胆红素作为人体的一种重要内源性物质,是临床诊断黄疸的主要依据,也是肝功能的重要指标。本文在简述胆红素代谢过程、代谢动力学及代谢异常的基础上,重点对有机阴离子转运多肽(organic anion transport polypeptide.OATP)和多药耐药相...胆红素作为人体的一种重要内源性物质,是临床诊断黄疸的主要依据,也是肝功能的重要指标。本文在简述胆红素代谢过程、代谢动力学及代谢异常的基础上,重点对有机阴离子转运多肽(organic anion transport polypeptide.OATP)和多药耐药相关蛋白(multidrug-associated protein.MRP)等转运体介导的胆红素转运、PXR和CAR等核受体对UGTlAl介导的胆红素代谢调控、药物对胆红素代谢的抑制和诱导,及其与胆红素相关病症关系等方面的最新进展进行归纳和总结,为进一步研究和揭示黄疸、高胆红素血症、新生儿黄疸等胆红素相关病症的发生原因和发生机制提供参考,并为其诊断、预防和治疗提供最新科学依据。展开更多
Bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have bee...Bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have been directed to the interactions between cancer cells and the bone microenvironment,including osteoclasts,osteoblasts,and bone stromal cells.Here,we explained the mechanism of interactions between prostate cancer cells and metastasis-associated cells within the bone microenvironment and further discussed the recent advances in targeted therapy of prostate cancer bone metastasis.This review also summarized the effects of bone microenvironment on prostate cancer metastasis and the related mechanisms,and provides insights for future prostate cancer metastasis studies.展开更多
Mannan-binding lectin(MBL)plays a key role in the lectin pathway of complement activation and can influence cytokine expression.Toll-like receptor 4(TLR4)is expressed extensively and has been demonstrated to be involv...Mannan-binding lectin(MBL)plays a key role in the lectin pathway of complement activation and can influence cytokine expression.Toll-like receptor 4(TLR4)is expressed extensively and has been demonstrated to be involved in lipopolysaccharide(LPS)-induced signaling.We first sought to determine whether MBL exposure could modulate LPS-induced inflammatory cytokine secretion and nuclear factor-kB(NF-kB)activity by using the monocytoid cell line THP-1.We then investigated the possible mechanisms underlying any observed regulatory effect.Using ELISA and reverse transcriptase polymerase chain reaction(RT-PCR)analysis,we found that at both the protein andmRNAlevels,treatment withMBLsuppresses LPS-induced tumor-necrosis factor(TNF)-a and IL-12 production in THP-1 cells.An electrophoretic mobility shift assay and western blot analysis revealed that MBL treatment can inhibit LPS-induced NF-kB DNA binding and translocation in THP-1 cells.While the binding of MBL to THP-1 cells was evident at physiological calcium concentrations,this binding occurred optimally in response to supraphysiological calcium concentrations.This binding can be partly inhibited by treatment with either a soluble form of recombinant TLR4 extracellular domain or anti-TLR4 monoclonal antibody(HTA125).Activation of THP-1 cells by LPS treatment resulted in increased MBL binding.We also observed that MBL could directly bind to the extracellular domain of TLR4 in a dose-dependent manner,and this interaction could attenuate the binding of LPS to cell surfaces.Taken together,these data suggest that MBL may affect cytokine expression through modulation of LPS-/TLR-signaling pathways.These findings suggest that MBL may play an important role in both immune regulation and the signaling pathways involved in cytokine networks.展开更多
Peroxisome proliferator-activated receptors(PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes(α, β, γ, and ...Peroxisome proliferator-activated receptors(PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes(α, β, γ, and δ). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPARα and PPARγ agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPARγ agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin Ⅱ receptor blockers, should be studied.This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases.展开更多
Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea an...Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal,gastric and colonic cancer.Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome(IBS)and inflammatory bowel disease(IBD).Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors,including the nuclear receptors:farnesoid X receptor(FXR),vitamin D receptor(VDR),pregnane X receptor(PXR),and constitutive androstane receptor(CAR);and G protein-coupled receptors(GPCRs):Takeda G protein-coupled receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and muscarinic acetylcholine receptor M3(M3R).For example,various studies provided evidence demonstrating the anti-inflammatory effects of FXR and TGR5 activation in models of intestinal inflammation.In addition,the activation of TGR5 in enteric neurons was recently shown to increase colonic motility,which may lead to bile acid-induced diarrhea(BAD).Interestingly,TGR5 induces the secretion of glucagon-like peptide-1(GLP-1)from L-cells to enhance insulin secretion and modulate glucose metabolism.Because of the importance of these receptors,agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea,respectively.This review summarizes current knowledge of the functional roles of bile acid receptors in the GI tract.展开更多
Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive gen...Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.展开更多
In order to explore the functions of retinol binding protein (RBP4) in regulation of gene expression, yeast two hybrid assay and transient co-transforming were used to detect the interactions between RBP4 and nuclear ...In order to explore the functions of retinol binding protein (RBP4) in regulation of gene expression, yeast two hybrid assay and transient co-transforming were used to detect the interactions between RBP4 and nuclear receptors and the effects of over-expressed RBP4 on trans-activation functions of human estrogen receptor related receptor 1 (hERR1) and human estrogen (hER). The requirement of activation function domain-2 (AF-2) for hER to interact with RBP4 was also detected by the yeast two hybrid assay. The results show that RBP4 could interact with many nuclear receptors including mouse estrogen receptor related receptor 3 (mERR3), retinoid X receptor (RXR), glucocorticoid receptor (GR), progestin receptor (PR), and androgen receptor (AR) in yeast cells. Over-expressed RBP4 could strongly enhance the trans-activation functions of hERR1 and hER in a dose-dependent manner, respectively. RBP4 could also interact with hER in an AF-2-dependent manner.展开更多
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well ...Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.展开更多
AIM:To investigate the relationship between the mast cell density(MCD)and the context of clinicopathological parameters and expression of p185,estrogen receptor(ER), and proliferating cell nuclear antigen(PCNA)in gast...AIM:To investigate the relationship between the mast cell density(MCD)and the context of clinicopathological parameters and expression of p185,estrogen receptor(ER), and proliferating cell nuclear antigen(PCNA)in gastric carcinoma. METHODS:Mast cell,p185,ER,and PCNA were detected using immunohistochemical S-P labeling method.Mast cell was counted in tissue of gastric carcinoma and regional lymph nodes respectively,and involved lymph nodes(ILN)were examined as usual. RESULTS:MCD was significantly related to both age and depth of penetration(x^2=4.688,P<0.05 for age and x^2=9.350, P<0.01 for depth of penetration)between MCD>21/0.03 mm^2 and MCD≤21/0.03 mm^2 in 100 patients;MCD in 1-6 ILN group patients was significantly higher than that in 7-15 ILN or>15 ILN group patients(u=6.881,8.055,P<0.01); There were significant differences intergroup in positive expression rate of p185,ER and PCNA between MCD>21/ 0.03 mm^2 and MCD≤21/0.03 mm^2 in 100 patients. CONCLUSION:Mast cell may have effect on inhibiting invasive growth of tumor,especially in the aged patients; The number of mast cells,in certain degree,may predicate the number of involved lymph nodes,which is valuable for assessment of prognosis;MCD was related to the expression of p185,ER,and PCNA in gastric carcinoma.It suggests that mast cell accumulation may inhibit the proliferation and the dissemination of the gastric carcinoma. INTRODUCTION Recently,many studies have reported on the association of mast cell with various tumorst.In several malignancies,mast cell has been found to correlate with growth,penetration and prognosis of tumor.Therefore,our study was undertaken to investigate the relationship between the mast cell density (MCD)and the context of clinicopathological parameters and expression of p 185,estrogen receptor(ER),and proliferating cell nuclear antigen(PCNA)in gastric carcinoma.展开更多
