BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2023
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IF 3.1
Xiaomei Wu,Bin Pang,Jianwei You,Leiye Yu,Ruobing Ren,Hongyang Wang,Li Chen
Sphingosine-1-phosphate (S1P) is an active signaling metabolite synthesized by blood cells, exported into blood stream, and can trigger many downstream signaling pathways with disease implications. Understanding how S1P is transported is of great values for dissecting the function of S1P, but most existing methods for measuring S1P transporter activity use radioactive substrates or involve multiple workup steps, hindering their broader uses. In this study, we develop a workflow combining sensitive LC-MS measurement and a cell-based transporter protein system to measure the export activity of S1P transporter proteins. Our workflow demonstrated good applications in studying different S1P transporters SPNS2 and MFSD2B, WT and mutated protein, and different protein substrates. In summary, we provide a simple yet versatile workflow for measuring the export activity of S1P transporters, facilitating future studies of S1P transport mechanism and drug development.
研究领域:
生物化学
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药理学
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分子生物学
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PubMed
高影响因子
Biochemistry and Cell Biology
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2018
·Vol. 96
·期 6
·
IF 2.25
Xingcai Zhang,Yuli Cai,Wei Zhang,Xianhai Chen
Idiopathic pulmonary fibrosis is an agnogenic chronic disorder with high morbidity and low survival rate. Quercetin is a flavonoid found in a variety of herbs with anti-fibrosis function. In this study, bleomycin was employed to induce a pulmonary fibrosis mouse model. The quercetin administration ameliorated bleomycin-induced pulmonary fibrosis, evidenced by the expression level changes of hydroxyproline, fibronectin, α-smooth muscle actin, Collagen I, and Collagen III. Similar results were observed in transforming growth factor (TGF)-β-treated human embryonic lung fibroblast (HELF). The bleomycin or TGF-β administration caused the increase of sphingosine-1-phosphate (S1P) level in pulmonary tissue and HELF cells, as well as its activation-required kinase, sphingosine kinase 1 (SphK1), and its degradation enzyme, sphinogosine-1-phosphate lyase (S1PL). However, the increase of S1P, SphK1, and S1PL was attenuated by application of quercetin. In addition, the effect of quercetin on fibrosis was abolished by the ectopic expression of SphK1. The colocalization of SphK1/S1PL and fibroblast specific protein 1 (FSP1) suggested the roles of fibroblasts in pulmonary fibrosis. In summary, we demonstrated that quercetin ameliorated pulmonary fibrosis in vivo and in vitro by inhibiting SphK1/S1P signaling.
研究领域:
药理学
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肺病学
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细胞生物学
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DOI
PubMed
高影响因子
Autophagy
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2025
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IF 14.3
Minghong Leng,Fenghe Yang,Junhui Zhao,Yufei Xiong,Yiqing Zhou,Mingyang Zhao,Shi Jia,Limei Liu,Qiaoxia Zheng,Lebin Gan,Jingjing Ye,Ming Zheng
Endurance exercise triggers adaptive responses especially in slow-twitch myofibers of skeletal muscles, leading to the remodeling of myofiber structure and the mitochondrial network. However, molecular mechanisms underlying these adaptive responses, with a focus on the fiber type-specific perspective, remains largely unknown. In this study we analyzed the alterations of transcriptomics and metabolomics in distinct skeletal myofibers in response to endurance exercise. We determined that genes associated with sphingolipid metabolism, namely those encoding SPHK1, S1PR1, and S1PR2, are enriched in slow-twitch but not fast-twitch myofibers from both mouse and human skeletal muscles, and found that the SPHK1-S1PR pathway is essential for adaptive responses of slow-twitch to endurance exercise. Importantly, we demonstrate that endurance exercise causes the accumulation of ceramides on stressed mitochondria, and the mitophagic degradation of ceramides results in an increase of the sphingosine-1-phosphate (S1P) level. The elevated S1P thereby facilitates mitochondrial adaptation and enhances endurance capacity via the SPHK1-S1PR1/S1PR2 axis in slow-twitch muscles. Moreover, administration of S1P improves endurance performance in muscle atrophy mice by emulating these adaptive responses. Our findings reveal that the SPHK1-S1P-S1PR1/S1PR2 axis through mitophagic degradation of ceramides in slow-twitch myofibers is the central mediator to endurance exercise and highlight a potential therapeutic target for ameliorating muscle atrophy diseases.Abbreviations CQ: chloroquine; DMD: Duchenne muscular dystrophy; EDL: extensor digitorum longus; FCCP: carbonyl cyanide p-trifluoromethoxyphenyl hydrazone; FUNDC1: FUN14 domain containing 1; GTEx: genotype-tissue expression; MYH: myosin heavy chain; mtDNA: mitochondrial DNA; PPARGC1A/PGC-1α: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; RG: red gastrocnemius; S1P: sphingosine-1-phosphate; S1PR: sphingosine-1-phosphate receptor; Sol: soleus; SPHK1: sphingosine kinase 1; TA: tibialis anterior; WG: white gastrocnemius
