The role of （pro）rennin receptor （PRR） in cardiomyocytes of a heart failure （HF） rat model was studied. Spontaneously hypertensive rats （SHR） with HF （SHR-HF） or not were identified by two-dimensional （2-D...The role of （pro）rennin receptor （PRR） in cardiomyocytes of a heart failure （HF） rat model was studied. Spontaneously hypertensive rats （SHR） with HF （SHR-HF） or not were identified by two-dimensional （2-D） ultrasound. Age-matched Wistar Kyoto normotensive （WKY） rats were used as controls. PRR short hair RNA （sh-RNA） was injected into the heart of SHR-HF. Simultaneously SHR and controls received the same shRNA injection into the heart. Scramble shRNA was injected into the heart as controls. The expression of PRR mRNA and protein in cardiomyocytes was detected by using real-time PCR and Western blotting respectively. The heart function was evaluated by 2-D ultrasound, including eject fraction （EF%）, fractional shortening （FS%）, left ventricle thickness （LV）, and in- ter-ventricular septal thickness （IVS）. The number of apoptotie cardiomyocytes was counted by using flow cytometry. The results showed that the mRNA and protein expression levels of PRR were signifi- cantly higher in cardiomyocytes of SHR-HF group than in those of SHR group or control group. The apoptosis of myocytes in SHR-HF group was increased as compared with SHR group or control group. After knock-down of PRR with shRNA in SHR-HF group, the apoptosis of myocytes was reduced, re- sulting in the improved heart function. It was suggested that down-regulation of PRR might protect the heart from development of HF in SHR-HF by inhibiting the apoptosis of cardiomyocytes.展开更多
(Pro)renin receptor [(P)RR], a receptor for renin and prorenin, was first cloned in 2002. Since then, the pathophysiological roles of(P)RR have been growing concerns.(P)RR binds renin and prorenin, with two important ...(Pro)renin receptor [(P)RR], a receptor for renin and prorenin, was first cloned in 2002. Since then, the pathophysiological roles of(P)RR have been growing concerns.(P)RR binds renin and prorenin, with two important consequences, nonproteolytic activation of prorenin, leading to the tissue renin-angiotensin system activation and the intracellular signalings. It is now also known to play an important role as vacuolar H+-ATPase associated protein, involving in Wnt signaling, main component of embryonic development. Extracellular domain of full-length(P)RR is cleaved in golgi-complex forming soluble(P)RR [s(P)RR]. The s(P)RR is now possible to be measured in human blood and urine. It is now measured in different pathophysiological states, and recent study showed that elevated plasma s(P)RR levels in the early stage of pregnancies are associated with higher incidence of gestational diabetes mellitus later in the pregnancies. Plasma s(P)RR levels of neonates are known to be higher than that of adults. It was also shown that, increased s(P)RR concentrations in cord blood, associated with a lower small for gestational age birth likelihood. These data suggests the involvement of(P)RR in embryo's growth. In thisreview article, we attempt to figure out the possible pathophysiological roles of the(P)RR in maternal glucose intolerance and embryo's growth, through reviewing previous studies.展开更多
