Given that lysophosphatidic acid（LPA） and the tetrodotoxin-resistant sodium channel Na_v1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA rece...Given that lysophosphatidic acid（LPA） and the tetrodotoxin-resistant sodium channel Na_v1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA_1（also known as EDG2） and Na_v1.8 in the dorsal root ganglion（DRG） contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in na？ve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Na_v1.8expression in L_（4-6）DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Na_v1.8expression in ipsilateral L_（4-6）DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Na_v1.8 and LPA remarkably enhanced Na_v1.8 currents in DRG neurons, and this was blocked by either a protein kinase C（PKC） inhibitor or a PKCe inhibitor. Overall, we demonstrated the modulation of Na_v1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.展开更多
AIM: To examine the expression of SphK1, an oncogenic kinase that produces sphingosine 1-phosphate (S1P), and its correlation with the expression of LPAR2, a major lysophosphatidic acid (LPA) receptor overexpressed in...AIM: To examine the expression of SphK1, an oncogenic kinase that produces sphingosine 1-phosphate (S1P), and its correlation with the expression of LPAR2, a major lysophosphatidic acid (LPA) receptor overexpressed in various cancers, in human colorectal cancer.METHODS: Real-time reverse-transcription polymerase chain reaction was used to measure the mRNA expression of SphK1, LPAR2, and the three major S1P receptors in 27 colorectal cancer samples and corresponding normal tissue samples. We also examined the correlation between the expression of SphK1 and LPAR2.RESULTS: Colorectal cancer tissue in 22 of 27 patients had higher levels of SphK1 mRNA than in normal tissue. In two-thirds of the samples, SphK1 mRNA expression was more than two-fold higher than in normal tissue. Consistent with previous reports, LPAR2 mRNA expression in 20 of 27 colorectal cancer tissue samples was higher compared to normal tissue samples. Expression profiles of all three major S1P receptors, S1PR1, S1PR2, and S1PR3, varied without any trend, with no significant difference in expression between cancer and normal tissues. A highly significant positive correlation was found between SphK1 and LPAR2 expression [Pearson’s correlation coefficient (r) = 0.784 and P < 0.01]. The mRNA levels of SphK1 and LPAR2 did not correlate with TNM stage.CONCLUSION: Our findings suggest that S1P and LPA may play important roles in the development of colorectal cancer via the upregulation of SphK1 and LPAR2, both of which could serve as new therapeutic targets in the treatment of colorectal cancer.展开更多
AIM： To study the effects of lysophosphatidic acid （LPA） on proliferation, adhesion, migration, and apoptosis in the human colon cancer cell line, SW480, and its mechanisms of action. METHODS： Methyl tetrazolium a...AIM： To study the effects of lysophosphatidic acid （LPA） on proliferation, adhesion, migration, and apoptosis in the human colon cancer cell line, SW480, and its mechanisms of action. METHODS： Methyl tetrazolium assay was used to assess cell proliferation. Flow cytometry was employed to detect cell apoptosis. Cell migration was measured by using a Boyden transweU migration chamber. Cell adhesion assay was performed in 96-well plates according to protocol. RESULTS： LPA significantly stimulated SW480 cell proliferation in a dose-dependent and timeependent manner compared with the control group （P 〈 0.05） while the mitogen-activated protein kinase （MAPK） inhibitor, PD98059, significantly blocked the LPA stimulation effect on proliferation. LPA also significantly stimulated adhesion and migration of SW480 cells in a dosedependent manner （P 〈 0.05）. Rho kinase inhibitor, Y-27632, significantly inhibited the upegulatory effect of LPA on adhesion and migration （P 〈 0.05）. LPA significantly protected cells from apoptosis induced by the chemotherapeutic drugs, cisplatin and 5-FU （P 〈 0.05）, but the phosphoinositide 3-kinase （PI3K） inhibitor, LY294002, significantly blocked the protective effect of LPA on apoptosis. CONCLUSION： LPA stimulated proliferation, adhesion,migration of 5W480 cells, and protected from apoptosis. The Ras/Raf-MAPK, G12/13-Rho-RhoA and PI3K- AKT/PKB signal pathways may be involved.展开更多
Lysophosphatidic acid(LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in submillimolar ran...Lysophosphatidic acid(LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in submillimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin(ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.展开更多
Objective: To observe the effect of Yangxueqingnao particles on rat vascular smooth muscle cell (VSMC) prolif- eration induced by lysophosphatidic acid (LPA). Methods: The amount of 3H-TdR (3H-thymidine) admixed in cu...Objective: To observe the effect of Yangxueqingnao particles on rat vascular smooth muscle cell (VSMC) prolif- eration induced by lysophosphatidic acid (LPA). Methods: The amount of 3H-TdR (3H-thymidine) admixed in cultured rat VSMC was measured and mitogen-activated protein kinase (MAPK) activity and lipid peroxidation end product malondialdehyde (MDA) content of the VSMC were assayed. Results: 1×10?9, 1×10?8, 1×10?7 mol/L LPA in a concentration dependent manner, induced the amount of 3H-TdR admixed, MAP kinase activity, and MDA content of the cultured rat VSMC to increase. However, 5%, 10%, and 15% Yangxueqingnao serum preincubation resulted in a decrease of 23.0%, 42.0%, and 52.0% (P<0.01) respectively in the amount of 3H-TdR admixed, a decline in VSMC MAP kinase activity of 13.9% (P<0.05), 29.6% (P<0.01), and 48.9% (P<0.01) respectively, and also, a decrease in MDA content of VSMC of 19.4%, 24.7%, and 43.2% (P<0.01) respectively, in the 1×10?7 mol/L LPA-treated VSMC. Conclusions: LPA activates the proliferation and lipid peroxidation of VSMC in a concentration dependent manner. The LPA-induced VSMC proliferation is related to the activity of MAP kinases, enzymes involved in an intracellular signalling pathway. The results of the present study showed that Yangxueqingnao particles can effectively inhibit LPA-induced VSMC proliferation, MAP kinase activation, and reduce lipid peroxidative lesion.展开更多
