly emphasized the metabolic feature "sphingolipid metabolism." Metabolites associated with the sphingolipid metabolism pathway were positively associated with increased microorganisms in dairy cows fed CFE, particularly Bacteroides. Serum lipidomics analysis showed that the total contents of ceramide and sphingomyelin were decreased by CFE addition. Some differentially abundant sphingolipid species were markedly associated with serum IL-6, TNF-α, LPS, and fecal Bacteroides. Metaproteomics revealed that dietary supplementation with CFE strongly impacted the overall fecal bacterial protein profile and function. In CFE cows, enzymes involved in carbon metabolism, sphingolipid metabolism, and valine, leucine, and isoleucine biosynthesis were upregulated. Conclusions: Our research indicates the importance of bacterial sphingolipids in maintaining hindgut symbiosis and homeostasis. Dietary supplementation with CFE can decrease systemic inflammation by maintaining hindgut microbiota homeostasis and regulating sphingolipid metabolism in dairy cows fed a high-starch diet. DkXCRUXMMRmrzaiG6xcXwa Video Abstract [ABSTRACT FROM AUTHOR]

Sphingolipids, as members of the large lipid family, are important components of plasma membrane. Sphingolipids participate in biological signal transduction to regulate various important physiological processes such as cell growth, apoptosis, senescence, and differentiation. Numerous studies have demonstrated that sphingolipids are strongly associated with glucose metabolism and insulin resistance. Insulin resistance, including peripheral insulin resistance and brain insulin resistance, is closely related to the occurrence and development of many metabolic diseases. In addition to metabolic diseases, like type 2 diabetes, brain insulin resistance is also involved in the progression of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the specific mechanism of sphingolipids in brain insulin resistance has not been systematically summarized. This article reviews the involvement of sphingolipids in brain insulin resistance, highlighting the role and molecular biological mechanism of sphingolipid metabolism in cognitive dysfunctions and neuropathological abnormalities of the brain. [ABSTRACT FROM AUTHOR]

Background: Cannabigerol (CBG), a non-psychotropic phytocannabinoid found in Cannabis sativa plants, has been the focus of recent studies due to its potential therapeutic properties. We proposed that by focusing on sphingolipid metabolism, which plays a critical role in insulin signaling and the development of insulin resistance, CBG may provide a novel therapeutic approach for metabolic disorders, particularly insulin resistance. Methods: In a rat model of insulin resistance induced by a high-fat, high-sucrose diet (HFHS), we aimed to elucidate the effect of intragastrically administered CBG on hepatic sphingolipid deposition and metabolism. Moreover, we also elucidated the expression of sphingolipid transporters and changes in the sphingolipid concentration in the plasma. Results: The results, surprisingly, showed a lack of changes in de novo ceramide synthesis pathway enzymes and significant enhancement in the expression of enzymes involved in ceramide catabolism, which was confirmed by changes in hepatic sphingomyelin, sphinganine, sphingosine-1-phosphate, and sphinganine-1-phosphate concentrations. Conclusions: The results suggest that CBG treatment may modulate sphingolipid metabolism in the liver and plasma, potentially protecting the liver against the development of metabolic disorders such as insulin resistance. [ABSTRACT FROM AUTHOR]

In this study, we aimed to determine whether asiatic acid (AA) exerts any therapeutic effects on rifampicin (RFP)‐ and isoniazid (INH)‐induced liver injury and elucidate the underlying mechanisms. Briefly, liver injury in mice was induced via RFP and INH administration. We investigated the effects and potential action mechanisms of AA on liver injury using transcriptomics, metabolomics and various examinations. We found that AA significantly ameliorated the pathological changes in liver tissues and decreased the transaminase activity, inflammation and oxidative stress damage. Transcriptomics revealed 147 differentially expressed genes (DEGs) between the AA and model groups that were enriched in metabolic and mitogen‐activated protein kinase (MAPK) signalling pathways. Metabolomics revealed 778 differentially expressed metabolites between the AA and model groups. Furthermore, integrated transcriptomics and metabolomics analyses revealed strong correlations between DEGs and differentially expressed metabolites and indicated that AA regulates the sphingolipid metabolism by inhibiting the expression of delta 4‐desaturase, sphingolipid 1. Experimental results confirmed that AA inhibited the MAPK signalling pathway. In summary, AA inhibits inflammation and oxidative stress damage by regulating the sphingolipid metabolism pathway and blocking the MAPK signalling pathway, thereby relieving the RFP/INH‐induced liver injury. [ABSTRACT FROM AUTHOR]

