Objective:To study the various processes involved in transcellular transport(TT) of huperzine A alone or in combination with ginkgolide B in Caco-2 and Madin-Darby canine renal(MDCK)cell monolayer.Methods:The transepi...Objective:To study the various processes involved in transcellular transport(TT) of huperzine A alone or in combination with ginkgolide B in Caco-2 and Madin-Darby canine renal(MDCK)cell monolayer.Methods:The transepithelial passage was assayed in the apical-to-basolateral(AP to BL) direction and opposite direction(BL to AP) in both cell lines.The determination of huperzine A and ginkgolide B were performed by high performance liquid chromatography(HPLC).The passage rates of huperzine A and ginkgolide B were calculated.Bi-directional TT(absorption and secretion) were taken in huperzine A and ginkgolide B in Caco-2 and MDCK cell monolayer.Results:TT absorption and secretion kinetics of huperzine A and ginkgolide B across two cells existed at the same time.The passage rates of huperzine A were increased significantly with adding different concentrations of ginkgolide B.Conclusions:The compound preparations of HA in combination with CB for dementia caused by cerebral ischemic have synergistic effects on the pharmacodynamics,and improve the bioavailability through BBB.展开更多
The blood-brain barrier is the interface through which the brain interacts with the milieu and consists mainly of a sophisticated network of brain endothelial cells that forms blood vessels and selectively moves molec...The blood-brain barrier is the interface through which the brain interacts with the milieu and consists mainly of a sophisticated network of brain endothelial cells that forms blood vessels and selectively moves molecules inside and outside the brain through multiple mechanisms of transport.Although brain endothelial cell function is crucial for brain homeostasis,their role in neurodegenerative diseases has historically not been considered with the same importance as other brain cells such as microglia,astroglia,neurons,or even molecules such as amyloid beta,Tau,or alpha-synuclein.Alzheimer's disease is the most common neurodegenerative disease,and brain endothelial cell dysfunction has been reported by several groups.However,its impairment has barely been considered as a potential therapeutic target.Here we review the most recent advances in the relationship between Alzheimer's disease and brain endothelial cells commitment and analyze the possible mechanisms through which their alterations contribute to this neurodegenerative disease,highlighting their inflammatory phenotype and the possibility of an impaired secretory pattern of brain endothelial cells that could contribute to the progression of this ailment.Finally,we discuss why shall brain endothelial cells be appreciated as a therapeutic target instead of solely an obstacle for delivering treatments to the injured brain in Alzheimer's disease.展开更多
The disequilibrium between the production of reactive oxygen(ROS) and nitrogen(RNS) species and their elimination by protective mechanisms leads to oxidative stress. Mitochondria are the main source of ROS as by-produ...The disequilibrium between the production of reactive oxygen(ROS) and nitrogen(RNS) species and their elimination by protective mechanisms leads to oxidative stress. Mitochondria are the main source of ROS as by-products of electron transport chain. Most of the time the intestine responds adequately against the oxidative stress, but with aging or under conditions that exacerbate the ROS and/or RNS production, the defenses are not enough and contribute to developing intestinal pathologies. The endogenous antioxidant defense system in gut includes glutathione(GSH) and GSH-dependent enzymes as major components. When the ROS and/or RNS production is exacerbated, oxidative stress occurs and the intestinal Ca2+ absorption is inhibited. GSH depleting drugs such as DLbuthionine-S,R-sulfoximine, menadione and sodium deoxycholate inhibit the Ca2+ transport from lumen to blood by alteration in the protein expression and/or activity of molecules involved in the Ca2+ transcellular and paracellular pathways through mechanisms of oxidative stress, apoptosis and/or autophagy. Quercetin, melatonin, lithocholic and ursodeoxycholic acids block the effect of those drugs in experimental animals by their antioxidant, anti-apoptotic and/or anti-autophagic properties. Therefore, they may become drugs of choice for treatment of deteriorated intestinal Ca2+ absorption under oxidant conditions such as aging, diabetes, gut inflammation and other intestinal disorders.展开更多