为探究脯氨酸(Proline,Pro)、谷氨酸(Glutamic Acid,Glu)二肽与鲜味受体分子相互作用,该研究合成了12个Pro、Glu二肽,以感官评价为基础,利用同源建模、分子对接技术研究Pro、Glu二肽与味觉受体第一家族亚型1(Taste Receptor Type 1 Memb...为探究脯氨酸(Proline,Pro)、谷氨酸(Glutamic Acid,Glu)二肽与鲜味受体分子相互作用,该研究合成了12个Pro、Glu二肽,以感官评价为基础,利用同源建模、分子对接技术研究Pro、Glu二肽与味觉受体第一家族亚型1(Taste Receptor Type 1 Member 1,T1R1)、味觉受体第一家族亚型3(Taste Receptor Type 1 Member 3,T1R3)和钙敏感受体(Calcium Sensitive Receptor,CaSR)的构效关系。结果表明:除脯氨酸-丝氨酸(Proline-serine,Pro-Ser)、缬氨酸-脯氨酸(Valine-proline,Val-Pro)和亮氨酸-谷氨酸(Leucine-glutamic Acid,Leu-Glu)不呈鲜,其余二肽的呈鲜阈值均低于谷氨酸钠阈值(0.3 mg/mL),其中γ-谷氨酸-蛋氨酸(γ-Glutamic Acid-methionine,γ-Glu-Met)和甘氨酸-谷氨酸(Glycine-glutamic Acid,Gly-Glu)的呈鲜阈值最低,为0.07 mg/mL。二肽与T1R1的关键结合位点为Asp147、Thr149、Ser172和Arg277,T1R1是Glu二肽呈鲜的重要受体;与T1R3的关键结合位点为Glu45、Ser147、Val277和His278,Ser147是N-γ-Glu二肽与T1R3受体的关键结合位点;与CaSR的关键结合位点为Leu173、Asn176、Gln179、Arg220、Ser244和Asp275,Glu二肽比Pro二肽更易与CaSR受体结合。二肽与受体主要通过氢键与疏水相互作用结合,呈味较强的二肽在对接时多嵌于受体结合口袋深处;呈味较弱的二肽有的位于结合口袋较浅的位置,有的其疏水区或亲水区暴露于受体表面。该研究有助于阐明鲜味肽与鲜味受体相互作用机制,为深入研究鲜味肽呈鲜机理奠定基础。展开更多
Background： Inflammation is often linked with the progress and poor outcome of lung cancer. The understanding of the relationship between tumor-associated macrophages （TAMs） and lung cancer cells involves in the un...Background： Inflammation is often linked with the progress and poor outcome of lung cancer. The understanding of the relationship between tumor-associated macrophages （TAMs） and lung cancer cells involves in the underlying mechanism of inflammatory cytokine production. Toll-like receptors （TLRs） are engaged in promoting the production of pro-inflammatory cytokines and play an important role in tumor immunology. Methods： To investigate the mechanisms by which TAMs influence the production of pro-inflammatory cytoldnes in lung cancer cells, we established an in vitro coculture system using TAMs and human non- small cell lung cancer （NSCLC） cell line SPC-A1. Levels of interleukin （IL）-113, IL-6 and IL-8 in SPC-A1 were evaluated by RT-PCR and cytometric bead array assay after being cocultured with TAMs. Expression changes of TLRs and TLRs signaling pathway proteins in SPC-Al were further confirmed by RT-PCR and western blot. The level changes of IL-1β, IL-6 and IL-8 in SPC-Al were also detected after the stimulation of TLRs agonists. Results： We found that the phenotype markers of TAMs were highly expressed after stimulating human monocyte cell line THP-1 by phorbol-12-myristate-β-acetate （PMA）. Higher mRNA and supernate secretion levels of IL-1β, IL-6 and IL-8 were detected in SPC-A1 after being eocultured with TAMs. We also found that TLR1, TLR6 and TLR7 were up-regulated in SPC-A1 in the coculture system with TAMs. Meanwhile, TLRs signaling pathway proteins were also significantly activated. Moreover, pre-treatment with agonist ligands for TLR1, TLR6 and TLR7 could dramatically promote inductions of IL-1β, IL-6 and IL-8. Conclusions： These findings demonstrated that TAMs may enhance IL-1β, IL-6 and IL-8 expressions via TLRs signaling pathway. We conclude that TAMs contribute to maintain the inflammation microenvironment and ultimately promote the development and progression of lung cancer.展开更多
Objective:To investigate the expression levels and clinical prognosis of tyrosine protein kinase-7(PTK7),human epidermal growth factor receptor 2(HER-2)and minichromosome maintenance protein 5(Mcm5)in esophageal squam...Objective:To investigate the expression levels and clinical prognosis of tyrosine protein kinase-7(PTK7),human epidermal growth factor receptor 2(HER-2)and minichromosome maintenance protein 5(Mcm5)in esophageal squamous cell carcinoma(ESCC)value.Methods:180 patients with ESCC were enrolled as the study subjects.Tumor tissues were collected and 100 paracancerous tissues were randomly collected.The expression levels of PTK7,HER-2 and Mcm5 proteins were detected by immunohistochemical staining,and their clinical pathological features and prognosis.Relationship.Results:The positive rates of PTK7,HER-2 and Mcm5 in