Background: Overweight (OW) and obesity have become increasingly serious public health problems worldwide. The clinical impact of washed microbiota transplantation (WMT) from healthy donors in OW patients is unclear. This study aimed to investigate the effect of WMT in OW patients. Methods: The changes in body mass index (BMI = weight (kg)/height (m)2), blood glucose, blood lipids and other indicators before and after WMT were compared. At the same time, 16S rRNA gene amplicon sequencing was performed on fecal samples of OW patients before and after transplantation. Finally, serum samples were tested for sphingolipids targeted by lipid metabolomics. Results: A total of 166 patients were included, including 52 in the OW group and 114 in the normal weight (NOW) group. For OW patients, WMT significantly improved the comprehensive efficacy of OW. In the short term (about 1 month) and medium term (about 2 months), a significant reduction in BMI was seen. At the same time, in the short term (about 1 month), liver fat attenuation (LFA), triglyceride (TG) and fasting blood glucose (FBG) were significantly reduced. In the long term (about 5 months), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), non-high-density lipoprotein (non-HDL-c), etc. were significantly reduced. WMT improved the gut microbiota of OW patients, and also had an improvement effect on OW patients by regulating sphingolipid metabolism. Conclusion: WMT had a significant improvement effect on OW patients. WMT could restore gut microbiota homeostasis and improve OW patients by regulating sphingolipid metabolism. [ABSTRACT FROM AUTHOR]

Background: Up-regulation of ceramides in pulmonary hypertension (PH), contributing to perturbations in sphingolipid homeostasis and the transition of cells to a senescence state. We assessed the safety, feasibility, and efficiency of acid ceramidase gene transfer in a rodent PH model. Methods: A model of PH was established by the combination of left pneumonectomy and injection of Sugen toxin. Magnetic resonance imaging and right heart catheterization confirmed development of PH. Animals were subjected to intratracheal administration of synthetic adeno-associated viral vector (Anc80L65) carrying the acid ceramidase (Anc80L65.AC), an empty capsid vector, or saline. Therapeutic efficacy was evaluated 8 weeks after gene delivery. Results: Hemodynamic assessment 4 weeks after PH model the development demonstrated an increase in the mean pulmonary artery pressure to 30.4 ± 2.13 mmHg versus 10.4 ± 1.65 mmHg in sham (p < 0.001), which was consistent with the definition of PH. We documented a significant increase in pulmonary vascular resistance in the saline-treated (6.79 ± 0.85 mm Hg) and empty capsid (6.94 ± 0.47 mm Hg) groups, but not in animals receiving Anc80L65.AC (4.44 ± 0.71 mm Hg, p < 0.001). Morphometric analysis demonstrated an increase in medial wall thickness in control groups in comparison to those treated with acid ceramidase. After acid ceramidase gene delivery, a significant decrease of pro-inflammatory factors, interleukins, and senescence markers was observed. Conclusion: Gene delivery of acid ceramidase provided tropism to pulmonary tissue and ameliorated vascular remodeling with right ventricular dysfunction in pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Abstract Background Icariin (ICA), an active ingredient extracted from Epimedium species, has shown promising results in the treatment of Alzheimer's disease (AD), although its potential therapeutic mechanism remains largely unknown. This study aimed to investigate the therapeutic effects and the underlying mechanisms of ICA on AD by an integrated analysis of gut microbiota, metabolomics, and network pharmacology (NP). Methods The cognitive impairment of mice was measured using the Morris Water Maze test and the pathological changes were assessed using hematoxylin and eosin staining. 16S rRNA sequencing and multi-metabolomics were performed to analyze the alterations in the gut microbiota and fecal/serum metabolism. Meanwhile, NP was used to determine the putative molecular regulation mechanism of ICA in AD treatment. Results Our results revealed that ICA intervention significantly improved cognitive dysfunction in APP/PS1 mice and typical AD pathologies in the hippocampus of the APP/PS1 mice. Moreover, the gut microbiota analysis showed that ICA administration reversed AD-induced gut microbiota dysbiosis in APP/PS1 mice by elevating the abundance of Akkermansia and reducing the abundance of Alistipe. Furthermore, the metabolomic analysis revealed that ICA reversed the AD-induced metabolic disorder via regulating the glycerophospholipid and sphingolipid metabolism, and correlation analysis revealed that glycerophospholipid and sphingolipid were closely related to Alistipe and Akkermansia. Moreover, NP indicated that ICA might regulate the sphingolipid signaling pathway via the PRKCA/TNF/TP53/AKT1/RELA/NFKB1 axis for the treatment of AD. Conclusion These findings indicated that ICA may serve as a promising therapeutic approach for AD and that the ICA-mediated protective effects were associated with the amelioration of microbiota disturbance and metabolic disorder. Graphical Abstract

