Objective： To explore the effects of neuregulins on ErbB2 receptor signal transduction pathway activation, and invasion and metastasis of non-overexpression ErbB2 breast cancer cell MDA-MB-231. Methods： The express...Objective： To explore the effects of neuregulins on ErbB2 receptor signal transduction pathway activation, and invasion and metastasis of non-overexpression ErbB2 breast cancer cell MDA-MB-231. Methods： The expressions of neuregulin were detected by immunocytochemistry and Western blot. MDA-MB-231 cells were treated with ErbB2 kinase inhibitor AG825. Proliferations were measured with MTT assay. Invasion and metastasis of MDA-ME-231 cells were evaluated with transwell chamber. The enzyme activities of MMP-2 and MMP-9 were detected by gelatin zymography. The expressions of MMP-2 and HIF-1α were detected by Western blot. Results： MDA-MB-231 cells expressed a relatively higher level of neuregulin. In Western blot, the positive reaction band was found at 44KD which coincides with the molecular weight of NRG. When MDA-MB-231 cells were treated with AG825, the proliferation was inhibited in a time-dose-dependent manner （P〈0.01）, invasion and metastasis were also depressed （P〈0.05）. The enzyme activities of MMP-2 and MMP-9 were lower （P〈0.05）. The expression levels of MMP-2 and HIF-lct were decreased （P〈0.05）. Conclusion： Our study indicates that neuregulins are synthesized in MDA-MB-231 cells as transmembrane proteins, neuregulins could activate ErbB2 receptor signal transduction pathway by autocrine or paracrine secretion, and induce invasion and metastasis of MDA-MB-231 cells.展开更多
Studies on ischemia/reperfusion(I/R)injury suggest that exogenous neural stem cells(NSCs)are ideal candidates for stem cell therapy reperfusion injury.However,NSCs are difficult to obtain owing to ethical limitations....Studies on ischemia/reperfusion(I/R)injury suggest that exogenous neural stem cells(NSCs)are ideal candidates for stem cell therapy reperfusion injury.However,NSCs are difficult to obtain owing to ethical limitations.In addition,the survival,differentiation,and proliferation rates of transplanted exogenous NSCs are low,which limit their clinical application.Our previous study showed that neuregulin1β(NRG1β)alleviated cerebral I/R injury in rats.In this study,we aimed to induce human umbilical cord mesenchymal stem cells into NSCs and investigate the improvement effect and mechanism of NSCs pretreated with 10 nM NRG1βon PC12 cells injured by oxygen-glucose deprivation/reoxygenation(OGD/R).Our results found that 5 and 10 nM NRG1βpromoted the generation and proliferation of NSCs.Co-culture of NSCs and PC12 cells under condition of OGD/R showed that pretreatment of NSCs with NRG1βimproved the level of reactive oxygen species,malondialdehyde,glutathione,superoxide dismutase,nicotinamide adenine dinucleotide phosphate,and nuclear factor erythroid 2-related factor 2(Nrf2)and mitochondrial damage in injured PC12 cells;these indexes are related to ferroptosis.Research has reported that p53 and solute carrier family 7 member 11(SLC7A11)play vital roles in ferroptosis caused by cerebral I/R injury.Our data show that the expression of p53 was increased and the level of glutathione peroxidase 4(GPX4)was decreased after RNA interference-mediated knockdown of SLC7A11 in PC12 cells,but this change was alleviated after co-culturing NSCs with damaged PC12 cells.These findings suggest that NSCs pretreated with NRG1βexhibited neuroprotective effects on PC12 cells subjected to OGD/R through influencing the level of ferroptosis regulated by p53/SLC7A11/GPX4 pathway.展开更多