Pregnane X receptor(PXR,NR 112)is a prototypical member of the nuclear receptor superfamily.PXR can be activated by both endobiotics and xenobiotics.As a key xenobiotic receptor,the cellular function of PXR is mostly ...Pregnane X receptor(PXR,NR 112)is a prototypical member of the nuclear receptor superfamily.PXR can be activated by both endobiotics and xenobiotics.As a key xenobiotic receptor,the cellular function of PXR is mostly exerted by its binding to the regulatory gene sequences in a liganddependent manner.Classical downstream target genes of PXR participate in xenobiotic responses,such as detoxification,metabolism and inflammation.Emerging evidence also implicates PXR signaling in the processes of apoptosis,cell cycle arrest,proliferation,angiogenesis and oxidative stress,which are closely related to cancer.Here,we discussed,in addition to the characterization of PXR per se,the biological function and regulatory mechanism of PXR signaling in cancer,and its potential for the targeted prevention and therapeutics.展开更多
AIM: To investigate the effect of different dietary fatty acids on hepatic inflammasome activation.METHODS: Wild-type C57BL/6 mice were fed either a high-fat diet or polyunsaturated fatty acid (PUFA)-enriched diet. Pr...AIM: To investigate the effect of different dietary fatty acids on hepatic inflammasome activation.METHODS: Wild-type C57BL/6 mice were fed either a high-fat diet or polyunsaturated fatty acid (PUFA)-enriched diet. Primary hepatocytes were treated with either saturated fatty acids (SFAs) or PUFAs as well as combined with lipopolysaccharide (LPS). The expression of NOD-like receptor protein 3 (NLRP3) inflammasome, peroxisome proliferator-activated receptor-γ and nuclear factor-kappa B (NF-κB) was determined by real-time PCR and Western blot. The activity of Caspase-1 and interleukine-1β production were measured.RESULTS: High-fat diet-induced hepatic steatosis was sufficient to induce and activate hepatic NLRP3 inflammasome. SFA palmitic acid (PA) directly activated NLRP3 inflammasome and increased sensitization to LPS-induced inflammasome activation in hepatocytes. In contrast, PUFA docosahexaenoic acid (DHA) had the potential to inhibit NLRP3 inflammasome expression in hepatocytes and partly abolished LPS-induced NLRP3 inflammasome activation. Furthermore, a high-fat diet increased but PUFA-enriched diet decreased sensitization to LPS-induced hepatic NLRP3 inflammasome activation in vivo. Moreover, PA increased but DHA decreased phosphorylated NF-κB p65 protein expression in hepatocytes.CONCLUSION: Hepatic NLRP3 inflammasome activation played an important role in the development of non-alcoholic fatty liver disease. Dietary SFAs and PUFAs oppositely regulated the activity of NLRP3 inflammasome through direct activation or inhibition of NF-κB.展开更多
文摘胆红素作为人体的一种重要内源性物质,是临床诊断黄疸的主要依据,也是肝功能的重要指标。本文在简述胆红素代谢过程、代谢动力学及代谢异常的基础上,重点对有机阴离子转运多肽(organic anion transport polypeptide.OATP)和多药耐药相关蛋白(multidrug-associated protein.MRP)等转运体介导的胆红素转运、PXR和CAR等核受体对UGTlAl介导的胆红素代谢调控、药物对胆红素代谢的抑制和诱导,及其与胆红素相关病症关系等方面的最新进展进行归纳和总结,为进一步研究和揭示黄疸、高胆红素血症、新生儿黄疸等胆红素相关病症的发生原因和发生机制提供参考,并为其诊断、预防和治疗提供最新科学依据。
基金This work was supported the National Natural Science Foundation of China(Nos.81803097 and 81602727)the Natural Science Foundation of Shandong Province(No.ZR2017QH005).
文摘Bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have been directed to the interactions between cancer cells and the bone microenvironment,including osteoclasts,osteoblasts,and bone stromal cells.Here,we explained the mechanism of interactions between prostate cancer cells and metastasis-associated cells within the bone microenvironment and further discussed the recent advances in targeted therapy of prostate cancer bone metastasis.This review also summarized the effects of bone microenvironment on prostate cancer metastasis and the related mechanisms,and provides insights for future prostate cancer metastasis studies.
基金This work was supported by the Natural Science Foundation of China(30972679).