AIM： To examine whether lysophosphatidic acid （LPA） induces phosphorylation of c-Met and epidermal growth factor receptor （EGFR）, both of which have been proposed as prognostic markers of colorectal cancer, and w...AIM： To examine whether lysophosphatidic acid （LPA） induces phosphorylation of c-Met and epidermal growth factor receptor （EGFR）, both of which have been proposed as prognostic markers of colorectal cancer, and whether LPA induces cyclooxygenase-2 （COX-2） expression in human colon cancer cells. METHODS： Using a human colon cancer cell line, LoVo cells, we performed immunoprecipitation analysis, followed by Western blot analysis. We also examined whether LPA induced COX-2 expression, by Western blot analysis. RESULTS： Immunoprecipitation analysis revealed that 10 μmol/L LPA induced tyrosine phosphorylation of c-Met and EGFR in LoVo cells within a few minutes. We found that c-Met tyrosine phosphorylation induced by LPA was not attenuated by pertussis toxin or a matrix metalloproteinase inhibitor, in marked contrast to the results for EGFR. In addition, 0.2-40 IJmol/L LPA induced COX-2 expression in a dose-dependent manner. CONCLUSION： Our results suggest that LPA acts upstream of various receptor tyrosine kinases （RTKs） and COX-2, and thus may act as a potent stimulator of colorectal cancer. 2005 The WJG Press and Elsevier Inc. All rights reserved.展开更多
Cancer is a predominant culprit behind worldwide death and accounts for up to 10 million deaths every year.Chemotherapy is the primary therapeutic method employed for cancer in clinical settings and is essential in co...Cancer is a predominant culprit behind worldwide death and accounts for up to 10 million deaths every year.Chemotherapy is the primary therapeutic method employed for cancer in clinical settings and is essential in controlling tumor progression.Despite the advances in this field,tumor invasion and metastasis during treatment remain a significant cause of treatment failure.Nevertheless,the underlying mechanisms involving such a disappointing phenomenon are still not fully elucidated.Vinorelbine(VNB)extends the lifespan of many cancer patients in the clinic as an emerging chemotherapy drug approved by Food and Drug Administration(FDA).However,VNB-induced tumor metastasis is still an intractable problem,which may be closely related to the abnormal oxidative stress generated during VNB-mediated treatment.Hence,the study aims to construct a reductive nanosystem loaded with VNB,called VNB-VNP,to improve cancer cure rates and reduce tumor metastasis.With the reductive component vitamin E,VNB-VNP can effectively reduce oxidative stress and significantly outperform free VNB in preventing tumor progression.The transcriptome analysis shows that VNB-VNP can alleviate the over-expression of ectonucleotide pyrophosphatase/phosphodiesterase 2(ENPP2),which may be the main reason why VNB-VNP can inhibit tumor invasion and metastasis.Overall,the research designs a new platform for VNB treatment,which demonstrates promising efficacy in inhibiting neoplastic progression and identifies a new mechanism associated with VNB-induced tumor metastasis,which may offer several valuable references for enhancing chemotherapy efficacy in clinical anti-tumor therapy.展开更多
Activated fibroblasts are major mediators of pulmonary fibrosis.Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix(ECM)in the lung interstitial sectio...Activated fibroblasts are major mediators of pulmonary fibrosis.Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix(ECM)in the lung interstitial section.Therefore,fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis(IPF).Here,we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1(LPA_(1))and the inflammatory pathway through tumor necrosis factorα-induced protein 3(TNFAIP3,also known as A20)in fibroblasts.First,we synthesized a series of LPA_(1) antagonists,AM095 and AM966,derived amino lipids(LA lipids)which were formulated into LA-lipid nanoparticles(LA-LNPs)encapsulating mRNA.Specifically,LA5-LNPs,with AM966 head group and biodegradable acetal lipid tails,showed efficient A20 mRNA delivery to lung fibroblasts in vitro(80.2%±1.5%)and ex vivo(17.2%±0.4%).When treated to primary mouse lung fibroblasts(MLF),this formulation inhibited fibroblast migration and collagen production,thereby slowing the progression of IPF.Overall,LA5-LNPs encapsulated with A20 mRNA is a novel platform offering a potential approach to regulate fibroblast activation for the treatment of IPF.展开更多
Despite their potential applications in future regenerative medicine, periodontal ligament stem cells(PDLSCs) are difficult to obtain in large amounts from patients. Therefore, maintaining sternness while expanding th...Despite their potential applications in future regenerative medicine, periodontal ligament stem cells(PDLSCs) are difficult to obtain in large amounts from patients. Therefore, maintaining sternness while expanding the cell numbers for medical use is the key to transitioning PDLSCs from the bench to the clinic. Lysophosphatidic acid(LPA), which is present in the human body and saliva, is a signaling molecule derived from phospholipids. In this study, we examined the effects of LPA on sternness maintenance in human PDLSCs. Several spindle-shaped and fibroblast-like periodontal ligament stem-like cell lines were established from PDLSC isolation. Among these cell lines, the most morphologically appropriate cell line was characterized. The expression levels of OCT4, NANOG(a stem cell marker), and CD90(a mesenchymal stem cell marker) were high. However, CD73(a negative marker of mesenchymal stem cells) expression was not observed. Notably, immunofluorescence analysis identified the expression of STRO-1, CD146(a mesenchymal stem cell marker), and sex determining region Y-box 2 at the protein level. In addition, lipid droplets were stained by Oil red O after the induction of adipogenesis for 21 days, and mineralized nodules were stained by Alizarin Red S after the induction of osteogenesis for 14 days. Alkaline phosphate staining also demonstrated the occurrence of osteogenesis. In summary, we established a human PDLSC line, which could be applied as a cell source for tissue regeneration in dental patients. However, further studies are needed to determine the detailed effects of LPA on PDLSCs.展开更多