Hollow conduits of natural or synthetic origins have shown acceptable regeneration results in short nerve gap repair;however,results are still not comparable with the current gold standard technique“autografts”.Holl...Hollow conduits of natural or synthetic origins have shown acceptable regeneration results in short nerve gap repair;however,results are still not comparable with the current gold standard technique“autografts”.Hollow conduits do not provide a successful regeneration outcome when it comes to critical nerve gap repair.Enriching the lumen of conduits with different extracellular materials and cells could provide a better biomimicry of the natural nerve regenerating environment and is expected to ameliorate the conduit performance.In this study,we evaluated nerve regeneration in vivo using hollow chitosan conduits or conduits enriched with fibrin-collagen hydrogels alone or with the further addition of adipose-derived mesenchymal stem cells in a 15 mm rat sciatic nerve transection model.Unexpected changes in the hydrogel consistency and structural stability in vivo led to a failure of nerve regeneration after 15 weeks.Nevertheless,the molecular assessment in the early regeneration phase(7,14,and 28 days)has shown an upregulation of useful regenerative genes in hydrogel enriched conduits compared with the hollow ones.Hydrogels composed of fibrin-collagen were able to upregulate the expression of soluble NRG1,a growth factor that plays an important role in Schwann cell transdifferentiation.The further enrichment with adipose-derived mesenchymal stem cells has led to the upregulation of other important genes such as ErbB2,VEGF-A,BDNF,c-Jun,and ATF3.展开更多
Neuregulin plays an important role in heart structure and function.Research discovered that recombinant neuregulin could reduce the degree of damage on myocardial cells caused by ischemia,hypoxia and viral infection.T...Neuregulin plays an important role in heart structure and function.Research discovered that recombinant neuregulin could reduce the degree of damage on myocardial cells caused by ischemia,hypoxia and viral infection.The primary structure,including N-terminal sequence,C-terminal sequence,PMF,accurate molecular mass,and disulfide bonding pattern of recombinant human neuregulin,have been identified by ESI-Q-TOF MS,Autoflex MALDI-TOF MS,9.4T Apex Q-FT MS and Ultraflex Ⅲ MALDI-TOF/TOF combining with two e]ymatic digestion.A abnormal peptide impurity in this drug was found and sequenced by Q-TOF MS and TOF/TOF MS,this is useful for the product quanlity control.展开更多
BACKGROUND： Recent studies have paid much attention to the newly found neuregulin-1, which might be closely linked to the molecular genetics of schizophrenia. OBJECTIVE： To investigate the association of neuregulin-...BACKGROUND： Recent studies have paid much attention to the newly found neuregulin-1, which might be closely linked to the molecular genetics of schizophrenia. OBJECTIVE： To investigate the association of neuregulin-related genes with schizophrenia, and to summarize the advancements in this current research. RETRIEVAL STRATEGY： Using the terms ＂neuregulins, gene, schizophrenia＂, we retrieved articles published from January 2000 to June 2007 from http：//www.ncbi.nlm.gov, http：//www.elsevier.lib.tsinghua.edu.cn, and http：//www.cjfd.cnki.net to identify studies addressing the association of neuregulin-related genes to schizophrenia. At the same time, we searched more than 10 medical journals by hand. The languages were limited to English and Chinese. Forty-two manuscripts were obtained and were firstly screened. Inclusion criteria： studies on neuregulins, schizophrenia, neuregulin-1, and the pathogenesis of schizophrenia, including randomized, blinded, and other original studies. Exclusion criteria： studies not related to schizophrenia, or repetitive studies. LITERATURE EVALUATION： The included 42 manuscripts were sorted. Twenty-one were selected as references for this article： fourteen were basic studies, and the remaining articles were case-controlled studies or other. DATA SYNTHESIS： Neuregulins are primarily expressed in the nervous system and heart, and limited expression is also seen in other tissues.. These proteins transmit signals among certain cells and play an important role in normal development of the nervous system. Neuregulin-1 is a typical neuregulin-related gene. Neuregulin genes are closely related to glutamatergic, GABAergic, and dopaminergic neurons. CONCLUSION： Neuregulin-related genes, such as neuregulin-1, are important and promising candidate genes for studying schizophrenia disease. Their roles in the onset of schizophrenia, neuregulin-related gene expression products, and correlations of ErbB receptor to schizophrenia symptoms need to be further investigated. Further studies of neuregulin-1 will hopefully provide powerful evidence for understanding the pathogenesis of schizophrenia.