研究领域:
运动生理学
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分子生物学
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代谢组学
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肌肉生物学
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DOI
PubMed
高影响因子
BME Frontiers
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2024
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IF 5
Jian Tang,Huiting Xu,Mingxi Li,Yang Liu,Fang Yang
Objective: The objective of this work is to design and fabricate a novel multifunctional nanocarrier combining thrombus-targeted imaging and ultrasound-mediated drug delivery for the theranostics of thrombotic diseases. Impact Statement: This study develops a new technology that can accurately visualize the thrombus and deliver drugs with controllable properties to diagnose and treat thrombotic diseases. Introduction: Thrombotic diseases are a serious threat to human life and health. The diagnosis and treatment of thrombotic diseases have always been a challenge. In recent years, nanomedicine has brought new ideas and new methods for the theranostics of thrombotic diseases. However, there are also many problems need to be solved, such as biosafety and stability of nanocarriers, early diagnosis, and timely treatment of thrombotic diseases, difficulty in clinical translation. Methods: The S1P@CD-PLGA-rtPA nanobubbles (NBs) were prepared by integrating sulfur hexafluoride (SF6)-loaded poly (D, L-lactide-co-glycolide) (PLGA) NBs, cyclodextrin (CD), sphingosine-1-phosphate (S1P), and recombinant tissue plasminogen activator (rtPA). Results: S1P@CD-PLGA-rtPA NBs had rapid and excellent thrombosis targeting imaging performance based on the specific interaction of S1P–S1PR1 (sphingosine-1-phosphate receptor 1). Furthermore, S1P@CD-PLGA-rtPA NBs that specifically targeting to the thrombosis regions could also respond to external ultrasound to achieve accurate and efficient delivery of rtPA to enhance the thrombolysis effectiveness and efficiency. Conclusion: This study proposes a new idea and strategy of targeting thrombus in rats via the specific interaction of S1P–S1PR1. On this basis, the acoustic response properties of bubble carriers could be fully utilized by combining thrombus-specific targeted imaging and ultrasound-mediated drug delivery for effective thrombolysis, which is expected to be applied in targeted diagnosis and treatment of thrombotic diseases in the future.
研究领域:
纳米医学
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治疗诊断学
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生物医学工程
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药学
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医学成像
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PubMed
高影响因子
Frontiers in Molecular Neuroscience
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2020
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IF 4.057
Chen Rong,Cao Xing,Luo Wenxiu,Yang Haodi,Luo Xinya,Yu Juming,Luo Jiaming
Multiple sclerosis (MS) is an inflammatory autoimmune disease affecting the central nervous system (CNS) that currently does not have any effective treatment. Experimental autoimmune encephalomyelitis (EAE) is often employed as a model to mimic the clinical manifestations of MS, mainly CNS demyelination. Coagulation is known to participate in crosstalk with inflammation and autoimmunity. We herein explored the correlation between the coagulation cascade and CNS immune diseases in vitro using primary astrocytes isolated from mice and in vivo using a mouse model of EAE. We showed that dabigatran, a clinical oral anti-coagulant drug, suppressed the thrombin-induced activation of astrocytes, and the underlying mechanisms are related to the activity of protease-activated receptor-1 (PAR-1), sphingosine-1-phosphate (S1P), and sphingosine kinases (SphKs). Importantly, dabigatran effectively recovered neurological function, reduced inflammation in the spinal cord, and prevented spinal cord demyelination caused by EAE. We suggest that dabigatran, a specific inhibitor of thrombin, antagonized the effect of thrombin in astrocytes by limiting the activation of PAR-1, in turn downregulating SphK1 and disrupting S1P receptor signaling. These findings reveal critical information about the relationship between coagulation mechanisms and CNS immune diseases and will contribute to the clinical translation and development of therapeutic strategies against MS.
