Biochemistry and Cell Biology
·
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
Journal of Natural Medicines
·
2017
·Vol. 72
·期 2
·390-398
·
IF 1.982
Lu Jianrao,Yi Yang,Pan Ronghua,Zhang Chuanfu,Han Haiyan,Chen Jie,Liu Wenrui
Renal ischemia reperfusion injury (RIRI) refers to the irreversible damage for renal function when blood perfusion is recovered after ischemia for an extended period, which is common in clinical surgeries and has been regarded as a major risk for acute renal failures (ARF) that is accompanied with unimaginably high morbidity and mortality. Hypoxia during ischemia followed by reoxygenation via reperfusion serves as a major event contributing to cell apoptosis, which has been widely accepted as the vital pathogenesis in RIRI. Preventing apoptosis in renal tubular epithelial cell has been considered as effective method for blocking RIRI. In this paper, we established a hypoxia/reoxygenation (H/R) injury model in human proximal tubular epithelial HK-2 cells. Here, we found increased SPHK1 levels in H/R injured HK-2 cells, which could be significantly down regulated after berberine treatment. Berberine has been reported to exert a protective effect on H/R-induced apoptosis of HK-2 cells. So, in our present study, we planned to investigate whether SPHK1 participated in the anti-apoptosis process of berberine in H/R injured HK-2 cells. Our study confirmed the protective effect of berberine against H/R-induced apoptosis in HK-2 cells through promoting cells viability, inhibiting cells apoptosis, and down-regulating p-P38, caspase-3, caspase-9 as well as SPHK1, while up regulating the ratio of Bcl-2/Bax. However, SPHK1 overexpression in HK-2 cells induced severe apoptosis, which can be significantly ameliorated with additional berberine treatment. We concluded that berberine could remarkably prevent H/R-induced apoptosis in HK-2 cells through down-regulating SPHK1 expression levels, and the mechanisms included the suppression of p38 MAPK activation and mitochondrial stress pathways.
研究领域:
肾病学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
Autophagy
·
2025
·
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
JOURNAL OF CHEMICAL RESEARCH
·
2022
·
IF 1.097
Tiandi Ding,HaiJiao Chen,Yan Li,Ying Li,Ying Zhi,Zhiqiang Qu,Qiang Sun,Qingqiang Yao,Bo Liu
Sphingosine kinase is a lipid kinase that catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate. Sphingosine-1-phosphate is a bioactive lipid that regulates biological processes. The overexpression of sphingosine kinases is related to a variety of pathophysiological conditions. For example, SphK1 has been shown to be highly expressed in various cancer cells including ovarian, cervical, colon, stomach, lung, and brain cancer. Inhibition of sphingosine kinases is a promising way to treat diseases such as cancer. Through computer-aided drug design, we have discovered a new SphK1 inhibitor named Amb30572637 (SAMS10). In this report, we describe the discovery process and biological characteristics. In biochemical experiments, SAMS10 shows a prominent inhibitory effect on SphK1, with an IC50 value of 9.8 μM. Subsequent MTT experiments show that SAMS10 has anticancer effects toward A549, SKVO3, A375, and LOVO cell lines and has essentially no cytotoxicity against the healthy cell L929. SAMS10 has significant inhibitory activity against the A549 and LOVO cell lines, with IC50 values of 14.64 and 14.48 μM, respectively. It belongs to a moderately active SphK1 inhibitor with lower anticancer activity than the control compound cisplatin, but the effect of SAMS10 toward SphK1 and its anticancer activity indicate that it is a promising lead compound for the development of effective SphK1 anticancer inhibitors.