展开更多
C-terminal sequence is important for the function of a protein.C-terminal sequencing is necessary for structure identification of recombinant drugs.In this paper,a new method based on CNBr cleavage coupled with ESI MS...C-terminal sequence is important for the function of a protein.C-terminal sequencing is necessary for structure identification of recombinant drugs.In this paper,a new method based on CNBr cleavage coupled with ESI MS/MS was established and successfully applied to C-terminal sequence analysis of recombinant human TNFR and neuregulin.Results showed,C-terminal sequences with 19 and 11 amino acids were identified respectively.This new method was sensitive,reproducible and useful for C-terminal sequence analysis of recombinant proteins.展开更多
Neuregulin-1(NRG1)signaling through the tyrosine kinase receptors erbB2 and erbB4 is required for cardiac morphogenesis,and it plays an essential role in maintaining the myocardial architecture during adulthood.The ty...Neuregulin-1(NRG1)signaling through the tyrosine kinase receptors erbB2 and erbB4 is required for cardiac morphogenesis,and it plays an essential role in maintaining the myocardial architecture during adulthood.The tyrosine kinase receptor erbB2 was first linked to the amplification and overexpression of erbb2 gene in a subtype of breast tumor cells,which is indicative of highly proliferative cells and likely a poor prognosis following conventional chemotherapy.The development of targeted therapies to block the survival of erbB2-positive cancer cells revealed that impaired NRG1 signaling through erbB2/erbB4 heterodimers combined with anthracycline chemotherapy may lead to dilated cardiomyopathy in a subpopulation of treated patients.The ventricular-specific deletion of either erbb2 or erbb4 manifested dilated cardiomyopathy,which is aggravated by the administration of doxorubicin.Based on the exacerbated toxicity displayed by the combined treatment,it is expected that the relevant pathways would be affected in a synergistic manner.This review examines the NRG1 activities that were monitored in different model systems,focusing on the emerging pathways and molecular targets,which may aid in understanding the acquired dilated cardiomyopathy that occurs under the conditions of NRG1-deficient signaling.展开更多
Epinephrine is often used for the treatment of patients with heart failure, low cardiac output and cardiac arrest. It can acutely improve hemodynamic parameters; however, it does not seem to improve longer term clinic...Epinephrine is often used for the treatment of patients with heart failure, low cardiac output and cardiac arrest. It can acutely improve hemodynamic parameters; however, it does not seem to improve longer term clinical outcomes. Therefore, we hypothesized that epinephrine may induce unfavorable changes in gene expression of cardiomyocyte. Thus, we investigated effects of epinephrine exposure on the mediation or modulation of gene expression of cultured cardiomyocytes at a genome-wide scale. Our investigation revealed that exposure of cardiomyocytes to epinephrine in an in vitro environment can up-regulate the expression ofangiopoietin-2 gene （~ 2.1 times）, and down-regulate the gene expression of neuregulin 1 （-3.7 times）, plasminogen activator inhibitor-1 （-2.4 times） and SPARC-related modular calcium-binding protein-2 （-4.5 times）. These changes suggest that epinephrine exposure may induce inhibition of angiogenesis-related gene expressions in cultured rat cardiomyocytes. The precise clinical significance of these changes in gene expression, which was induced by epinephrine exposure, warrants further experimental and clinical investigations.展开更多
