Neurodegenerative diseases constitute a broad category of diseases caused by the degeneration of the neurons.They are mainly manifested by the gradual loss of neuron structure and function and eventually can cause dea...Neurodegenerative diseases constitute a broad category of diseases caused by the degeneration of the neurons.They are mainly manifested by the gradual loss of neuron structure and function and eventually can cause death or loss of neurons.As the global population ages rapidly,increased people are being diagnosed with neurodegenerative diseases.It has been established that the onset of Alzheimer’s disease(AD)is closely linked with increasing age and its major pathological features include amyloid-beta plaques(Aβ),Tau hyperphosphorylation,Neurofibrillary tangles(NFTs),neuronal death as well as synaptic loss.The involvement of microglia is crucial in the pathogenesis and progression of AD and exhibits a dual role.For instance,in the early stage of AD,microglia surface membrane proteins or receptors can participate in immunophagocytosis,and anti-inflammatory functions and act as a physical barrier after recognizing various ligands such as Aβand NFTs.However,in the later stage of the disease,membrane receptors on the surface of microglia can cause its activation to release a substantial quantity of pro-inflammatory factors.Which can amplify the neuroinflammatory response.The rapid decline of normal immune phagocytosis can result in the continuous accumulation of abnormal proteins,leading to neuronal dysfunction and destruction of the formed physical barrier as well as the neurovascular microenvironment.It can also increase the transformation of microglia from anti-inflammatory phenotype M2 to pro-inflammatory phenotype M1,induce severe neuronal injury or apoptosis,and aggravate the progression of AD.Due to few articles have focused on the AD-related membrane protein receptors on microglia,thus in this paper,we have reviewed several representative microglial membrane proteins or receptors about their specific roles and functions implicated in AD,and expect that there will be more in-depth research and scientific research results in the treatment of AD by targeted regulation of microglia membrane protein receptors in the future.展开更多
Adrenocortical carcinoma(ACC)is a rare and highly aggressive endocrine malignancy with limited therapeutic options and a substantial risk of postoperative recurrence.Mitotane remains the only US Food and Drug Administ...Adrenocortical carcinoma(ACC)is a rare and highly aggressive endocrine malignancy with limited therapeutic options and a substantial risk of postoperative recurrence.Mitotane remains the only US Food and Drug Administration(USFDA)and the European Medicines Agency(EMA)approved agent specifically for ACC.Its antitumor activity involves disruption of cholesterol trafficking,inhibition of steroidogenic enzymes,and mitochondrial dysfunction,leading to selective cytotoxicity in adrenocortical cells.Current evidence indicates that maintaining therapeutic plasma concentrations between 14 mg/L and 20 mg/L is critical for clinical benefit,underscoring the importance of therapeutic drug monitoring.Mitotane is used in both adjuvant and advanced disease settings;however,its highly variable pharmacokinetics,broad endocrine disruptions,and frequent gastrointestinal and neurological toxicities require individualized dosing strategies and comprehensive supportive care.This review summarizes recent advances in the understanding of mitotane’s molecular mechanisms,pharmacogenetic determinants,clinical efficacy,and adverse-effect profile,with an emphasis on laboratory monitoring and practical considerations for optimizing treatment in ACC.展开更多
基金This study was supported by grants from the Science and Technology Innovation Fund Project of Dalian(No.2021JJ13SN55).
文摘Neurodegenerative diseases constitute a broad category of diseases caused by the degeneration of the neurons.They are mainly manifested by the gradual loss of neuron structure and function and eventually can cause death or loss of neurons.As the global population ages rapidly,increased people are being diagnosed with neurodegenerative diseases.It has been established that the onset of Alzheimer’s disease(AD)is closely linked with increasing age and its major pathological features include amyloid-beta plaques(Aβ),Tau hyperphosphorylation,Neurofibrillary tangles(NFTs),neuronal death as well as synaptic loss.The involvement of microglia is crucial in the pathogenesis and progression of AD and exhibits a dual role.For instance,in the early stage of AD,microglia surface membrane proteins or receptors can participate in immunophagocytosis,and anti-inflammatory functions and act as a physical barrier after recognizing various ligands such as Aβand NFTs.However,in the later stage of the disease,membrane receptors on the surface of microglia can cause its activation to release a substantial quantity of pro-inflammatory factors.Which can amplify the neuroinflammatory response.The rapid decline of normal immune phagocytosis can result in the continuous accumulation of abnormal proteins,leading to neuronal dysfunction and destruction of the formed physical barrier as well as the neurovascular microenvironment.It can also increase the transformation of microglia from anti-inflammatory phenotype M2 to pro-inflammatory phenotype M1,induce severe neuronal injury or apoptosis,and aggravate the progression of AD.Due to few articles have focused on the AD-related membrane protein receptors on microglia,thus in this paper,we have reviewed several representative microglial membrane proteins or receptors about their specific roles and functions implicated in AD,and expect that there will be more in-depth research and scientific research results in the treatment of AD by targeted regulation of microglia membrane protein receptors in the future.
基金supported by the National Natural Science Foundation of China(Nos.82403817 and 82170797)Shanghai Municipal Health Commission,China(Nos.20224Y0088,2022YQ021 and 202440098)+1 种基金Shanghai Municipal Science and Technology Commission,China(No.24QA2705200)Shanghai Shenkang Hospital Development Center,China(Nos.SHDC2024CRI081,SHDC22022301,SHDC22025304 and SHDC2025CCS022).
文摘Adrenocortical carcinoma(ACC)is a rare and highly aggressive endocrine malignancy with limited therapeutic options and a substantial risk of postoperative recurrence.Mitotane remains the only US Food and Drug Administration(USFDA)and the European Medicines Agency(EMA)approved agent specifically for ACC.Its antitumor activity involves disruption of cholesterol trafficking,inhibition of steroidogenic enzymes,and mitochondrial dysfunction,leading to selective cytotoxicity in adrenocortical cells.Current evidence indicates that maintaining therapeutic plasma concentrations between 14 mg/L and 20 mg/L is critical for clinical benefit,underscoring the importance of therapeutic drug monitoring.Mitotane is used in both adjuvant and advanced disease settings;however,its highly variable pharmacokinetics,broad endocrine disruptions,and frequent gastrointestinal and neurological toxicities require individualized dosing strategies and comprehensive supportive care.This review summarizes recent advances in the understanding of mitotane’s molecular mechanisms,pharmacogenetic determinants,clinical efficacy,and adverse-effect profile,with an emphasis on laboratory monitoring and practical considerations for optimizing treatment in ACC.