Background Diarrhea is a common clinical feature of ulcerative colitis resulting from unbalanced intestinal fluid and salt absorption and secretion.The Cl-/HCO3-exchanger SLC26A3 is strongly expressed in the mid-dista...Background Diarrhea is a common clinical feature of ulcerative colitis resulting from unbalanced intestinal fluid and salt absorption and secretion.The Cl-/HCO3-exchanger SLC26A3 is strongly expressed in the mid-distal colon and plays an essential role in colonic Cl-absorption and HCO3-secretion.Sic26a3 expression is up-regulated by lysophosphatidic acid （LPA） in vitro.Our study was designed to investigate the effects of LPA on SLC26A3 expression and the diarrheal phenotype in a mouse colitis model.Methods Colitis was induced in C57BL/6 mice by adding 4％ of dextran sodium sulfate （DSS） to the drinking water.The mice were assigned to LPA treatment DSS group,phosphate-buffered saline （PBS） treatment DSS group,DSS only group and untreated mice with a completely randomized design.Diarrhea severity was evaluated by measuring mice weight,disease activity index （DAI）,stool water content and macroscopic evaluation of colonic damage.The effect of LPA treatment on Sic26a3 mRNA level and protein expression in the different groups of mice was investigated by quantitative PCR and Western blotting.Results All mice treated with DSS lost weight,but the onset and severity of weight loss was attenuated in the LPA treatment DSS group.The increases in stool water content and the macroscopic inflammation score in LPA treatment DSS group were significantly lower compared to DSS control group or PBS treatment DSS group （（18.89±8.67）％ vs.（28.97±6.95）％ or （29.48±6.71）％,P=0.049,P=0.041,respectively and 2.67±0.81 vs.4.5±0.83 or 4.5±0.54,P=0.020,P=0.006,respectively）,as well as the increase in DAI （P=0.004,P=0.008,respectively）.LPA enema resulted in higher Slc26a3 mRNA and protein expression levels compared to PBS-treated and untreated DSS colitis mice.Conclusion LPA increases Slc26a3 expression in the inflamed intestine and reduces diarrhea severity in DSS-induced colitis,suggesting LPA might be a therapeutic strategy in the treatment of colitis associated diarrhea.展开更多
Rho-associated protein kinase is an essential regulator of cytoskeletal dynamics during the process of neurite extension. However, whether Rho kinase regulates microtubule remodeling or the distri- bution of adhesive ...Rho-associated protein kinase is an essential regulator of cytoskeletal dynamics during the process of neurite extension. However, whether Rho kinase regulates microtubule remodeling or the distri- bution of adhesive proteins to mediate neurite outgrowth remains unclear. By specifically modulat- ing Rho kinase activity with pharmacological agents, we studied the morpho-dynamics of neurite outgrowth. We found that lysophosphatidic acid, an activator of Rho kinase, inhibited neurite out- growth, which could be reversed by Y-27632, an inhibitor of Rho kinase. Meanwhile, reorganization of microtubules was noticed during these processes, as indicated by their significant changes in the soma and growth cone. In addition, exposure to lysophosphatidic acid led to a decreased mem- brane distribution of vinculin, a focal adhesion protein in neurons, whereas Y-27632 recruited vin- culin to the membrane. Taken together, our data suggest that Rho kinase regulates rat hippocampal neurite growth and microtubule formation via a mechanism associated with the redistribution of vinculin.展开更多
AIM: To clarify whether Lysophosphatidic acid (LPA) activates the nuclear translocation of nuclear factor-κB (NF-κB) in pancreatic cancer. METHODS: Panc-1, a human pancreatic cancer cell line, was used throughout th...AIM: To clarify whether Lysophosphatidic acid (LPA) activates the nuclear translocation of nuclear factor-κB (NF-κB) in pancreatic cancer. METHODS: Panc-1, a human pancreatic cancer cell line, was used throughout the study. The expression of LPA receptors was confirmed by reverse-transcript polymerase chain reaction (RT-PCR). Cytosolic free calcium was measured by fluorescent calcium indicator fura-2, and the localization of NF-κB was visualized by immunofluorescent method with or without various agents, which effect cell signaling. RESULTS: Panc-1 expressed LPA receptors, LPA1, LPA2 and LPA3. LPA caused the elevation of cytosolic free calcium dose-dependently. LPA also caused the nuclear translocation of NF-κB. Cytosolic free calcium was attenuated by pertussis toxin (PTX) and U73122, an inhibitor of phospholipase C. The translocation of NF-κB was similarly attenuated by PTX and U73122, but phorbol ester, an activator of protein kinase C, alone did not translocate NF-κB. Furthermore, the translocation of NF-κB was completely blocked by Ca2+ chelator BAPTA-AM. Thapsigargin, an endoplasmic- reticulum Ca2+-ATPase pump inhibitor, also promoted the translocation of NF-κB. Staurosporine, a proteinkinase C inhibitor, attenuated translocation of NF-κB induced by LPA. CONCLUSION: These findings suggest that protein kinase C is activated endogenously in Panc-1, and protein kinase C is essential for activating NF-κB with cytosolic calcium and that LPA induces the nuclear translocation of NF-κB in Panc-1 by mobilizing cytosolic free calcium.展开更多