Traumatic injuries of peripheral nerves represent common casualties and their social impact is considerably high. Although peripheral nerves retain a good regeneration potential, the clinical outcome after nerve lesio...Traumatic injuries of peripheral nerves represent common casualties and their social impact is considerably high. Although peripheral nerves retain a good regeneration potential, the clinical outcome after nerve lesion is far from being satisfactory and functional recovery is almost never complete, especially in the case of large nerve defects, that result in loss or diminished sensitivity and/or motor activity of the innervated target organs. Therefore, to improve the outcome after nerve damage, or in peripheral neuropathies, there is a need for further research in nerve repair and regeneration to identify factors that promote axonal regrowth, remvelination and target reinnervation.展开更多
Objective:To study the recovery effect of neuregulin (Nrg-1) on the sciatic nerve constriction injury as well as the expression of Nrg-1 downstream signaling molecules in sciatic nerve tissue.Methods: SD rats were sel...Objective:To study the recovery effect of neuregulin (Nrg-1) on the sciatic nerve constriction injury as well as the expression of Nrg-1 downstream signaling molecules in sciatic nerve tissue.Methods: SD rats were selected as the experimental animals and divided into sham operation + saline intervention group (group A), sciatic nerve constriction model + saline intervention group (group B) and sciatic nerve constriction model + Nrg-1 intervention group (group C). 2 weeks, 4 weeks and 8 weeks after intervention, the sciatic nerve function parameters were detected;8 weeks after intervention, the levels of fibrosis molecules and Nrg-1 downstream molecules in sciatic nerve tissue were determined.Results: 2 weeks, 4 weeks and 8 weeks after intervention, sciatic nerve MCV and CMAP amplitudes of group B were significantly lower than those of group A, and the sciatic nerve MCV and CMAP amplitudes of group C were significantly higher than those of group B;8 weeks after intervention, CTGF, Col-I, Col-III, MMP2, MMP9 and PTEN levels in sciatic nerve tissue of group B were significantly higher than those of group A while ErbB, Akt and PI3K levels were significantly lower than those of group A;CTGF, Col-I, Col-III, MMP2, MMP9 and PTEN levels in sciatic nerve tissue of group C were significantly lower than those of group B while ErbB, Akt and PI3K levels were significantly higher than those of group B.Conclusion: Neuregulin can activate the PI3K/Akt to exert the recovery effect on sciatic nerve constriction injury.展开更多
Background: Hereditary spastic paraplegia (HSP) are classified clinically as pure when progressive spasticity occurs in isolation or complicated when other neurologic abnormalities are present. At least 22 genetic loc...Background: Hereditary spastic paraplegia (HSP) are classified clinically as pure when progressive spasticity occurs in isolation or complicated when other neurologic abnormalities are present. At least 22 genetic loci have been linked to HSP, 8 of which are autosomal recessive (ARHSP). HSP complicated with the presence of thin corpus callosum (HSP-TCC) is a common subtype of HSP. One genetic locus has been identified on chromosome 15q13-q15 (SPG11) for HSP-TCC, but some HSP-TCC families have not been linked to this locus. Methods: The authors characterized two families clinically and radiologically and performed a genome-wide scan and linkage analysis. Results: The two families had complicated ARHSP. The affected individuals in Family A had thin corpus callosum and