ESCC tissues were significantly higher than those in adjacent tissues(P<0.05).The positive rate of PTK7 in lymphatic metastasis was significantly higher than that in lymphatic metastasis(P<0.05).The tumor body diameter was greater than 2 cm,the TNM stage was stage III and IV,and the HER-2 positive rate of ESCC tissues with lymphatic metastasis was significantly increased(P<0.05).The positive rate of Mcm5 in stage III and IV and combined lymphatic metastasis ESCC was higher in TNM stage(P<0.05).The expression level of PTK7 in ESCC tissues was positively correlated with lymphatic metastasis(P<0.05).HER-2 was positively correlated with TNM stage and lymphatic metastasis(P<0.05).Mcm5 was positively correlated with tumor size,TNM stage and lymphatic metastasis(P<0.05).The tumor-free survival of PTK7,HER-2,and Mcm5-positive ESCC patients was significantly shorter than that of the negative group(P<0.05).Conclusion:The expression levels of PTK7,HER-2,and Mcm5 were significantly up-regulated in ESCC tissues,and high levels of HER-2 and Mcm5 predicted more severe pathological stage and lymphatic metastasis,and PTK7,HER-2,Mcm5 and worse.Prognosis is related.展开更多
Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyeliti...Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed an only partial inhibition of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting that down-regulation of lymphocytic S1P1 is insufficient to explain the therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial fibrillary acidic protein, an activation marker of astrocytes, in the CNS of EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was higher as compared with those of the other S1P receptor subtypes and phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes. S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly and treatment with FTY720-P or SEW2871 inhibited production of these pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by astrocytes. Consequently, it is highly probable that the therapeutic effects of FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th cells from the draining lymph nodes but also activation of astrocytes in the CNS.展开更多
文摘The role of （pro）rennin receptor （PRR） in cardiomyocytes of a heart failure （HF） rat model was studied. Spontaneously hypertensive rats （SHR） with HF （SHR-HF） or not were identified by two-dimensional （2-D） ultrasound. Age-matched Wistar Kyoto normotensive （WKY） rats were used as controls. PRR short hair RNA （sh-RNA） was injected into the heart of SHR-HF. Simultaneously SHR and controls received the same shRNA injection into the heart. Scramble shRNA was injected into the heart as controls. The expression of PRR mRNA and protein in cardiomyocytes was detected by using real-time PCR and Western blotting respectively. The heart function was evaluated by 2-D ultrasound, including eject fraction （EF%）, fractional shortening （FS%）, left ventricle thickness （LV）, and in- ter-ventricular septal thickness （IVS）. The number of apoptotie cardiomyocytes was counted by using flow cytometry. The results showed that the mRNA and protein expression levels of PRR were signifi- cantly higher in cardiomyocytes of SHR-HF group than in those of SHR group or control group. The apoptosis of myocytes in SHR-HF group was increased as compared with SHR group or control group. After knock-down of PRR with shRNA in SHR-HF group, the apoptosis of myocytes was reduced, re- sulting in the improved heart function. It was suggested that down-regulation of PRR might protect the heart from development of HF in SHR-HF by inhibiting the apoptosis of cardiomyocytes.