OBJECTIVE: To evaluate the effect of acupuncture on neuroinflammation in traumatic brain injury(TBI) rats by stimulating Yamen(GV 15), Fengfu(GV16), Baihui(GV 20), Shuigou(GV 26) and Hegu(LI 4)acupoints and to investi...OBJECTIVE: To evaluate the effect of acupuncture on neuroinflammation in traumatic brain injury(TBI) rats by stimulating Yamen(GV 15), Fengfu(GV16), Baihui(GV 20), Shuigou(GV 26) and Hegu(LI 4)acupoints and to investigate the mechanism underpinning this effect.METHODS: A TBI model was induced in SpragueDawley rats using Feeney's freefall impact method.Acupuncture to stimulate the Yamen(GV 15), Fengfu(GV 16), Baihui(GV 20), Shuigou(GV 26) and Hegu(LI 4) acupoints was performed on the TBI rats. After 3 consecutive days of acupuncture treatment, we investigated signal molecules, receptors and microglia related to neuroinflammation in brain tissue of the TBI rats and analyzed the possi-ble mechanism underlying the effect of acupuncture on neuroinflammation.RESULTS: After the acupuncture treatment, ionized calcium binding adaptor molecule 1(Iba1), a protein specific to microglia, was investigated. In the cortical layer of damaged brain tissue in TBI rats,the Iba1-positive area was 3.3% ± 0.9% in the rats that received acupuncture compared with 5.2% ±1.4% in the TBI rats that did not receive acupuncture, and the microglia were smaller with more slender protrusions in the acupuncture-treated rats.This result indicates that acupuncture can significantly reduce microglia activation in TBI rats. A possible mechanism for this effect is that acupuncture reduces the expression of autotaxin and lysophosphatidic acid. Together, these constitute the autotaxin-lysophosphatidic acid axis, which induces microglial activation in the brains of TBI rats. Acupuncture treatment may downregulate the expression of Lysophosphatidic acid(LPA) receptor(LPAR) 1 and LPAR2 on the microglial cytomembrane, which affects the microglia activation process.CONCLUSION: Acupuncture stimulating the Yamen(GV 15), Fengfu(GV 16), Baihui(GV 20),Shuigou(GV 26) and Hegu(LI 4) acupoints can effectively inhibit the development of neuroinflammation after TBI. One possible mechanism for this effect is that acupuncture downregulates LPA synthesis and affects the展开更多
In addition to its contributing role in the development of chronic liver diseases, chronic hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, particularly, cutaneous-based disorders incl...In addition to its contributing role in the development of chronic liver diseases, chronic hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, particularly, cutaneous-based disorders including those with pruritus as a symptom. Pruritus is frequently associated with the development of chronic liver diseases such as cholestasis and chronic viral infection, and the accumulation of bile acids in patients’ sera and tissues as a consequence of liver damage is considered the main cause of pruritus. In addition to their role in dietary lipid absorption, bile acids can trigger the activation of specific receptors, such as the G protein-coupled bile acid receptor (GPBA/ TGR5). These types of receptors are known to play a crucial role in the modulation of the systemic actions of bile acids. TGR5 expression in primary sensory neurons triggers the activation of the transient receptor potential vanilloid 1 (TRPV1) leading to the induction of pruritus by an unknown mechanism. Although the pathologic phenomenon of pruritus is common, there is no uniformly effective therapy available. Understanding the mechanisms regulating the occurrence of pruritus together with the conduction of large-scale clinical and evidence-based studies, may help to create a standard treatment protocol. This review focuses on the etiopathogenesis and treatment strategies of pruritus associated with chronic HCV infection.展开更多
The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis.Cell metabolism dysregulation is an important cause of tumor occurrence,development,and metastas...The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis.Cell metabolism dysregulation is an important cause of tumor occurrence,development,and metastasis.As one of the important characteristics of tumors,cell metabolism dysregulation is attracting increasing research attention.Phospholipids are an indispensable substance in the metabolism in various tumor cells.Phospholipid metabolites have become important cell signaling molecules.The pathological role of lysophosphatidic acid(LPA)in tumors was identified in the early 1990s.Currently,LPA inhibitors have entered clinical trials but are not yet used in clinical treatment.Autotaxin(ATX)has lysophospholipase D(lysoPLD)activity and can regulate LPA levels in vivo.The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors.According to our recent pre-experimental results,KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis.However,no relevant research has been reported.Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy.In this paper,the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis,their physiological functions in tumors,and their roles in gastrointestinal cancers and target therapy are reviewed.展开更多
基金supported by the National Natural Science Foundation of China (81200854)the Natural Science Foundation of Jiangxi Province, China (20122BAB215027)+1 种基金the Science Foundation of the Educational Committee of Jiangxi Province, China (GJJ12064)the International Postdoctoral Exchange Fellowship Program, China (20150062)
文摘Given that lysophosphatidic acid（LPA） and the tetrodotoxin-resistant sodium channel Na_v1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA_1（also known as EDG2） and Na_v1.8 in the dorsal root ganglion（DRG） contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in na？ve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Na_v1.8expression in L_（4-6）DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Na_v1.8expression in ipsilateral L_（4-6）DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Na_v1.8 and LPA remarkably enhanced Na_v1.8 currents in DRG neurons, and this was blocked by either a protein kinase C（PKC） inhibitor or a PKCe inhibitor. Overall, we demonstrated the modulation of Na_v1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.