研究领域:
药理学
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癌症研究
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药物发现
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生物化学
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分子生物学
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DOI
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2026
·
IF 3.5
Pingping Bai,Zhuhua Wu,Yan Qiao,Xinran Nie,Gege Niu,Yan Zhang,Xiaohan Yang,Li Wei,Yong Qi
Sitosterol-Beta alleviated hypoxia and SU5416-induced pulmonary hypertension in mice. • Sitosterol-Beta suppressed excessive proliferation and migration of pulmonary artery smooth muscle cells. • Sitosterol-Beta inhibited SPHK1 expression and S1P production in pulmonary artery smooth muscle cells. • Sitosterol-Beta blocked S1P-mediated inflammation in macrophages. Pulmonary hypertension (PH) is an irreversible and life-threatening disease, characterized by sustainedly elevated pulmonary arterial pressure. The excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) and perivascular inflammation are primary pathological features. Sitosterol-Beta is a phytosterol with extensive anti-inflammatory roles. This study aims to investigate the effects of Sitosterol-Beta on PH. In our study, the PH was induced in mouse by chronic hypoxia insult (10% O 2 ) and subcutaneous injection of vascular endothelial growth factor receptor inhibitor SU5416, and Sitosterol-Beta was delivered into mouse via orally taken. Mouse primary PASMCs were cultured with 1% O 2 to mimic hypoxic condition, and treated with Sitosterol-Beta. The results revealed that Sitosterol-Beta restrained PH-induced right ventricular systolic pressure increase, right ventricular hypertrophy, thickening and fibrosis of pulmonary artery, and perivascular inflammation. Sphingosine kinase 1 (SPHK1) was screened as the potential target of Sitosterol-Beta. Sitosterol-Beta inhibited SPHK1 expression and sphingosine-1-phosphate (S1P) production in lung. In vitro , Sitosterol-Beta suppressed hypoxia-induced excessive proliferation, migration and endothelial-to-mesenchymal transition of primary PASMCs, and blocked S1P-mediated inflammation in macrophages. The effects of Sitosterol-Beta on PASMCs were abrogated by overexpression of SPHK1. In conclusion, this study demonstrated that Sitosterol-Beta improved PH in mouse by targeting SPHK1, which may provide novel insights for prevention and therapy of PH. Download: Download high-res image (275KB) Download: Download full-size image
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PubMed
高影响因子
Cell Metabolism
·
2024
·
IF 27.7
Xiaoqian Ji,Zihao Chen,Qiyuan Wang,Bin Li,Yan Wei,Yun Li,Jianqing Lin,Weisheng Cheng,Yijie Guo,Shilin Wu,Longkun Mao,Yuzhou Xiang,Tian Lan,Shanshan Gu,Meng Wei,Joe Z. Zhang,Lan Jiang,Jia Wang,Jin Xu,Nan Cao
Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.
研究领域:
心血管生物学
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再生医学
·
分子生物学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Yanhong Bu,Hong Wu,Ran Deng,Yan Wang,Peirong Gan,Xintong Dong,Jiangtao Ke
Angiogenesis driven by aerobic glycolysis in endothelial cells sustains rheumatoid arthritis (RA) progression. Geniposide (GE), an iridoid ether extracted from the Rubiaceae plant Gardenia jasminoides J. Ellis, has shown anti-angiogenic potential in experimental arthritis. However, its role in metabolic regulation of angiogenesis remains unclear. The purpose was to explore the roles of GE on metabolism in angiogenesis and potential mechanisms. Adjuvant arthritis (AA) rat models and human umbilical vein endothelial cells (HUVECs) were established. Network pharmacology predicted potential targets of GE, while metabolomics analysis was conducted on RA patient serum and AA rat synovial tissue. The role of PFKFB3, a key glycolytic enzyme, was validated by gene silencing and pharmacological interventions. The signaling axis was further explored using inhibitors, agonists, and protein interaction assays. The role of the key glycolytic enzyme PFKFB3 and the upstream–downstream relationship of the signaling axis were validated through gene silencing and pharmacological intervention. GE improved angiogenesis in vivo and in vitro models, and PFKFB3 may be a potential target. Metabolomics has shown that GE significantly inhibited the elevated levels of glycolysis metabolism in arthritis rats, which may be related to the inhibition of PFKFB3 expression. PFKFB3-siRNA down-regulated angiogenesis in HUVECs, demonstrating that PFKFB3-mediated glycolysis was involved in angiogenesis. SphK1-siRNA indicated that PFKFB3 was regulated and activated by the SphK1-PI3K-AKt signal and induced a high level of glycolytic metabolism phenotype. GE intervention significantly downregulated the levels of glycolysis metabolism in arthritis models by inhibiting the SphK1-PI3K-AKt-PFKFB3 signal. The SphK1-PI3K-Akt-PFKB3 signal is the metabolic mechanism of the natural product active ingredient GE in anti-angiogenesis, revealing the important role of glycolytic metabolism in RA angiogenesis. This provides new insights into metabolic regulation in RA treatment and potential therapeutic strategies for metabolic targeted interventions.