Qi Wu,1,&ast; Xingxing Wu,1,&ast; Mao Wang,2,&ast; Kexin Liu,1 Yuge Li,1 Xiaoyu Ruan,1 Lin Qian,1 Lingchang Meng,3 Zhiting Sun,3 Lei Zhu,1 Jing Wu,3 Genglin Mu3 1Gastroenterology Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Ethics Committee, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 3Institute of Chinese Medicine, Nanjing University, Nanjing Drum Tower Hospital, Drum Tower Clinical Medicine College of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Wu; Genglin Mu, Nanjing Drum Tower Hospital, Drum Tower Clinical Medicine College of the Nanjing University of Chinese Medicine, 321, Zhongshan Road, Nanjing, Jiangsu, People’s Republic of China, Tel +86 13451825475, Email wujing@njucm.edu.cn; glyydwsj@163.comBackground: Baicalin is an important active flavonoid isolated from the roots of Scutellaria baicalensis (S. baicalensis), a well-known traditional Chinese herb used in treating inflammatory bowel disease (IBD). The objectives of this study were to assess the potential benefit of baicalin in experimental colitis, as well as to investigate metabolic biomarkers of experimental colitis in conjunction with network pharmacology.Methods: Using a widely utilized network pharmacology technique, baicalin’s targets and pathways were predicted. Simultaneously, experimental colitis was induced by intrarectal administration of TNBS. Histopathology examinations were performed to confirm pathological changes. Plasma samples were examined by using an untargeted metabolomics technique based on ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) to screen differential metabolites and associated metabolic pathways. Additionally, network pharmacology and integrated analysis of metabolomics were used to identify the primary targets.Results: Through network pharmacology research, tumor necrosis factor (TNF), interleukin 6 (IL6), serine/threonine-protein kinase (AKT1), and other 7 proteins were found to be the main targets of baicalin against IBD. The untargeted metabolomics results showed that 47 metabolites in glycerophospholipids and sphingolipid metabolism were involved as key pathways in the experimental colitis model group. 19 metabolites, including Sphingomyelin (SM d42:2, SM d42:1, SM d34:1), Lysophosphatidic acids (LPA 18:4), 1-Palmitoylglycerophosphocholine, and 17(18)-EpETE were demonstrated as key metabolites for baicalin to exert effects. Moreover, udp-glucose ceramide glucosyltransferase (UGCG), sphingomyelin synthase 1 (SGMS1), and sphingosine kinase (SPHK1) were predicted as sphingolipids-linked targets of baicalin against experimental colitis by integrative analysis.Conclusion: Based on these results, it implies that sphingolipid metabolism and sphingolipid signaling pathway might be acted as therapeutic mechanism for baicalin against experimental colitis.Keywords: baicalin, inflammatory bowel disease, sphingolipid metabolism, metabolomics, network pharmacology, inflammation

Non-small cell lung cancer (NSCLC) is one of the main malignant tumors with high mortality and short survival time. Immunotherapy has become the standard treatment for advanced NSCLC, but it has the problems of drug resistance and low response rate. Therefore, obtaining effective biomarkers to predict and enhance immune checkpoint inhibitors (ICIs) efficacy in NSCLC is important. Sphingolipid metabolism is recently found to be closely involved in tumor immunotherapy. CERS4, an important sphingolipid metabolizing enzyme, is positively correlated with the efficacy of anti-PD-1 therapy for NSCLC. Upregulation of CERS4 expression could improve the efficacy of anti-PD-1 therapy for NSCLC. High expression of CERS4 could downregulate the expression of Rhob in tumor. Significantly, the ratio of CD4+/CD8+ T cell increased and the ratio of Tim-3+/CD8+ T cell decreased in spleen and peripheral blood cells. When Rhob was knocked out, the efficacy of PD-1 mAb treatment increased, and the frequency of Tim-3+ CD8+ T cell decreased. This finding further confirmed the role of sphingolipid metabolites in regulating the immunotherapeutic function of NSCLC. These metabolites may improve the efficacy of PD-1 mAb in NSCLC by regulating the CERS4/Rhob/Tim-3 axis. Overall, this study provided a potential and effective target for predicting and improving the efficacy of ICIs for NSCLC. It also provided a new perspective for the study on the mechanisms of ICIs resistance for NSCLC.