基金Supported by Grant 2010 from Tokyo MetropolisJapan
文摘AIM: To examine the expression of SphK1, an oncogenic kinase that produces sphingosine 1-phosphate (S1P), and its correlation with the expression of LPAR2, a major lysophosphatidic acid (LPA) receptor overexpressed in various cancers, in human colorectal cancer.METHODS: Real-time reverse-transcription polymerase chain reaction was used to measure the mRNA expression of SphK1, LPAR2, and the three major S1P receptors in 27 colorectal cancer samples and corresponding normal tissue samples. We also examined the correlation between the expression of SphK1 and LPAR2.RESULTS: Colorectal cancer tissue in 22 of 27 patients had higher levels of SphK1 mRNA than in normal tissue. In two-thirds of the samples, SphK1 mRNA expression was more than two-fold higher than in normal tissue. Consistent with previous reports, LPAR2 mRNA expression in 20 of 27 colorectal cancer tissue samples was higher compared to normal tissue samples. Expression profiles of all three major S1P receptors, S1PR1, S1PR2, and S1PR3, varied without any trend, with no significant difference in expression between cancer and normal tissues. A highly significant positive correlation was found between SphK1 and LPAR2 expression [Pearson’s correlation coefficient (r) = 0.784 and P < 0.01]. The mRNA levels of SphK1 and LPAR2 did not correlate with TNM stage.CONCLUSION: Our findings suggest that S1P and LPA may play important roles in the development of colorectal cancer via the upregulation of SphK1 and LPAR2, both of which could serve as new therapeutic targets in the treatment of colorectal cancer.
文摘AIM： To study the effects of lysophosphatidic acid （LPA） on proliferation, adhesion, migration, and apoptosis in the human colon cancer cell line, SW480, and its mechanisms of action. METHODS： Methyl tetrazolium assay was used to assess cell proliferation. Flow cytometry was employed to detect cell apoptosis. Cell migration was measured by using a Boyden transweU migration chamber. Cell adhesion assay was performed in 96-well plates according to protocol. RESULTS： LPA significantly stimulated SW480 cell proliferation in a dose-dependent and timeependent manner compared with the control group （P 〈 0.05） while the mitogen-activated protein kinase （MAPK） inhibitor, PD98059, significantly blocked the LPA stimulation effect on proliferation. LPA also significantly stimulated adhesion and migration of SW480 cells in a dosedependent manner （P 〈 0.05）. Rho kinase inhibitor, Y-27632, significantly inhibited the upegulatory effect of LPA on adhesion and migration （P 〈 0.05）. LPA significantly protected cells from apoptosis induced by the chemotherapeutic drugs, cisplatin and 5-FU （P 〈 0.05）, but the phosphoinositide 3-kinase （PI3K） inhibitor, LY294002, significantly blocked the protective effect of LPA on apoptosis. CONCLUSION： LPA stimulated proliferation, adhesion,migration of 5W480 cells, and protected from apoptosis. The Ras/Raf-MAPK, G12/13-Rho-RhoA and PI3K- AKT/PKB signal pathways may be involved.
基金Supported by the National Natural Science Foundation of China,No.31401510
文摘Lysophosphatidic acid(LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in submillimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin(ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.
基金Project (No. 491010-W50339) supported by Chinese Traditional Medicine Administration Bureau of Zhejiang Province, China
文摘Objective: To observe the effect of Yangxueqingnao particles on rat vascular smooth muscle cell (VSMC) prolif- eration induced by lysophosphatidic acid (LPA). Methods: The amount of 3H-TdR (3H-thymidine) admixed in cultured rat VSMC was measured and mitogen-activated protein kinase (MAPK) activity and lipid peroxidation end product malondialdehyde (MDA) content of the VSMC were assayed. Results: 1×10?9, 1×10?8, 1×10?7 mol/L LPA in a concentration dependent manner, induced the amount of 3H-TdR admixed, MAP kinase activity, and MDA content of the cultured rat VSMC to increase. However, 5%, 10%, and 15% Yangxueqingnao serum preincubation resulted in a decrease of 23.0%, 42.0%, and 52.0% (P<0.01) respectively in the amount of 3H-TdR admixed, a decline in VSMC MAP kinase activity of 13.9% (P<0.05), 29.6% (P<0.01), and 48.9% (P<0.01) respectively, and also, a decrease in MDA content of VSMC of 19.4%, 24.7%, and 43.2% (P<0.01) respectively, in the 1×10?7 mol/L LPA-treated VSMC. Conclusions: LPA activates the proliferation and lipid peroxidation of VSMC in a concentration dependent manner. The LPA-induced VSMC proliferation is related to the activity of MAP kinases, enzymes involved in an intracellular signalling pathway. The results of the present study showed that Yangxueqingnao particles can effectively inhibit LPA-induced VSMC proliferation, MAP kinase activation, and reduce lipid peroxidative lesion.