文摘Mannan-binding lectin(MBL)plays a key role in the lectin pathway of complement activation and can influence cytokine expression.Toll-like receptor 4(TLR4)is expressed extensively and has been demonstrated to be involved in lipopolysaccharide(LPS)-induced signaling.We first sought to determine whether MBL exposure could modulate LPS-induced inflammatory cytokine secretion and nuclear factor-kB(NF-kB)activity by using the monocytoid cell line THP-1.We then investigated the possible mechanisms underlying any observed regulatory effect.Using ELISA and reverse transcriptase polymerase chain reaction(RT-PCR)analysis,we found that at both the protein andmRNAlevels,treatment withMBLsuppresses LPS-induced tumor-necrosis factor(TNF)-a and IL-12 production in THP-1 cells.An electrophoretic mobility shift assay and western blot analysis revealed that MBL treatment can inhibit LPS-induced NF-kB DNA binding and translocation in THP-1 cells.While the binding of MBL to THP-1 cells was evident at physiological calcium concentrations,this binding occurred optimally in response to supraphysiological calcium concentrations.This binding can be partly inhibited by treatment with either a soluble form of recombinant TLR4 extracellular domain or anti-TLR4 monoclonal antibody(HTA125).Activation of THP-1 cells by LPS treatment resulted in increased MBL binding.We also observed that MBL could directly bind to the extracellular domain of TLR4 in a dose-dependent manner,and this interaction could attenuate the binding of LPS to cell surfaces.Taken together,these data suggest that MBL may affect cytokine expression through modulation of LPS-/TLR-signaling pathways.These findings suggest that MBL may play an important role in both immune regulation and the signaling pathways involved in cytokine networks.
文摘Peroxisome proliferator-activated receptors(PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes(α, β, γ, and δ). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPARα and PPARγ agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPARγ agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin Ⅱ receptor blockers, should be studied.This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases.
基金The work in the authors'laboratories was supported by merit review grants from the Department of Veterans Affairs,United States(VA):BX000152(W.A.Alrefai)and BX002011(P.K.Dudeja)F30 grant DK117535(A.L.Ticho)and R01 grants:DK109709(W.A.Alrefai),DK54016(P.K.Dudeja),DK81858(P.K.Dudeja),DK92441(P.K.Dudeja),DK98170(R.K.Gill),from the USA National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health,United States.
文摘Bile acids modulate several gastrointestinal(GI)functions including electrolyte secretion and absorption,gastric emptying,and small intestinal and colonic motility.High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal,gastric and colonic cancer.Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome(IBS)and inflammatory bowel disease(IBD).Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors,including the nuclear receptors:farnesoid X receptor(FXR),vitamin D receptor(VDR),pregnane X receptor(PXR),and constitutive androstane receptor(CAR);and G protein-coupled receptors(GPCRs):Takeda G protein-coupled receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and muscarinic acetylcholine receptor M3(M3R).For example,various studies provided evidence demonstrating the anti-inflammatory effects of FXR and TGR5 activation in models of intestinal inflammation.In addition,the activation of TGR5 in enteric neurons was recently shown to increase colonic motility,which may lead to bile acid-induced diarrhea(BAD).Interestingly,TGR5 induces the secretion of glucagon-like peptide-1(GLP-1)from L-cells to enhance insulin secretion and modulate glucose metabolism.Because of the importance of these receptors,agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea,respectively.This review summarizes current knowledge of the functional roles of bile acid receptors in the GI tract.
基金Supported by Fondo per gli Investimenti della Ricerca di BaseNo.RBAP10MY35_002+1 种基金Ente Cassa di Risparmio di Firenzeand Fior Gen ONLUS to Galli A
文摘Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.
文摘In order to explore the functions of retinol binding protein (RBP4) in regulation of gene expression, yeast two hybrid assay and transient co-transforming were used to detect the interactions between RBP4 and nuclear receptors and the effects of over-expressed RBP4 on trans-activation functions of human estrogen receptor related receptor 1 (hERR1) and human estrogen (hER). The requirement of activation function domain-2 (AF-2) for hER to interact with RBP4 was also detected by the yeast two hybrid assay. The results show that RBP4 could interact with many nuclear receptors including mouse estrogen receptor related receptor 3 (mERR3), retinoid X receptor (RXR), glucocorticoid receptor (GR), progestin receptor (PR), and androgen receptor (AR) in yeast cells. Over-expressed RBP4 could strongly enhance the trans-activation functions of hERR1 and hER in a dose-dependent manner, respectively. RBP4 could also interact with hER in an AF-2-dependent manner.
基金Supported by Fondo per gli Investimenti della Ricerca di Base(FIRB)(RBAP10MY35_002)by Ente Cassa di Risparmio di Firenzeby FiorGen ONLUS to Galli A
文摘Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.