mental retardation, whereas in Family B two of three affected individuals had epilepsy. In both families linkage analysis identified a locus on chromosome 8 between markers D8S1820 and D8S532 with the highest combined lod score of 7.077 at marker D8S505. This 9 cM interval located on 8p12-p11.21 represents a new locus for ARHSP-TCC. Neuregulin and KIF13B genes, located within this interval, are interesting functional candidate genes for this HSP form. Conclusion: Two consanguineous families with complicated autosomal recessive hereditary spastic paraplegia were clinically characterized and genetically mapped to a new locus on 8p12-p11.21.展开更多
文摘Objective： To explore the effects of neuregulins on ErbB2 receptor signal transduction pathway activation, and invasion and metastasis of non-overexpression ErbB2 breast cancer cell MDA-MB-231. Methods： The expressions of neuregulin were detected by immunocytochemistry and Western blot. MDA-MB-231 cells were treated with ErbB2 kinase inhibitor AG825. Proliferations were measured with MTT assay. Invasion and metastasis of MDA-ME-231 cells were evaluated with transwell chamber. The enzyme activities of MMP-2 and MMP-9 were detected by gelatin zymography. The expressions of MMP-2 and HIF-1α were detected by Western blot. Results： MDA-MB-231 cells expressed a relatively higher level of neuregulin. In Western blot, the positive reaction band was found at 44KD which coincides with the molecular weight of NRG. When MDA-MB-231 cells were treated with AG825, the proliferation was inhibited in a time-dose-dependent manner （P〈0.01）, invasion and metastasis were also depressed （P〈0.05）. The enzyme activities of MMP-2 and MMP-9 were lower （P〈0.05）. The expression levels of MMP-2 and HIF-lct were decreased （P〈0.05）. Conclusion： Our study indicates that neuregulins are synthesized in MDA-MB-231 cells as transmembrane proteins, neuregulins could activate ErbB2 receptor signal transduction pathway by autocrine or paracrine secretion, and induce invasion and metastasis of MDA-MB-231 cells.
基金supported by the National Natural Science Foundation of China,No.81973501the Natural Science Foundation of Shandong Province,No.ZR2019MH009(both to YLG).
文摘Studies on ischemia/reperfusion(I/R)injury suggest that exogenous neural stem cells(NSCs)are ideal candidates for stem cell therapy reperfusion injury.However,NSCs are difficult to obtain owing to ethical limitations.In addition,the survival,differentiation,and proliferation rates of transplanted exogenous NSCs are low,which limit their clinical application.Our previous study showed that neuregulin1β(NRG1β)alleviated cerebral I/R injury in rats.In this study,we aimed to induce human umbilical cord mesenchymal stem cells into NSCs and investigate the improvement effect and mechanism of NSCs pretreated with 10 nM NRG1βon PC12 cells injured by oxygen-glucose deprivation/reoxygenation(OGD/R).Our results found that 5 and 10 nM NRG1βpromoted the generation and proliferation of NSCs.Co-culture of NSCs and PC12 cells under condition of OGD/R showed that pretreatment of NSCs with NRG1βimproved the level of reactive oxygen species,malondialdehyde,glutathione,superoxide dismutase,nicotinamide adenine dinucleotide phosphate,and nuclear factor erythroid 2-related factor 2(Nrf2)and mitochondrial damage in injured PC12 cells;these indexes are related to ferroptosis.Research has reported that p53 and solute carrier family 7 member 11(SLC7A11)play vital roles in ferroptosis caused by cerebral I/R injury.Our data show that the expression of p53 was increased and the level of glutathione peroxidase 4(GPX4)was decreased after RNA interference-mediated knockdown of SLC7A11 in PC12 cells,but this change was alleviated after co-culturing NSCs with damaged PC12 cells.These findings suggest that NSCs pretreated with NRG1βexhibited neuroprotective effects on PC12 cells subjected to OGD/R through influencing the level of ferroptosis regulated by p53/SLC7A11/GPX4 pathway.
