Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve deve...Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve development and maturation.Its cleavable extracellular domain(ECD)is readily detectable in various biological fluids including plasma,serum and urine.There is evidence for increased p75NTR ECD levels in neurodegenerative diseases such as Alzheimer’s disease,amyotrophic lateral sclerosis,age-related dementia,schizophrenia,and diabetic neuropathy.Whether p75^(NTR) ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders,and whether it could potentially lead to the development of targeted therapies,remains an open question.In this review,we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases.We also highlight areas that require further investigation to better understand the role of p75^(NTR) ECD in the clinical diagnosis and management of neurodegenerative disorders.展开更多
Aim:Angiogenesis is observed in acute myeloid leukemia(AML).AML cells abnormally proliferate and are resistant to death.Positive regulators of angiogenesis,VEGF-A and matrix metalloproteinases(MMPs)2 and 9 are markers...Aim:Angiogenesis is observed in acute myeloid leukemia(AML).AML cells abnormally proliferate and are resistant to death.Positive regulators of angiogenesis,VEGF-A and matrix metalloproteinases(MMPs)2 and 9 are markers of disease status in AML.The natural phloroglucinol hyperforin(HF)displays antitumoral properties of potential pharmacological interest.Herein,we investigated the effects of HF on MMP-2/9 and VEGF-A expression and survival of primary AML cells.Methods:Blood and bone marrow samples were collected in 45 patients with distinct subtypes defined by French American British classification,i.e.,M0,M1,M2,M3,M4,and M5.Levels of MMPs and VEGF-A in leukemic blood cells and culture supernatants were determined by RT-PCR,ELISA,and gelatin zymography(MMPs).The balance between cell death and survival was assessed by flow cytometry with analysis of phosphatidylserine externalization and caspase-3 activation.Results:The administration of HF promoted a caspase-associated apoptosis in primary AML blasts(from blood and bone marrow),but not normal blood cells and monocytes.In addition,HF inhibited the levels of secreted proMMP-2,proMMP-9,and VEGF-A without altering transcripts.The induction of apoptosis by HF significantly paralleled the inhibition of MMP-2/9 and VEGF-A release by HF.No differences were seen in response to the deleterious effects of HF between AML cells of distinct subtypes.Conclusion:Our results suggest that HF,through its proapoptotic and potential antiangiogenic properties(by inhibiting MMP-2/9 and VEGF-A)on primary AML cells,might be a useful experimental agent,in combination with existing drugs,for new therapeutic approaches in the treatment of this incurable disease.展开更多
文摘Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve development and maturation.Its cleavable extracellular domain(ECD)is readily detectable in various biological fluids including plasma,serum and urine.There is evidence for increased p75NTR ECD levels in neurodegenerative diseases such as Alzheimer’s disease,amyotrophic lateral sclerosis,age-related dementia,schizophrenia,and diabetic neuropathy.Whether p75^(NTR) ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders,and whether it could potentially lead to the development of targeted therapies,remains an open question.In this review,we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases.We also highlight areas that require further investigation to better understand the role of p75^(NTR) ECD in the clinical diagnosis and management of neurodegenerative disorders.
基金supported by the French National Institute of Health and Medical Research(INSERM).This research received no external funding.
文摘Aim:Angiogenesis is observed in acute myeloid leukemia(AML).AML cells abnormally proliferate and are resistant to death.Positive regulators of angiogenesis,VEGF-A and matrix metalloproteinases(MMPs)2 and 9 are markers of disease status in AML.The natural phloroglucinol hyperforin(HF)displays antitumoral properties of potential pharmacological interest.Herein,we investigated the effects of HF on MMP-2/9 and VEGF-A expression and survival of primary AML cells.Methods:Blood and bone marrow samples were collected in 45 patients with distinct subtypes defined by French American British classification,i.e.,M0,M1,M2,M3,M4,and M5.Levels of MMPs and VEGF-A in leukemic blood cells and culture supernatants were determined by RT-PCR,ELISA,and gelatin zymography(MMPs).The balance between cell death and survival was assessed by flow cytometry with analysis of phosphatidylserine externalization and caspase-3 activation.Results:The administration of HF promoted a caspase-associated apoptosis in primary AML blasts(from blood and bone marrow),but not normal blood cells and monocytes.In addition,HF inhibited the levels of secreted proMMP-2,proMMP-9,and VEGF-A without altering transcripts.The induction of apoptosis by HF significantly paralleled the inhibition of MMP-2/9 and VEGF-A release by HF.No differences were seen in response to the deleterious effects of HF between AML cells of distinct subtypes.Conclusion:Our results suggest that HF,through its proapoptotic and potential antiangiogenic properties(by inhibiting MMP-2/9 and VEGF-A)on primary AML cells,might be a useful experimental agent,in combination with existing drugs,for new therapeutic approaches in the treatment of this incurable disease.