研究领域:
神经科学
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免疫学
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药理学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Chanyuan Su,Hang Chen,Yuanming Yan,Beilei Li,Qin Chen,Zhaoyang Chen,Yukun Luo
Farnesol mitigates post-MI ventricular remodeling and fibrosis. • Multi-omics reveal farnesol upregulates the SPHK2/S1P pathway. • Increased S1P synthesis blunts pro-fibrotic SMAD3 signaling. • Pharmacological SPHK2 blockade in vivo reverses these benefits. • Modulating SPHK2 offers a potential post-MI therapeutic strategy. Pathological ventricular remodeling following myocardial infarction (MI) is driven by dysregulated pro-fibrotic signaling and metabolic maladaptation. This study aimed to investigate whether farnesol, an endogenous mevalonate pathway intermediate with cardioprotective properties, mitigates post-MI fibrotic remodeling by pharmacologically modulating sphingolipid metabolism. MI was induced in C57BL/6 mice via permanent coronary artery ligation, followed by daily intragastric administration of farnesol (2 mg/kg) for 14 days. Cardiac structural and functional indices, alongside inflammatory and fibrotic cascades, were evaluated. The underlying molecular mechanisms were elucidated using transcriptomic and untargeted metabolomic profiling. In vivo target validation was achieved through pharmacological blockade of sphingosine kinase 2 (SPHK2) using opaganib. Farnesol treatment significantly preserved left ventricular systolic function and attenuated interstitial fibrosis. At the cellular level, farnesol facilitated inflammatory resolution by reducing acute neutrophil infiltration and promoting reparative M2 macrophage polarization, while restraining aberrant myofibroblast activation. Multi-omics integration revealed that farnesol modulated sphingolipid metabolism by selectively upregulating SPHK2 and increasing sphingosine-1-phosphate (S1P) synthesis. Activation of the SPHK2/S1P axis subsequently attenuated pro-fibrotic signaling via transforming growth factor-beta (TGF-β)/SMAD3. Crucially, targeted in vivo inhibition of SPHK2 with opaganib substantially reversed farnesol-induced suppression of SMAD3 and its downstream cardioprotective effects. These findings suggest that farnesol confers cardioprotection against post-MI remodeling, an effect closely associated with the pharmacological upregulation of the SPHK2/S1P axis and the subsequent attenuation of TGF-β/SMAD3-mediated fibrogenesis. Together, these findings highlight crosstalk between the mevalonate and sphingolipid pathways, supporting modulation of SPHK2 as a potential therapeutic strategy for the clinical management of post-MI heart failure. Farnesol attenuates post-MI ventricular remodeling through targeted modulation of sphingolipid metabolism. By upregulating the SPHK2/S1P axis, farnesol blocks pro-fibrotic TGF-β/SMAD3 signaling and subsequent fibrotic gene transcription. This metabolic intervention facilitates inflammatory resolution, restrains myofibroblast activation, and ultimately preserves left ventricular systolic function. Download: Download high-res image (276KB) Download: Download full-size image
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高影响因子
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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2026
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IF 4.3
Zihang Yuan,Jie Wang,Haoran Zhang,Yingying Miao,Yuanyuan Chai,Anqin Li,Qianhui Tang,Qingyu Chen,Luyong Zhang,Qinwei Yu,Zhenzhou Jiang
Effective first-line treatments for cholestasis are limited, leading to poor outcomes and liver transplantation after ursodeoxycholic (UDCA)/obeticholic acid (OCA) intolerance. We investigated the role of cholangiocyte sphingosine-1-phosphate receptor 1 (S1PR1) in cholestasis pathogenesis to identify new therapeutic targets. We generated cholangiocyte-specific S1pr1 knockout mice ( S1pr1 ΔIBEC ). Cholestasis models included bile duct ligation (BDL) (14 days) and 0.5% cholic acid (CA) diet (4 months). The level of Sphingosine-1-phosphate (S1P) and its receptor, especially S1PR1 in cholangiocytes were significantly increased in both BDL or 0.5% CA diet models. Sphingosine kinase 1 (SphK1)-derived S1P from hepatic stellate cells (HSCs)/endothelial cells activated cholangiocyte S1PR1, promoting Stat3 phosphorylation and releasing interleukin-6 (IL-6)/C-C motif chemokine (CCL) 7, which remodeled the inflammatory microenvironment and exacerbated liver injury. S1PR1 deletion significantly reduced liver injury, fibrosis, and inflammation. Likewise, treatment with a specific inhibitor of cholangiocyte S1PR1, W146, slightly improved liver injury induced by BDL. The functional effect of S1PR1 in cholangiocyte was further strengthened by our design of the nanoparticle-delivered W146. This demonstrated that cholangiocytes-specific deletion of S1PR1 can alleviate liver fibrosis and injury caused by biliary obstruction or chronic cholestasis, which helps to develop S1PR1 as a target for the treatment of liver fibrosis and cholestasis.