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PubMed
高影响因子
Chinese Journal of Natural Medicines
·
2020
·
IF 2.014
Li YAO,Yu-Xia YANG,Hui CAO,Huan-Huan REN,Zheng NIU,Ling SHI
Osthole is observed to have the capacity to treat pulmonary arterial hypertension (PAH) in rats, but molecular mechanism is still unknown. The present study aims to discover therapeutic targets and explore therapeutic mechanism of osthole against PAH from metabolic perspective. A rat model with PAH was successfully established with MCT, following osthole administration, then untargeted metabolomics assay was performed using UPLC-Q-TOF-MS to identify differential metabolites and associated metabolic pathways, at last mechanism investigation was done by qRT-PCR, Western blot and ELISA. Differential metabolites characterized in rats with PAH were mostly assigned to sphingolipid metabolism, synthesis of unsaturated fatty acids, glycolysis, nucleotide metabolism, steroid hormone biosynthesis. Furthermore, osthole reversed high level of S1P by modulating metabolic enzyme Sphk1 in rats with PAH. In addition, osthole inhibited the expression of Sphk1 by downregulating microRNA-21, phosphorylation of Akt, phosphorylation of mTOR in vivo and in vitro . These results demonstrated that metabolomics is a promising approach to discover potential drug target for PAH treatment. Importantly, our findings further elucidated therapeutic mechanism of osthole, a natural product, having a role of metabolic regulator to potentially treat PAH by targeting inhibition of Sphk1/S1P via microRNA-21-PI3K/Akt/mTOR signal pathway. Altogether, this discovery paves a critical foundation for enabling osthole to be a candidate compound to treat PAH.
研究领域:
药理学
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心血管疾病
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代谢紊乱
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产品关联
DOI
PubMed
高影响因子
Science China-Life Sciences
·
2026
·
IF 9.5
Wu Di,Zhao Xinhui,Pu Yajing,Lu Qianwen,Shui Jiulei,Chen Yichu,Yang Kang,Yang Bangyi,Li Gaoxiang,Zhou Hong,Zhou Meng
Graft-versus-host disease (GVHD) remains a major challenge in successful allogeneic hematopoietic stem cell transplantation. Here, we report that inhibiting sphingosine kinase 1 (SPHK1), an enzyme that phosphorylates sphingosine to bioactive sphingosine-1-phosphate (S1P), effectively ameliorates acute GVHD (aGVHD) without compromising the graft-versus-leukemia effect. The absence of SPHK1 in the host exerts a beneficial effect on maintaining gut homeostasis by limiting intestinal epithelial cell (IEC) and intestinal stem cell (ISC) injury. This reduces gut permeability and prevents bacterial translocation, decreasing MHC II levels in IECs and donor T-cell infiltration. Persistent endoplasmic reticulum (ER) stress is observed during GVHD in the gastrointestinal tract and contributes to IEC injury. SPHK1 deficiency attenuates IEC damage by alleviating ER stress, which can be reversed by supplementation with exogenous S1P. FTY720, an S1P receptor antagonist, significantly inhibits ER stress-induced IEC injury. Our findings highlight the pathogenic role of host SPHK1 in gastrointestinal injury during aGVHD and suggest that targeting SPHK1 could be a therapeutic strategy for managing this condition.