文摘AIM:To investigate the relationship between the mast cell density(MCD)and the context of clinicopathological parameters and expression of p185,estrogen receptor(ER), and proliferating cell nuclear antigen(PCNA)in gastric carcinoma. METHODS:Mast cell,p185,ER,and PCNA were detected using immunohistochemical S-P labeling method.Mast cell was counted in tissue of gastric carcinoma and regional lymph nodes respectively,and involved lymph nodes(ILN)were examined as usual. RESULTS:MCD was significantly related to both age and depth of penetration(x^2=4.688,P<0.05 for age and x^2=9.350, P<0.01 for depth of penetration)between MCD>21/0.03 mm^2 and MCD≤21/0.03 mm^2 in 100 patients;MCD in 1-6 ILN group patients was significantly higher than that in 7-15 ILN or>15 ILN group patients(u=6.881,8.055,P<0.01); There were significant differences intergroup in positive expression rate of p185,ER and PCNA between MCD>21/ 0.03 mm^2 and MCD≤21/0.03 mm^2 in 100 patients. CONCLUSION:Mast cell may have effect on inhibiting invasive growth of tumor,especially in the aged patients; The number of mast cells,in certain degree,may predicate the number of involved lymph nodes,which is valuable for assessment of prognosis;MCD was related to the expression of p185,ER,and PCNA in gastric carcinoma.It suggests that mast cell accumulation may inhibit the proliferation and the dissemination of the gastric carcinoma. INTRODUCTION Recently,many studies have reported on the association of mast cell with various tumorst.In several malignancies,mast cell has been found to correlate with growth,penetration and prognosis of tumor.Therefore,our study was undertaken to investigate the relationship between the mast cell density (MCD)and the context of clinicopathological parameters and expression of p 185,estrogen receptor(ER),and proliferating cell nuclear antigen(PCNA)in gastric carcinoma.
基金funded by the National Natural Science Foundation of China(81772972 and 81572703)Guangdong Natural Science Foundation(2015A030313449+4 种基金China)Guangdong Science and Technology Project“Public Research and Capacity Building”Special Project Fund(2014A020212285China)Department of Education,Guangdong Government under the Toptier University Development Scheme for Research and Control of Infectious Diseases(2016026,2015060,and 2015089China).
文摘Pregnane X receptor(PXR,NR 112)is a prototypical member of the nuclear receptor superfamily.PXR can be activated by both endobiotics and xenobiotics.As a key xenobiotic receptor,the cellular function of PXR is mostly exerted by its binding to the regulatory gene sequences in a liganddependent manner.Classical downstream target genes of PXR participate in xenobiotic responses,such as detoxification,metabolism and inflammation.Emerging evidence also implicates PXR signaling in the processes of apoptosis,cell cycle arrest,proliferation,angiogenesis and oxidative stress,which are closely related to cancer.Here,we discussed,in addition to the characterization of PXR per se,the biological function and regulatory mechanism of PXR signaling in cancer,and its potential for the targeted prevention and therapeutics.
基金Supported by The National Natural Science Foundation of ChinaNO.81170374 and NO.81470842 to Hua J
文摘AIM: To investigate the effect of different dietary fatty acids on hepatic inflammasome activation.METHODS: Wild-type C57BL/6 mice were fed either a high-fat diet or polyunsaturated fatty acid (PUFA)-enriched diet. Primary hepatocytes were treated with either saturated fatty acids (SFAs) or PUFAs as well as combined with lipopolysaccharide (LPS). The expression of NOD-like receptor protein 3 (NLRP3) inflammasome, peroxisome proliferator-activated receptor-γ and nuclear factor-kappa B (NF-κB) was determined by real-time PCR and Western blot. The activity of Caspase-1 and interleukine-1β production were measured.RESULTS: High-fat diet-induced hepatic steatosis was sufficient to induce and activate hepatic NLRP3 inflammasome. SFA palmitic acid (PA) directly activated NLRP3 inflammasome and increased sensitization to LPS-induced inflammasome activation in hepatocytes. In contrast, PUFA docosahexaenoic acid (DHA) had the potential to inhibit NLRP3 inflammasome expression in hepatocytes and partly abolished LPS-induced NLRP3 inflammasome activation. Furthermore, a high-fat diet increased but PUFA-enriched diet decreased sensitization to LPS-induced hepatic NLRP3 inflammasome activation in vivo. Moreover, PA increased but DHA decreased phosphorylated NF-κB p65 protein expression in hepatocytes.CONCLUSION: Hepatic NLRP3 inflammasome activation played an important role in the development of non-alcoholic fatty liver disease. Dietary SFAs and PUFAs oppositely regulated the activity of NLRP3 inflammasome through direct activation or inhibition of NF-κB.