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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 6.514
Dongdong Luo,Zhikun Guo,Xuecui Zhao,Lijuan Wu,Xiaochun Liu,Yingzhi Zhang,Yuhang Zhang,Zirong Deng,Xianjun Qu,Shuxiang Cui,Shengbiao Wan
Sphingosine-1-phosphate receptor 2 (S1PR2) has been identified as a brand-new GPCR target for designing antagonists to reverse 5-FU resistance. We herein report the structural optimization and structure-activity relationship of JTE-013 derivatives as S1PR2 antagonists. Compound 9d was the most potent S1PR2 antagonist (K D = 34.8 nM) among developed compounds. Here, compound 9d could significantly inhibit the expression of dihydropyrimidine dehydrogenase (DPD) to reverse 5-FU-resistance in HCT116 DPD and SW620/5-FU cells. Further mechanism studies demonstrated that compound 9d not only inhibited S1PR2 but also affected the transcription of S1PR2. In addition, compound 9d also showed acceptable selectivity to normal cells (NCM460). Importantly, compound 9d with suitable pharmacokinetic properties could significantly reverse 5-FU-resistance in the HCT116 DPD and SW620/5-FU xenograft models without obvious toxicity, in which the inhibition rates of 5-FU were increased from 23.97% to 65.29% and 27.23% to 60.81%, respectively. Further immunohistochemistry and western blotting analysis also demonstrated that compound 9d significantly decreases the expression of DPD in tumor and liver tissues. These results indicated that compound 9d is a promising lead compound to reverse 5-FU-resistance for colorectal cancer therapy.
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PubMed
高影响因子
Journal of Neuroinflammation
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2026
·Vol. 23
·期 1
·71
·
IF 11.5
Geng Fan,Zhao Na,Zhou Lv,Liu Xue-ting,Chen Xiu,Wang Zhi-Tian,Zhang Zhi-Jun,Ren Qing-Guo
Background Alzheimer’s disease (AD) is characterized by extracellular Aβ deposition and tau hyperphosphorylation, leading to synaptic dysfunction and cognitive decline. Mounting evidence indicates that circadian rhythm disorders are associated with increased AD risks. Growing evidence implicates the microbiota-gut-brain axis and its metabolites as critical modulators of both circadian physiology and AD pathology. However, the molecular mechanism through which circadian disturbance modulates gut-brain communication to influence AD pathogenesis remains poorly understood. Methods Core circadian clock gene expression was assessed across four AD human brain datasets, and found Cry2 to be the only gene consistently downregulated. To investigate its functional role in vivo, we established a mouse model with hippocampal-specific Cry2 knockdown. Cognitive performance, gut microbiota composition, and metabolic alterations were evaluated using the Morris water maze, 16 S rRNA sequencing, and untargeted metabolomics, respectively. Intestinal barrier integrity, blood-brain barrier function, and neuroinflammatory signaling were examined through immunohistochemistry, immunofluorescence, and Western blotting. The contribution of microbiota disturbance was tested using fecal microbiota transplantation (FMT). The involvement of sphingolipid signaling was further assessed through FMT, pharmacological modulation with the S1PR agonist FTY720, NLRP3 knockout mice, and microglial assays. Results We found that the expression of Cry2 consistently decreased in the AD group in four AD-related datasets. Then, knockdown of Cry2 in the hippocampus ( shCry2 ) caused dysbiosis of gut microbiota, intestinal barrier impairment, cognitive dysfunction and tau pathology in mice. Intriguingly, along with the disturbance in intestinal sphingolipid metabolism pathways, activation of the S1P/NLRP3/IL-1β pathway was found in the brain of shCry2 mice. Transplantation of “ shCry2 microbiota” mimicked the pathological and behavioral changes induced by hippocampal Cry2 deficiency. Administration of S1PR agonist FTY720 significantly improved cognitive impairment and decreased the expression of NLRP3 in shCry2 mice, and knockdown of Cry2 in NLRP3 −/− mice alleviated tau pathology and cognitive impairment. FTY720 and S1PR1 antagonist W146 dose-dependently modulated the expression of NLRP3 in BV2 cells. Overexpressing Cry2 in the hippocampus significantly alleviated the tau pathology and cognitive decline in APP/PS1 mice. Conclusion Hippocampal Cry2 deficiency leads to cognitive impairment through the gut-brain axis mediated S1P/NLRP3/IL-1β pathway and might provide a potential therapeutic target for AD.