基金funded by the Spanish “Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, Ministerio de Economía y Competitividad (Instituto de Salud Carlos Ⅲ),grants Nos. FIS PI14-1343, FIS PI17-0393, and FIS PI20-0318 co-financed by the “Fondo Europeo de Desarrollo Regional ERDF-FEDER European Union”grant No. P18-RT-5059 by “Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020),Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Junta de Andalucía, España”grant No. A-CTS-498-UGR18 by “Programa Operativo FEDER Andalucía 2014–2020, Universidad de Granada, Junta de Andalucía, España”, co-funded by ERDF-FEDER, the European Union (all to VC)
文摘Hollow conduits of natural or synthetic origins have shown acceptable regeneration results in short nerve gap repair;however,results are still not comparable with the current gold standard technique“autografts”.Hollow conduits do not provide a successful regeneration outcome when it comes to critical nerve gap repair.Enriching the lumen of conduits with different extracellular materials and cells could provide a better biomimicry of the natural nerve regenerating environment and is expected to ameliorate the conduit performance.In this study,we evaluated nerve regeneration in vivo using hollow chitosan conduits or conduits enriched with fibrin-collagen hydrogels alone or with the further addition of adipose-derived mesenchymal stem cells in a 15 mm rat sciatic nerve transection model.Unexpected changes in the hydrogel consistency and structural stability in vivo led to a failure of nerve regeneration after 15 weeks.Nevertheless,the molecular assessment in the early regeneration phase(7,14,and 28 days)has shown an upregulation of useful regenerative genes in hydrogel enriched conduits compared with the hollow ones.Hydrogels composed of fibrin-collagen were able to upregulate the expression of soluble NRG1,a growth factor that plays an important role in Schwann cell transdifferentiation.The further enrichment with adipose-derived mesenchymal stem cells has led to the upregulation of other important genes such as ErbB2,VEGF-A,BDNF,c-Jun,and ATF3.
文摘目的建立神经调节蛋白1(Neuregulin1,NRG1)蛋白测定方法并探测阳性亚型精神分裂症患者血清NRG1蛋白水平变化。方法应用双抗体夹心法原理,以单克隆IgG NRG1抗体作为标记抗体,与该单克隆抗体抗原结合表位不同的NRG1多克隆抗体作为包被抗体,125I作为放射标记物,建立间接NRG1蛋白放射免疫测定方法,并测定33名正常对照和21例首发阳性亚型精神分裂症患者治疗前、治疗1周末、2周末、3周末和4周末血清NRG1蛋白变化。所有患者服用维思通4～6 mg/d。结果双抗体夹心法可以用于间接测定血清NRG1蛋白;患者组治疗前、治疗1周末、2周末、3周末NRG1蛋白平均每分钟计数(countings per minute,CPM)低于对照组,差异均有统计学意义(t值分别为5.33、4.61、4.24、2.86,P值均小于0.01),第4周末与对照组间差异无统计学意义(P>0.05)。患者组不同治疗时间NRG1水平的差异有统计学意义(F=6.37,P<0.001),第4周与第1周、第2周、第3周相比差异有统计意义(P<0.05),余两两差异均无统计学意义(P>0.05)。PANSS减分率与CPM的变化无明显相关(r=0.27,P=0.25)。结论阳性亚型精神分裂症患者血清NRG1蛋白水平降低,经抗精神病药物治疗后可恢复。
文摘Neuregulin plays an important role in heart structure and function.Research discovered that recombinant neuregulin could reduce the degree of damage on myocardial cells caused by ischemia,hypoxia and viral infection.The primary structure,including N-terminal sequence,C-terminal sequence,PMF,accurate molecular mass,and disulfide bonding pattern of recombinant human neuregulin,have been identified by ESI-Q-TOF MS,Autoflex MALDI-TOF MS,9.4T Apex Q-FT MS and Ultraflex Ⅲ MALDI-TOF/TOF combining with two e]ymatic digestion.A abnormal peptide impurity in this drug was found and sequenced by Q-TOF MS and TOF/TOF MS,this is useful for the product quanlity control.