基金Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a grant from the Ministry of Health, Labour and Welfare of Japan
文摘AIM： To examine whether lysophosphatidic acid （LPA） induces phosphorylation of c-Met and epidermal growth factor receptor （EGFR）, both of which have been proposed as prognostic markers of colorectal cancer, and whether LPA induces cyclooxygenase-2 （COX-2） expression in human colon cancer cells. METHODS： Using a human colon cancer cell line, LoVo cells, we performed immunoprecipitation analysis, followed by Western blot analysis. We also examined whether LPA induced COX-2 expression, by Western blot analysis. RESULTS： Immunoprecipitation analysis revealed that 10 μmol/L LPA induced tyrosine phosphorylation of c-Met and EGFR in LoVo cells within a few minutes. We found that c-Met tyrosine phosphorylation induced by LPA was not attenuated by pertussis toxin or a matrix metalloproteinase inhibitor, in marked contrast to the results for EGFR. In addition, 0.2-40 IJmol/L LPA induced COX-2 expression in a dose-dependent manner. CONCLUSION： Our results suggest that LPA acts upstream of various receptor tyrosine kinases （RTKs） and COX-2, and thus may act as a potent stimulator of colorectal cancer. 2005 The WJG Press and Elsevier Inc. All rights reserved.
基金supported by the National Natural Science Foundation of China(No.81973246)Public Welfare Project of Zhejiang Natural Science Foundation(No.GF22H308848).
文摘Cancer is a predominant culprit behind worldwide death and accounts for up to 10 million deaths every year.Chemotherapy is the primary therapeutic method employed for cancer in clinical settings and is essential in controlling tumor progression.Despite the advances in this field,tumor invasion and metastasis during treatment remain a significant cause of treatment failure.Nevertheless,the underlying mechanisms involving such a disappointing phenomenon are still not fully elucidated.Vinorelbine(VNB)extends the lifespan of many cancer patients in the clinic as an emerging chemotherapy drug approved by Food and Drug Administration(FDA).However,VNB-induced tumor metastasis is still an intractable problem,which may be closely related to the abnormal oxidative stress generated during VNB-mediated treatment.Hence,the study aims to construct a reductive nanosystem loaded with VNB,called VNB-VNP,to improve cancer cure rates and reduce tumor metastasis.With the reductive component vitamin E,VNB-VNP can effectively reduce oxidative stress and significantly outperform free VNB in preventing tumor progression.The transcriptome analysis shows that VNB-VNP can alleviate the over-expression of ectonucleotide pyrophosphatase/phosphodiesterase 2(ENPP2),which may be the main reason why VNB-VNP can inhibit tumor invasion and metastasis.Overall,the research designs a new platform for VNB treatment,which demonstrates promising efficacy in inhibiting neoplastic progression and identifies a new mechanism associated with VNB-induced tumor metastasis,which may offer several valuable references for enhancing chemotherapy efficacy in clinical anti-tumor therapy.
基金the Maximizing Investigators’Research Award(No.R35GM119679)the National Institute of General Medical Sciences(No.R35GM144117)+1 种基金the support from the Professor Sylvan G.Frank Graduate Fellowshipthe Presidential Fellowship.
文摘Activated fibroblasts are major mediators of pulmonary fibrosis.Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix(ECM)in the lung interstitial section.Therefore,fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis(IPF).Here,we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1(LPA_(1))and the inflammatory pathway through tumor necrosis factorα-induced protein 3(TNFAIP3,also known as A20)in fibroblasts.First,we synthesized a series of LPA_(1) antagonists,AM095 and AM966,derived amino lipids(LA lipids)which were formulated into LA-lipid nanoparticles(LA-LNPs)encapsulating mRNA.Specifically,LA5-LNPs,with AM966 head group and biodegradable acetal lipid tails,showed efficient A20 mRNA delivery to lung fibroblasts in vitro(80.2%±1.5%)and ex vivo(17.2%±0.4%).When treated to primary mouse lung fibroblasts(MLF),this formulation inhibited fibroblast migration and collagen production,thereby slowing the progression of IPF.Overall,LA5-LNPs encapsulated with A20 mRNA is a novel platform offering a potential approach to regulate fibroblast activation for the treatment of IPF.