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高影响因子
ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Hu You-tian,Liu Zhi-wei,Zhang Tong-hui,Ma Yu-e,He Lei,Zhang Jie,Zhou Yue-yang,Vidal-Puig Antonio,Pan De-jing,Wu Fang
Thymic egress is a crucial process for thymocyte maturation, strictly regulated by sphingosine-1-phosphate lyase (S1PL). Recently, cystathionine γ-lyase (CSE), one of the enzymes producing hydrogen sulfide (H 2 S), has emerged as a vital immune process regulator. However, the molecular connection between CSE, H 2 S and thymic egress remains largely unexplored. In this study, we investigated the regulatory function of CSE in the thymic egress of immune cells. We showed that genetic knockout of CSE or pharmacological inhibition by CSE enzyme inhibitor NSC4056 or D , L -propargylglycine (PAG) significantly enhanced the migration of mature lymphocytes and monocytes from the thymus to the peripheral blood, and this redistribution effect could be reversed by treatment with NaHS, an exogenous donor of H 2 S. In addition, the CSE-generated H 2 S significantly increased the levels of S1P in the peripheral blood, thymus and spleen of mice, suppressed the production of proinflammatory cytokines and rescued pathogen-induced sepsis in cells and in vivo. Notably, H 2 S or polysulfide inhibited S1PL activity in cells and an in vitro purified enzyme assay. We found that this inhibition relied on a newly identified C 203 XC 205 redox motif adjacent to the enzyme’s active site, shedding light on the biochemical mechanism of S1PL regulation. In conclusion, this study uncovers a new function and mechanism for CSE-derived H 2 S in thymic egress and provides a potential drug target for treating S1P-related immune diseases.
研究领域:
免疫学
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生物化学
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药理学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
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IF 10
Jian Tang,Yang Liu,Mingxi Li,Xiao Wang,Anning Du,Ning Gu,Fang Yang
Vascular inflammation is an early manifestation and common pathophysiological basis of numerous cardiovascular and cerebrovascular diseases. However, effective surveillance methods are lacking. In this study, sulfur hexafluoride (SF 6 )-loaded polylactic acid- co -glycolic acid (PLGA) nanobubbles (NBs) with a surface assembly of cyclodextrin (CD) and sphingosine-1-phosphate (S1P) (S1P@CD-PLGA NBs) are designed. The characterization results show that S1P@CD-PLGA NBs with diameters of ≈200 nm have good stability, biosafety, and ultrasound imaging-enhancement effects. When interacting with inflammatory vascular endothelial cells, S1P molecules encapsulated in cyclodextrin cavities exhibit a rapid, excellent, and stable targeting effect owing to their specific interaction with the highly expressed S1P receptor 1 (S1PR1) on the inflammatory vascular endothelial cells. Particularly, the S1P–S1PR1 interaction further activates the downstream signaling pathway of S1PR1 to reduce the expression of tumor necrosis factor-α (TNF-α) to protect endothelial cells. Furthermore, mouse models of carotid endothelial injuries and mesenteric thrombosis demonstrate that S1P@CD-PLGA NBs have excellent capabilities for in vivo targeting imaging. In summary, this study proposes a new strategy of using S1P to target inflammatory vascular endothelial cells while reducing the expression of TNF-α, which has the potential to be utilized in the targeted surveillance and treatment of vascular inflammatory diseases.
研究领域:
心血管疾病
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生物医学工程
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分子生物学
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诊疗学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2022
·
IF 7.129
Chao Zhao,Hu Zhang,Jingjing Zhou,Qiwei Liu,Qiang Lu,Ying Zhang,Xiaojin Yu,Shizhi Wang,Ran Liu,Yuepu Pu,Lihong Yin
Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD + in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC.
研究领域:
肿瘤学
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代谢组学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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