文摘BACKGROUND： Recent studies have paid much attention to the newly found neuregulin-1, which might be closely linked to the molecular genetics of schizophrenia. OBJECTIVE： To investigate the association of neuregulin-related genes with schizophrenia, and to summarize the advancements in this current research. RETRIEVAL STRATEGY： Using the terms ＂neuregulins, gene, schizophrenia＂, we retrieved articles published from January 2000 to June 2007 from http：//www.ncbi.nlm.gov, http：//www.elsevier.lib.tsinghua.edu.cn, and http：//www.cjfd.cnki.net to identify studies addressing the association of neuregulin-related genes to schizophrenia. At the same time, we searched more than 10 medical journals by hand. The languages were limited to English and Chinese. Forty-two manuscripts were obtained and were firstly screened. Inclusion criteria： studies on neuregulins, schizophrenia, neuregulin-1, and the pathogenesis of schizophrenia, including randomized, blinded, and other original studies. Exclusion criteria： studies not related to schizophrenia, or repetitive studies. LITERATURE EVALUATION： The included 42 manuscripts were sorted. Twenty-one were selected as references for this article： fourteen were basic studies, and the remaining articles were case-controlled studies or other. DATA SYNTHESIS： Neuregulins are primarily expressed in the nervous system and heart, and limited expression is also seen in other tissues.. These proteins transmit signals among certain cells and play an important role in normal development of the nervous system. Neuregulin-1 is a typical neuregulin-related gene. Neuregulin genes are closely related to glutamatergic, GABAergic, and dopaminergic neurons. CONCLUSION： Neuregulin-related genes, such as neuregulin-1, are important and promising candidate genes for studying schizophrenia disease. Their roles in the onset of schizophrenia, neuregulin-related gene expression products, and correlations of ErbB receptor to schizophrenia symptoms need to be further investigated. Further studies of neuregulin-1 will hopefully provide powerful evidence for understanding the pathogenesis of schizophrenia.
文摘C-terminal sequence is important for the function of a protein.C-terminal sequencing is necessary for structure identification of recombinant drugs.In this paper,a new method based on CNBr cleavage coupled with ESI MS/MS was established and successfully applied to C-terminal sequence analysis of recombinant human TNFR and neuregulin.Results showed,C-terminal sequences with 19 and 11 amino acids were identified respectively.This new method was sensitive,reproducible and useful for C-terminal sequence analysis of recombinant proteins.
基金Supported by National Research Council of Argentina,CONICET PIP N°0722
文摘Neuregulin-1(NRG1)signaling through the tyrosine kinase receptors erbB2 and erbB4 is required for cardiac morphogenesis,and it plays an essential role in maintaining the myocardial architecture during adulthood.The tyrosine kinase receptor erbB2 was first linked to the amplification and overexpression of erbb2 gene in a subtype of breast tumor cells,which is indicative of highly proliferative cells and likely a poor prognosis following conventional chemotherapy.The development of targeted therapies to block the survival of erbB2-positive cancer cells revealed that impaired NRG1 signaling through erbB2/erbB4 heterodimers combined with anthracycline chemotherapy may lead to dilated cardiomyopathy in a subpopulation of treated patients.The ventricular-specific deletion of either erbb2 or erbb4 manifested dilated cardiomyopathy,which is aggravated by the administration of doxorubicin.Based on the exacerbated toxicity displayed by the combined treatment,it is expected that the relevant pathways would be affected in a synergistic manner.This review examines the NRG1 activities that were monitored in different model systems,focusing on the emerging pathways and molecular targets,which may aid in understanding the acquired dilated cardiomyopathy that occurs under the conditions of NRG1-deficient signaling.
基金supported by internal funding from the Department of Anesthesiology and Perioperative Medicine
文摘Epinephrine is often used for the treatment of patients with heart failure, low cardiac output and cardiac arrest. It can acutely improve hemodynamic parameters; however, it does not seem to improve longer term clinical outcomes. Therefore, we hypothesized that epinephrine may induce unfavorable changes in gene expression of cardiomyocyte. Thus, we investigated effects of epinephrine exposure on the mediation or modulation of gene expression of cultured cardiomyocytes at a genome-wide scale. Our investigation revealed that exposure of cardiomyocytes to epinephrine in an in vitro environment can up-regulate the expression ofangiopoietin-2 gene （~ 2.1 times）, and down-regulate the gene expression of neuregulin 1 （-3.7 times）, plasminogen activator inhibitor-1 （-2.4 times） and SPARC-related modular calcium-binding protein-2 （-4.5 times）. These changes suggest that epinephrine exposure may induce inhibition of angiogenesis-related gene expressions in cultured rat cardiomyocytes. The precise clinical significance of these changes in gene expression, which was induced by epinephrine exposure, warrants further experimental and clinical investigations.