基金supported,in part,by a grant from the"Korea Research Fellowship(KRF)Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science and ICT(NRF-2015HlD3A1066175)"the"NRF Grant funded by the Ministry of Science and ICT(NRF-2016RIDIAIB-03933191,NRF-2017RIA2B4002546)"+1 种基金the"Global Research and Development Center(GRDC)Program through the NRF funded by the Ministry of Science and ICT(NRF-2017KlA4A3014959)""Korea Institute of Planning and Evaluation for Technology in Food,Agriculture,Forestry and Fisheries(IPET)through Agri-Bio industry Technology Development Program,funded by Ministry of Agriculture,Food and Rural Affairs(MAFRA)(318016-5)",Republic of Korea
文摘Despite their potential applications in future regenerative medicine, periodontal ligament stem cells(PDLSCs) are difficult to obtain in large amounts from patients. Therefore, maintaining sternness while expanding the cell numbers for medical use is the key to transitioning PDLSCs from the bench to the clinic. Lysophosphatidic acid(LPA), which is present in the human body and saliva, is a signaling molecule derived from phospholipids. In this study, we examined the effects of LPA on sternness maintenance in human PDLSCs. Several spindle-shaped and fibroblast-like periodontal ligament stem-like cell lines were established from PDLSC isolation. Among these cell lines, the most morphologically appropriate cell line was characterized. The expression levels of OCT4, NANOG(a stem cell marker), and CD90(a mesenchymal stem cell marker) were high. However, CD73(a negative marker of mesenchymal stem cells) expression was not observed. Notably, immunofluorescence analysis identified the expression of STRO-1, CD146(a mesenchymal stem cell marker), and sex determining region Y-box 2 at the protein level. In addition, lipid droplets were stained by Oil red O after the induction of adipogenesis for 21 days, and mineralized nodules were stained by Alizarin Red S after the induction of osteogenesis for 14 days. Alkaline phosphate staining also demonstrated the occurrence of osteogenesis. In summary, we established a human PDLSC line, which could be applied as a cell source for tissue regeneration in dental patients. However, further studies are needed to determine the detailed effects of LPA on PDLSCs.
基金This study was supported by grants from National Natural Science Foundation of China （No. 81100264, No. 81360076, and No. 81100498）, the Hubei Provincial Health Department Foundation for Young Scholars （QJX2012-04） and the Deutsche Forschungsgemeinschaft SFB621/C9 （to US）.Acknowledgment： The authors thank the participants involved in this study and Dr. Ma Ruling for helping with data analysis.
文摘Background Diarrhea is a common clinical feature of ulcerative colitis resulting from unbalanced intestinal fluid and salt absorption and secretion.The Cl-/HCO3-exchanger SLC26A3 is strongly expressed in the mid-distal colon and plays an essential role in colonic Cl-absorption and HCO3-secretion.Sic26a3 expression is up-regulated by lysophosphatidic acid （LPA） in vitro.Our study was designed to investigate the effects of LPA on SLC26A3 expression and the diarrheal phenotype in a mouse colitis model.Methods Colitis was induced in C57BL/6 mice by adding 4％ of dextran sodium sulfate （DSS） to the drinking water.The mice were assigned to LPA treatment DSS group,phosphate-buffered saline （PBS） treatment DSS group,DSS only group and untreated mice with a completely randomized design.Diarrhea severity was evaluated by measuring mice weight,disease activity index （DAI）,stool water content and macroscopic evaluation of colonic damage.The effect of LPA treatment on Sic26a3 mRNA level and protein expression in the different groups of mice was investigated by quantitative PCR and Western blotting.Results All mice treated with DSS lost weight,but the onset and severity of weight loss was attenuated in the LPA treatment DSS group.The increases in stool water content and the macroscopic inflammation score in LPA treatment DSS group were significantly lower compared to DSS control group or PBS treatment DSS group （（18.89±8.67）％ vs.（28.97±6.95）％ or （29.48±6.71）％,P=0.049,P=0.041,respectively and 2.67±0.81 vs.4.5±0.83 or 4.5±0.54,P=0.020,P=0.006,respectively）,as well as the increase in DAI （P=0.004,P=0.008,respectively）.LPA enema resulted in higher Slc26a3 mRNA and protein expression levels compared to PBS-treated and untreated DSS colitis mice.Conclusion LPA increases Slc26a3 expression in the inflamed intestine and reduces diarrhea severity in DSS-induced colitis,suggesting LPA might be a therapeutic strategy in the treatment of colitis associated diarrhea.
基金supported by the National Natural Science Foundation of China,No.31170941the Fundamental Research Funds for the Central Universities,No.21612424the Science and Technology Planning Project of Guangdong Province,No.2010B031600102
文摘Rho-associated protein kinase is an essential regulator of cytoskeletal dynamics during the process of neurite extension. However, whether Rho kinase regulates microtubule remodeling or the distri- bution of adhesive proteins to mediate neurite outgrowth remains unclear. By specifically modulat- ing Rho kinase activity with pharmacological agents, we studied the morpho-dynamics of neurite outgrowth. We found that lysophosphatidic acid, an activator of Rho kinase, inhibited neurite out- growth, which could be reversed by Y-27632, an inhibitor of Rho kinase. Meanwhile, reorganization of microtubules was noticed during these processes, as indicated by their significant changes in the soma and growth cone. In addition, exposure to lysophosphatidic acid led to a decreased mem- brane distribution of vinculin, a focal adhesion protein in neurons, whereas Y-27632 recruited vin- culin to the membrane. Taken together, our data suggest that Rho kinase regulates rat hippocampal neurite growth and microtubule formation via a mechanism associated with the redistribution of vinculin.