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PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Jie Chen,Yuanyuan Wang,Caixin Chen,Xianshu Song,Xiuting Shen,Di Cao,Zhongxiang Zhao
Background Ilex pubescens Hook. et Arn (IP), traditionally known for its properties of promoting blood circulation, swelling and pain relief, heat clearing, and detoxification, has been used in the treatment of thromboangiitis obliterans (TAO). Despite its traditional applications, the specific mechanisms by which IP exerts its therapeutic effects on TAO remain unclear. Aim of the study This study aims to uncover the underlying mechanisms in the therapeutic effects of IP on TAO, employing network pharmacology and metabolomic approaches. Methods In this study, a rat TAO model was established by injecting sodium laurate through the femoral artery, followed by the oral administration of IP for 7 days. Plasma coagulation parameters were measured to assess the therapeutic effects of IP. The potential influence on the femoral artery and gastrocnemius muscle was histopathologically evaluated. Network pharmacology was employed to predict relevant targets and model pathways for TAO. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was used for the metabolic profile analysis of rat plasma. Immunohistochemistry (IHC) was used to verify the mechanisms by which IP promotes blood circulation in TAO. Results The study revealed that IP improved blood biochemical function in TAO and played a significant role in vascular protection and maintaining normal blood vessels and gastrocnemius morphologies. Network pharmacology showed that IP compounds play a therapeutic role in modulating lipids and atherosclerosis. Metabolomic analysis revealed that the pathways involved in sphingolipid metabolism and steroid biosynthesis were significantly disrupted. The joint analysis showed a strong correlation between lysophosphatidylcholine and IP components, including triterpenoid and iridoid components, which support the curative action of IP through the modulation of sphingolipid metabolism. Furthermore, decreased expression levels of SPHK1/S1PR1, TNF-α, IL-1β, and IL-6 were observed in the IP-treated group, suggesting that IP exerts a protective effect on the vasculature primarily by regulating of the SPHK1/S1PR1 signaling pathway. Conclusion In this study, we found that IP protects the vasculature against injury and treats TAO by regulating the steady-state disturbance of the sphingolipid pathway. These findings suggest that IP promotes vasculature by modulating sphingolipid metabolism and SPHK1/S1PR1 signaling pathway and reduce levels of inflammatory factors, offering new insights into its therapeutic potential.
研究领域:
药理学
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代谢组学
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网络生物学
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炎症
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血管生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Molecular Biosciences
·
2021
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IF 5.246
Zhou Peipei,Zhou Lin,Shi Yingying,Li Zhuolun,Liu Liwei,Zuo Lihua,Zhang Jun,Liang Shuhong,Kang Jian,Du Shuzhang,Yang Jing,Sun Zhi,Zhang Xiaojian
The incidence of cerebral ischemic stroke characterized by high mortality is increasing every year. Danshen Chuanxiongqin Injection (DSCXQ), a traditional Chinese medicine (TCM) preparation, is often applied to treat cerebral apoplexy and its related sequelae. However, there is a lack of systematic research on how DSCXQ mediates its protective effects against cerebral ischemia stroke. Metabolomic analysis based on UHPLC-Q-Orbitrap HRMS was employed to explore the potential mechanisms of DSCXQ on ischemic stroke induced by transient middle cerebral artery occlusion (MCAO). Pattern analysis and metabolomic profiling, combined by multivariate analysis disclosed that 55 differential metabolites were identified between Sham group and Model group, involving sphingolipid metabolism, glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, primary bile acid biosynthesis, pantothenate and CoA synthesis and valine, leucine and isoleucine biosynthesis pathways. DSCXQ could reverse brain metabolic deviations in stroke by significantly upregulating the levels of L-tryptophan, Lyso (18:0/0:0), LPC (18:2), Indole-3-methyl acetate, and downregulating the levels of sphinganine 1-phosphate, L-threonic acid, glutaconic acid and N6,N6,N6-Trimethyl-L-lysine. In our study, we focused on the neuroprotective effects of DSCXQ against neuroinflammatory responses and neuronal apoptosis on a stroke model based on sphingolipid metabolism. The expressions of Sphk1, S1PR1, CD62P, Bcl-2, Bax, and cleaved Caspase-3 in brain tissue were evaluated. The neurological deficit, cerebral infarct size and behavioral abnormality were estimated. Results showed that DSCXQ intervention significantly reduced cerebral infarct size, ameliorated behavioral abnormality, inhibited the expression of Sphk1, S1PR1, CD62P, Bax, Cleaved Caspase-3, while increased the level of Bcl-2, and prevented neuronal apoptosis. The limitations are that our study mainly focused on the verification of sphingolipid metabolism pathway in stroke, and while other metabolic pathways left unverified. Our study indicates that SphK1-SIP axis may potentiate neuroinflammatory responses and mediate brain damage through neuronal apoptosis, and DSCXQ could suppress the activity of SphK1-SIP axis to protect brain tissue in cerebral ischemia. In conclusion, this study facilitates our understanding of metabolic changes in ischemia stroke and the underlying mechanisms related to the clinical application of DSCXQ.
研究领域:
药理学
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神经科学
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代谢组学
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中医药
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
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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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DOI
PubMed
高影响因子
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