Accumulating evidence in several model organisms indicates that reduced sphingolipid biosynthesis promotes longevity, although underlying mechanisms remain unclear. In yeast, sphingolipid depletion induces a state resembling amino acid restriction, which we hypothesizedmight be due to altered stability ofamino acid transporters at the plasmamembrane. To test this, wemeasured surface abundance for a diverse panel of membrane proteins in the presence of myriocin, a sphingolipid biosynthesis inhibitor, in Saccharomyces cerevisiae. Unexpectedly, we found that surface levels of most proteins examined were either unaffected or increased during myriocin treatment, consistent with an observed decrease in bulk endocytosis. In contrast, sphingolipid depletion triggered selective endocytosis of the methionine transporter Mup1. Unlike methionine-induced Mup1 endocytosis, myriocin triggered Mup1 endocytosis that required the Rsp5 adaptor Art2, C-terminal lysine residues of Mup1 and the formation of K63-linked ubiquitin polymers. These findings reveal cellular adaptation to sphingolipid depletion by ubiquitin-mediated remodeling of nutrient transporter composition at the cell surface. [ABSTRACT FROM AUTHOR]

Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification, quantification, comparison, and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells. The results show that 16 significantly changed sphingolipids (including Cer, CerG1, and SPHm) were identified during viral infection. Our data confirmed previously recognized facts that viral infection led to a shift toward virus-specific sphingolipids, which is consistent with the down-regulation of genes involved in the host de novo sphingolipid biosynthesis. Moreover, we revealed the upregulation of virus-encoded homologous genes participating in de novo sphingolipids biosynthesis and virus-specific hydroxylated long chain bases (LCBs) as phytoCer, suggesting the competitive inhibition of host sphingolipid synthesis to produce the required building blocks for viral production, replication, and assembly. Additionally, Cer 40:1;2, Cer 40: 2;2 isomer, and CerG1 39:0;2, Cer 39: 0;2 as novel metabolite markers might indicate the general dysfunctions in E. huxleyi in response to viral infection. Our results show that viral infection led to a profound remodeling of host sphingolipidome, by which viruses depend on the hijacking of host sphingolipid metabolism to support the viral life cycle. [ABSTRACT FROM AUTHOR]

Background and objectives: Disease severity and prognosis of coronavirus disease 2019 (COVID-19) disease with other viral infections can be affected by the oropharyngeal microbiome. However, limited research had been carried out to uncover how these diseases are differentially affected by the oropharyngeal microbiome of the patient. Here, we aimed to explore the characteristics of the oropharyngeal microbiota of COVID-19 patients and compare them with those of patients with similar symptoms. Methods: COVID-19 was diagnosed in patients through the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Characterization of the oropharyngeal microbiome was performed by metatranscriptomic sequencing analyses of oropharyngeal swab specimens from 144 COVID-19 patients, 100 patients infected with other viruses, and 40 healthy volunteers. Results: The oropharyngeal microbiome diversity in patients with SARS-CoV-2 infection was different from that of patients with other infections. Prevotella and Aspergillus could play a role in the differentiation between patients with SARSCoV-2 infection and patients with other infections. Prevotella could also influence the prognosis of COVID-19 through a mechanism that potentially involved the sphingolipid metabolism regulation pathway. Conclusion: The oropharyngeal microbiome characterization was different between SARS-CoV-2 infection and infections caused by other viruses. Prevotella could act as a biomarker for COVID-19 diagnosis and of host immune response evaluation in SARS-CoV-2 infection. In addition, the crosstalk among Prevotella, SARS-CoV-2, and sphingolipid metabolism pathways could provide a basis for the precise diagnosis, prevention, control, and treatment of COVID-19. [ABSTRACT FROM AUTHOR]

Abstract Acute lung injury (ALI) is a respiratory disease with high morbidity and mortality rates and is the primary cause of death in children and the elderly around the world. The use of Chinese foods in the complementary and alternative treatment of ALI has attracted more and more attention. This study aimed to explore the anti‐ALI activity of Chinese functional foods Rosa roxburghii Tratt fruit polyphenols (RRTP). RRTP was administered to lipopolysaccharide‐induced ALI mice, and its protective effects were comprehensively evaluated by lung histopathological examination, wet/dry (W/D) ratio, and cytokine production. Metabolomics analysis was used to identify the differential metabolites and metabolic pathways in plasma, and molecular docking and systemic biology‐based network pharmacology assay were performed to explore the active components and potential therapeutic targets. The results indicated that RRTP significantly attenuated the severity of pathological changes and pulmonary capillary permeability. Furthermore, RRTP limited the increase in tumor necrosis factor alpha (TNF‐α), interleukin 1β (IL‐1β), and interleukin 6 (IL‐6) levels and the decrease in interleukin 10 (IL‐10) levels in ALI mice. Metabolomics studies revealed that RRTP markedly affected 19 different metabolites, three amino acid metabolism pathways, and sphingolipid metabolism. Moreover, network pharmacology identified AKT1 (AKT serine/threonine kinase 1), TP53, IL‐6, VEGFA (vascular endothelial growth factor A), and TNF (tumor necrosis factor) as the most promising target proteins, while quercetin, luteolin, and kaempferol were the core active components of RRTP. This study investigated the complex mechanisms of RRTP against ALI for the first time, and provided a foundation for the application of RRTP as a functional food, facilitating the research of nutritional food additives for the adjuvant treatment of ALI.