基金The Research Committee of Intractable Pancreatic Diseases, provided by the Ministry of Health, Labour, and Welfare, Japan, No. 50253448
文摘AIM: To clarify whether Lysophosphatidic acid (LPA) activates the nuclear translocation of nuclear factor-κB (NF-κB) in pancreatic cancer. METHODS: Panc-1, a human pancreatic cancer cell line, was used throughout the study. The expression of LPA receptors was confirmed by reverse-transcript polymerase chain reaction (RT-PCR). Cytosolic free calcium was measured by fluorescent calcium indicator fura-2, and the localization of NF-κB was visualized by immunofluorescent method with or without various agents, which effect cell signaling. RESULTS: Panc-1 expressed LPA receptors, LPA1, LPA2 and LPA3. LPA caused the elevation of cytosolic free calcium dose-dependently. LPA also caused the nuclear translocation of NF-κB. Cytosolic free calcium was attenuated by pertussis toxin (PTX) and U73122, an inhibitor of phospholipase C. The translocation of NF-κB was similarly attenuated by PTX and U73122, but phorbol ester, an activator of protein kinase C, alone did not translocate NF-κB. Furthermore, the translocation of NF-κB was completely blocked by Ca2+ chelator BAPTA-AM. Thapsigargin, an endoplasmic- reticulum Ca2+-ATPase pump inhibitor, also promoted the translocation of NF-κB. Staurosporine, a proteinkinase C inhibitor, attenuated translocation of NF-κB induced by LPA. CONCLUSION: These findings suggest that protein kinase C is activated endogenously in Panc-1, and protein kinase C is essential for activating NF-κB with cytosolic calcium and that LPA induces the nuclear translocation of NF-κB in Panc-1 by mobilizing cytosolic free calcium.
基金Supported by the Natural Science Foundation of China(No.81704156)the Natural Science Foundation of Guangdong Province,China(No.2016A030310093,2017A030310024)+1 种基金Administration of Traditional Chinese Medicine of Guangdong Province,China(No.20161067,20181070)the Fundamental Research Funds for the Central Universities,China(No.21616318)。
文摘OBJECTIVE: To evaluate the effect of acupuncture on neuroinflammation in traumatic brain injury(TBI) rats by stimulating Yamen(GV 15), Fengfu(GV16), Baihui(GV 20), Shuigou(GV 26) and Hegu(LI 4)acupoints and to investigate the mechanism underpinning this effect.METHODS: A TBI model was induced in SpragueDawley rats using Feeney's freefall impact method.Acupuncture to stimulate the Yamen(GV 15), Fengfu(GV 16), Baihui(GV 20), Shuigou(GV 26) and Hegu(LI 4) acupoints was performed on the TBI rats. After 3 consecutive days of acupuncture treatment, we investigated signal molecules, receptors and microglia related to neuroinflammation in brain tissue of the TBI rats and analyzed the possi-ble mechanism underlying the effect of acupuncture on neuroinflammation.RESULTS: After the acupuncture treatment, ionized calcium binding adaptor molecule 1(Iba1), a protein specific to microglia, was investigated. In the cortical layer of damaged brain tissue in TBI rats,the Iba1-positive area was 3.3% ± 0.9% in the rats that received acupuncture compared with 5.2% ±1.4% in the TBI rats that did not receive acupuncture, and the microglia were smaller with more slender protrusions in the acupuncture-treated rats.This result indicates that acupuncture can significantly reduce microglia activation in TBI rats. A possible mechanism for this effect is that acupuncture reduces the expression of autotaxin and lysophosphatidic acid. Together, these constitute the autotaxin-lysophosphatidic acid axis, which induces microglial activation in the brains of TBI rats. Acupuncture treatment may downregulate the expression of Lysophosphatidic acid(LPA) receptor(LPAR) 1 and LPAR2 on the microglial cytomembrane, which affects the microglia activation process.CONCLUSION: Acupuncture stimulating the Yamen(GV 15), Fengfu(GV 16), Baihui(GV 20),Shuigou(GV 26) and Hegu(LI 4) acupoints can effectively inhibit the development of neuroinflammation after TBI. One possible mechanism for this effect is that acupuncture downregulates LPA synthesis and affects the
文摘In addition to its contributing role in the development of chronic liver diseases, chronic hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, particularly, cutaneous-based disorders including those with pruritus as a symptom. Pruritus is frequently associated with the development of chronic liver diseases such as cholestasis and chronic viral infection, and the accumulation of bile acids in patients’ sera and tissues as a consequence of liver damage is considered the main cause of pruritus. In addition to their role in dietary lipid absorption, bile acids can trigger the activation of specific receptors, such as the G protein-coupled bile acid receptor (GPBA/ TGR5). These types of receptors are known to play a crucial role in the modulation of the systemic actions of bile acids. TGR5 expression in primary sensory neurons triggers the activation of the transient receptor potential vanilloid 1 (TRPV1) leading to the induction of pruritus by an unknown mechanism. Although the pathologic phenomenon of pruritus is common, there is no uniformly effective therapy available. Understanding the mechanisms regulating the occurrence of pruritus together with the conduction of large-scale clinical and evidence-based studies, may help to create a standard treatment protocol. This review focuses on the etiopathogenesis and treatment strategies of pruritus associated with chronic HCV infection.
基金Supported by the National Natural Science Foundation of China,No.81672465the Science and Technology Program of Liaoning Province,No.2019JH8/10300080。
文摘The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis.Cell metabolism dysregulation is an important cause of tumor occurrence,development,and metastasis.As one of the important characteristics of tumors,cell metabolism dysregulation is attracting increasing research attention.Phospholipids are an indispensable substance in the metabolism in various tumor cells.Phospholipid metabolites have become important cell signaling molecules.The pathological role of lysophosphatidic acid(LPA)in tumors was identified in the early 1990s.Currently,LPA inhibitors have entered clinical trials but are not yet used in clinical treatment.Autotaxin(ATX)has lysophospholipase D(lysoPLD)activity and can regulate LPA levels in vivo.The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors.According to our recent pre-experimental results,KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis.However,no relevant research has been reported.Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy.In this paper,the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis,their physiological functions in tumors,and their roles in gastrointestinal cancers and target therapy are reviewed.