文摘(Pro)renin receptor [(P)RR], a receptor for renin and prorenin, was first cloned in 2002. Since then, the pathophysiological roles of(P)RR have been growing concerns.(P)RR binds renin and prorenin, with two important consequences, nonproteolytic activation of prorenin, leading to the tissue renin-angiotensin system activation and the intracellular signalings. It is now also known to play an important role as vacuolar H+-ATPase associated protein, involving in Wnt signaling, main component of embryonic development. Extracellular domain of full-length(P)RR is cleaved in golgi-complex forming soluble(P)RR [s(P)RR]. The s(P)RR is now possible to be measured in human blood and urine. It is now measured in different pathophysiological states, and recent study showed that elevated plasma s(P)RR levels in the early stage of pregnancies are associated with higher incidence of gestational diabetes mellitus later in the pregnancies. Plasma s(P)RR levels of neonates are known to be higher than that of adults. It was also shown that, increased s(P)RR concentrations in cord blood, associated with a lower small for gestational age birth likelihood. These data suggests the involvement of(P)RR in embryo's growth. In thisreview article, we attempt to figure out the possible pathophysiological roles of the(P)RR in maternal glucose intolerance and embryo's growth, through reviewing previous studies.
文摘为探究脯氨酸(Proline,Pro)、谷氨酸(Glutamic Acid,Glu)二肽与鲜味受体分子相互作用,该研究合成了12个Pro、Glu二肽,以感官评价为基础,利用同源建模、分子对接技术研究Pro、Glu二肽与味觉受体第一家族亚型1(Taste Receptor Type 1 Member 1,T1R1)、味觉受体第一家族亚型3(Taste Receptor Type 1 Member 3,T1R3)和钙敏感受体(Calcium Sensitive Receptor,CaSR)的构效关系。结果表明:除脯氨酸-丝氨酸(Proline-serine,Pro-Ser)、缬氨酸-脯氨酸(Valine-proline,Val-Pro)和亮氨酸-谷氨酸(Leucine-glutamic Acid,Leu-Glu)不呈鲜,其余二肽的呈鲜阈值均低于谷氨酸钠阈值(0.3 mg/mL),其中γ-谷氨酸-蛋氨酸(γ-Glutamic Acid-methionine,γ-Glu-Met)和甘氨酸-谷氨酸(Glycine-glutamic Acid,Gly-Glu)的呈鲜阈值最低,为0.07 mg/mL。二肽与T1R1的关键结合位点为Asp147、Thr149、Ser172和Arg277,T1R1是Glu二肽呈鲜的重要受体;与T1R3的关键结合位点为Glu45、Ser147、Val277和His278,Ser147是N-γ-Glu二肽与T1R3受体的关键结合位点;与CaSR的关键结合位点为Leu173、Asn176、Gln179、Arg220、Ser244和Asp275,Glu二肽比Pro二肽更易与CaSR受体结合。二肽与受体主要通过氢键与疏水相互作用结合,呈味较强的二肽在对接时多嵌于受体结合口袋深处;呈味较弱的二肽有的位于结合口袋较浅的位置,有的其疏水区或亲水区暴露于受体表面。该研究有助于阐明鲜味肽与鲜味受体相互作用机制,为深入研究鲜味肽呈鲜机理奠定基础。
基金the technical support from National Key Clinical Department of Laboratory Medicine of Jiangsu Province Hospitalsupported by National Natural Science Foundation of China(No. 81272324,81371894)+1 种基金Key Laboratory for Medicine of Jiangsu Province of China(No.XK201114)project funded by the Priority Academic Program Development ofJiangsu Higher Education Institutions
文摘Background： Inflammation is often linked with the progress and poor outcome of lung cancer. The understanding of the relationship between tumor-associated macrophages （TAMs） and lung cancer cells involves in the underlying mechanism of inflammatory cytokine production. Toll-like receptors （TLRs） are engaged in promoting the production of pro-inflammatory cytokines and play an important role in tumor immunology. Methods： To investigate the mechanisms by which TAMs influence the production of pro-inflammatory cytoldnes in lung cancer cells, we established an in vitro coculture system using TAMs and human non- small cell lung cancer （NSCLC） cell line SPC-A1. Levels of interleukin （IL）-113, IL-6 and IL-8 in SPC-A1 were evaluated by RT-PCR and cytometric bead array assay after being cocultured with TAMs. Expression changes of TLRs and TLRs signaling pathway proteins in SPC-Al were further confirmed by RT-PCR and western blot. The level changes of IL-1β, IL-6 and IL-8 in SPC-Al were also detected after the stimulation of TLRs agonists. Results： We