基金funding from the European Community’s Seventh Framework Programme(FP7-HEALTH-2011)under grant agreement No.278612(BIOHYBRID),from MIUR and from Compagnia di San Paolo(MOVAG)
文摘Traumatic injuries of peripheral nerves represent common casualties and their social impact is considerably high. Although peripheral nerves retain a good regeneration potential, the clinical outcome after nerve lesion is far from being satisfactory and functional recovery is almost never complete, especially in the case of large nerve defects, that result in loss or diminished sensitivity and/or motor activity of the innervated target organs. Therefore, to improve the outcome after nerve damage, or in peripheral neuropathies, there is a need for further research in nerve repair and regeneration to identify factors that promote axonal regrowth, remvelination and target reinnervation.
文摘Objective:To study the recovery effect of neuregulin (Nrg-1) on the sciatic nerve constriction injury as well as the expression of Nrg-1 downstream signaling molecules in sciatic nerve tissue.Methods: SD rats were selected as the experimental animals and divided into sham operation + saline intervention group (group A), sciatic nerve constriction model + saline intervention group (group B) and sciatic nerve constriction model + Nrg-1 intervention group (group C). 2 weeks, 4 weeks and 8 weeks after intervention, the sciatic nerve function parameters were detected;8 weeks after intervention, the levels of fibrosis molecules and Nrg-1 downstream molecules in sciatic nerve tissue were determined.Results: 2 weeks, 4 weeks and 8 weeks after intervention, sciatic nerve MCV and CMAP amplitudes of group B were significantly lower than those of group A, and the sciatic nerve MCV and CMAP amplitudes of group C were significantly higher than those of group B;8 weeks after intervention, CTGF, Col-I, Col-III, MMP2, MMP9 and PTEN levels in sciatic nerve tissue of group B were significantly higher than those of group A while ErbB, Akt and PI3K levels were significantly lower than those of group A;CTGF, Col-I, Col-III, MMP2, MMP9 and PTEN levels in sciatic nerve tissue of group C were significantly lower than those of group B while ErbB, Akt and PI3K levels were significantly higher than those of group B.Conclusion: Neuregulin can activate the PI3K/Akt to exert the recovery effect on sciatic nerve constriction injury.
文摘Background: Hereditary spastic paraplegia (HSP) are classified clinically as pure when progressive spasticity occurs in isolation or complicated when other neurologic abnormalities are present. At least 22 genetic loci have been linked to HSP, 8 of which are autosomal recessive (ARHSP). HSP complicated with the presence of thin corpus callosum (HSP-TCC) is a common subtype of HSP. One genetic locus has been identified on chromosome 15q13-q15 (SPG11) for HSP-TCC, but some HSP-TCC families have not been linked to this locus. Methods: The authors characterized two families clinically and radiologically and performed a genome-wide scan and linkage analysis. Results: The two families had complicated ARHSP. The affected individuals in Family A had thin corpus callosum and mental retardation, whereas in Family B two of three affected individuals had epilepsy. In both families linkage analysis identified a locus on chromosome 8 between markers D8S1820 and D8S532 with the highest combined lod score of 7.077 at marker D8S505. This 9 cM interval located on 8p12-p11.21 represents a new locus for ARHSP-TCC. Neuregulin and KIF13B genes, located within this interval, are interesting functional candidate genes for this HSP form. Conclusion: Two consanguineous families with complicated autosomal recessive hereditary spastic paraplegia were clinically characterized and genetically mapped to a new locus on 8p12-p11.21.
