The critical role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease(AD):AD is a progressive neurodegenerative disease characterized by cognitive decline,memory impairment,and behavioral changes.Wit...The critical role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease(AD):AD is a progressive neurodegenerative disease characterized by cognitive decline,memory impairment,and behavioral changes.With an estimated 50 million people being affected worldwide,the incidence of AD is constantly increasing globally.The hallmark of AD is the accumulation of amyloid-beta protein(Aβ)in the form of amyloid plaques and hyperphosphorylated tau protein in the form of neurofibrillary tangles.However,increasing evidence suggests that calcium ion(Ca2+)dysregulation also plays a crucial role in the pathogenesis of AD(Calvo-Rodriguez and Bacskai,2021).As a key second messenger,Ca2+regulates a wide range of cellular processes,including the release of neurotransmitters,gene expression,and cell death.Ca^(2+)also regulates the activity of Calcium/calmodulin-dependent protein kinase II,which is critical for synaptic plasticity,learning,and memory(Kaushik et al.,2022).Alternation in the Ca^(2+)signal is an early event in the pathogenesis of AD,which can lead to synaptic dysfunction,neuronal loss,and cognitive impairment.展开更多
Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate ba...Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate back into the systemic circulation.The aim of the present study was to develop an intravenous formulation of HM30181 A(HM)to inhibit P-gp in the brain to effectively deliver paclitaxel(PTX)for the treatment of malignant glioma.Methods:Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies:i)spray-drying[polyvinlypyrrolidone(PVP)-HM]and ii)solvent evaporation[HP-β-cyclodextrin(cyclodextrin)-HM].The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells.Blood and brain pharmacokinetic parameters were also determined,and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model.Results:Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro,cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM.Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg,and the mice began to lose weight at doses above this level.Cyclodextrin-HM(10 mg/kg)administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model,according to both tumor volume measurement and survival time(P<0.05).Conclusions:In a mouse orthotopic brain tumor model,the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.展开更多
Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by cartilage and bone damage with the presence of pannus formation which causes uncontrollable proliferation and invasion of fibroblast-like syno...Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by cartilage and bone damage with the presence of pannus formation which causes uncontrollable proliferation and invasion of fibroblast-like synoviocytes(FLS).Since rheumatoid arthritis is a chronic disorder,the patients normally need to undergo prolonged antirheumatic treatment with the use of disease-modifying antirheumatic drugs(DMARDs),steroids,and nonsteroidal anti-inflammatory drugs(NSAIDs).The efficacy of such long-term pharmaceutical intervention can be significantly affected by the development of drug resistance.The pathological relationship between rheumatoid arthritis and cancer hinted that some chemotherapeutic drugs,such as methotrexate(MTX),could be used for RA treatment.This idea was reinforced by the analysis of mutations in p53 tumor suppressor gene.Around 50%of p53 somatic mutations observed from various cancers are also identified in the synovium of RA patients1(Fig.1A).Of note,the hyperplastic synovium in RA with overexpressed p53 mutants contributed to the destruction of joints in patients with erosive RA.展开更多
基金supported by grants from the Macao Science and Technology Development Fund(Project code:002/2023/ALC)Foshan Medicine Dengfeng Project of China 2019-2021(to BYKL).
文摘The critical role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease(AD):AD is a progressive neurodegenerative disease characterized by cognitive decline,memory impairment,and behavioral changes.With an estimated 50 million people being affected worldwide,the incidence of AD is constantly increasing globally.The hallmark of AD is the accumulation of amyloid-beta protein(Aβ)in the form of amyloid plaques and hyperphosphorylated tau protein in the form of neurofibrillary tangles.However,increasing evidence suggests that calcium ion(Ca2+)dysregulation also plays a crucial role in the pathogenesis of AD(Calvo-Rodriguez and Bacskai,2021).As a key second messenger,Ca2+regulates a wide range of cellular processes,including the release of neurotransmitters,gene expression,and cell death.Ca^(2+)also regulates the activity of Calcium/calmodulin-dependent protein kinase II,which is critical for synaptic plasticity,learning,and memory(Kaushik et al.,2022).Alternation in the Ca^(2+)signal is an early event in the pathogenesis of AD,which can lead to synaptic dysfunction,neuronal loss,and cognitive impairment.
基金supported by a FDCT grant from the Macao Science and Technology Development Fund(Grant No.061/2014/A2)。
文摘Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate back into the systemic circulation.The aim of the present study was to develop an intravenous formulation of HM30181 A(HM)to inhibit P-gp in the brain to effectively deliver paclitaxel(PTX)for the treatment of malignant glioma.Methods:Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies:i)spray-drying[polyvinlypyrrolidone(PVP)-HM]and ii)solvent evaporation[HP-β-cyclodextrin(cyclodextrin)-HM].The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells.Blood and brain pharmacokinetic parameters were also determined,and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model.Results:Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro,cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM.Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg,and the mice began to lose weight at doses above this level.Cyclodextrin-HM(10 mg/kg)administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model,according to both tumor volume measurement and survival time(P<0.05).Conclusions:In a mouse orthotopic brain tumor model,the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.
基金supported by an FDCT grant from the Macao Science and Technology Development Fund(Project code:0003/2019/AKP)the Joint Fund of Wuyi University-Macao(No.2019WGALH01).
文摘Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by cartilage and bone damage with the presence of pannus formation which causes uncontrollable proliferation and invasion of fibroblast-like synoviocytes(FLS).Since rheumatoid arthritis is a chronic disorder,the patients normally need to undergo prolonged antirheumatic treatment with the use of disease-modifying antirheumatic drugs(DMARDs),steroids,and nonsteroidal anti-inflammatory drugs(NSAIDs).The efficacy of such long-term pharmaceutical intervention can be significantly affected by the development of drug resistance.The pathological relationship between rheumatoid arthritis and cancer hinted that some chemotherapeutic drugs,such as methotrexate(MTX),could be used for RA treatment.This idea was reinforced by the analysis of mutations in p53 tumor suppressor gene.Around 50%of p53 somatic mutations observed from various cancers are also identified in the synovium of RA patients1(Fig.1A).Of note,the hyperplastic synovium in RA with overexpressed p53 mutants contributed to the destruction of joints in patients with erosive RA.