found that the phenotype markers of TAMs were highly expressed after stimulating human monocyte cell line THP-1 by phorbol-12-myristate-β-acetate （PMA）. Higher mRNA and supernate secretion levels of IL-1β, IL-6 and IL-8 were detected in SPC-A1 after being eocultured with TAMs. We also found that TLR1, TLR6 and TLR7 were up-regulated in SPC-A1 in the coculture system with TAMs. Meanwhile, TLRs signaling pathway proteins were also significantly activated. Moreover, pre-treatment with agonist ligands for TLR1, TLR6 and TLR7 could dramatically promote inductions of IL-1β, IL-6 and IL-8. Conclusions： These findings demonstrated that TAMs may enhance IL-1β, IL-6 and IL-8 expressions via TLRs signaling pathway. We conclude that TAMs contribute to maintain the inflammation microenvironment and ultimately promote the development and progression of lung cancer.
基金Subject of Nanchong Science and Technology Bureau.Project No:18SXHZ0381.
文摘Objective:To investigate the expression levels and clinical prognosis of tyrosine protein kinase-7(PTK7),human epidermal growth factor receptor 2(HER-2)and minichromosome maintenance protein 5(Mcm5)in esophageal squamous cell carcinoma(ESCC)value.Methods:180 patients with ESCC were enrolled as the study subjects.Tumor tissues were collected and 100 paracancerous tissues were randomly collected.The expression levels of PTK7,HER-2 and Mcm5 proteins were detected by immunohistochemical staining,and their clinical pathological features and prognosis.Relationship.Results:The positive rates of PTK7,HER-2 and Mcm5 in ESCC tissues were significantly higher than those in adjacent tissues(P<0.05).The positive rate of PTK7 in lymphatic metastasis was significantly higher than that in lymphatic metastasis(P<0.05).The tumor body diameter was greater than 2 cm,the TNM stage was stage III and IV,and the HER-2 positive rate of ESCC tissues with lymphatic metastasis was significantly increased(P<0.05).The positive rate of Mcm5 in stage III and IV and combined lymphatic metastasis ESCC was higher in TNM stage(P<0.05).The expression level of PTK7 in ESCC tissues was positively correlated with lymphatic metastasis(P<0.05).HER-2 was positively correlated with TNM stage and lymphatic metastasis(P<0.05).Mcm5 was positively correlated with tumor size,TNM stage and lymphatic metastasis(P<0.05).The tumor-free survival of PTK7,HER-2,and Mcm5-positive ESCC patients was significantly shorter than that of the negative group(P<0.05).Conclusion:The expression levels of PTK7,HER-2,and Mcm5 were significantly up-regulated in ESCC tissues,and high levels of HER-2 and Mcm5 predicted more severe pathological stage and lymphatic metastasis,and PTK7,HER-2,Mcm5 and worse.Prognosis is related.
文摘Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed an only partial inhibition of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting that down-regulation of lymphocytic S1P1 is insufficient to explain the therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial fibrillary acidic protein, an activation marker of astrocytes, in the CNS of EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was higher as compared with those of the other S1P receptor subtypes and phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes. S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly and treatment with FTY720-P or SEW2871 inhibited production of these pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by astrocytes. Consequently, it is highly probable that the therapeutic effects of FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th cells from the draining lymph nodes but also activation of astrocytes in the CNS.