Intestinal Ca2+ absorption is a crucial physiological process for maintaining bone mineralization and Ca2+ homeostasis. It occurs through the transcellular and paracellular pathways. The first route comprises 3steps: ...Intestinal Ca2+ absorption is a crucial physiological process for maintaining bone mineralization and Ca2+ homeostasis. It occurs through the transcellular and paracellular pathways. The first route comprises 3steps: the entrance of Ca2+ across the brush border membranes(BBM) of enterocytes through epithelial Ca2+ channels TRPV6, TRPV5, and Cav1.3; Ca2+ movement from the BBM to the basolateral membranes by binding proteins with high Ca2+ affinity(such as CB9k); and Ca2+ extrusion into the blood. Plasma membrane Ca2+ ATPase(PMCA1b) and sodium calcium exchanger(NCX1) are mainly involved in the exit of Ca2+ from enterocytes. A novel molecule, the 4.1R protein, seems to be a partner of PMCA1 b, since both molecules colocalize and interact. The paracellular pathway consists of Ca2+ transport through transmembrane proteins of tight junction structures, such as claudins 2, 12, and 15. There is evidence of crosstalk between the transcellular and paracellular pathways in intestinal Ca2+ transport. When intestinal oxidative stress is triggered, there is a decrease in the expression of several molecules of both pathways that inhibit intestinal Ca2+ absorption. Normalization of redox status in the intestine with drugs such as quercetin, ursodeoxycholic acid, or melatonin return intestinal Ca2+ transport to control values. Calcitriol [1,25(OH)2D3] is the major controlling hormone of intestinal Ca2+ transport. It increases the gene and protein expression of most of the molecules involved in both pathways. PTH, thyroid hormones, estrogens, p ro l a c t i n, g ro w t h h o r m o n e, a n d g l u c o c o r t i c o i d s apparently also regulate Ca2+ transport by direct action, indirect mechanism mediated by the increase of renal 1,25(OH)2D3 production, or both. Different physiological conditions, such as growth, pregnancy, lactation, and aging, adjust intestinal Ca2+ absorption according to Ca2+ demands. Better knowledge of the molecular details of intestinal Ca2+ absorption could lead to the development of nutritional and medical strategies for optimizing the efficiency of intestinal Ca2+ absorption and preventing osteoporosis and other pathologies related to Ca2+ metabolism.展开更多
Ca2+has an important role in the maintenance of the skeleton and is involved in the main physiological processes.Its homeostasis is controlled by the intestine,kidney,bone and parathyroid glands.The intestinal Ca2+abs...Ca2+has an important role in the maintenance of the skeleton and is involved in the main physiological processes.Its homeostasis is controlled by the intestine,kidney,bone and parathyroid glands.The intestinal Ca2+absorption occurs mainly via the paracellular and the transcellular pathways.The proteins involved in both ways are regulated by calcitriol and other hormones as well as dietary factors.Fibroblast growth factor 23(FGF-23)is a strong antagonist of vitamin D action.Part of the intestinal Ca2+movement seems to be vitamin D independent.Intestinal Ca2+absorption changes according to different physiological conditions.It is promoted under high Ca2+demands such as growth,pregnancy,lactation,dietary Ca2+deficiency and high physical activity.In contrast,the intestinal Ca2+transport decreases with aging.Oxidative stress inhibits the intestinal Ca2+absorption whereas the antioxidants counteract the effects of prooxidants leading to the normalization of this physiological process.Several pathologies such as celiac disease,inflammatory bowel diseases,Turner syndrome and others occur with inhibition of intestinal Ca2+absorption,some hypercalciurias show Ca2+hyperabsorption,most of these alterations are related to the vitamin D endocrine system.Further research work should be accomplished in order not only to know more molecular details but also to detect possible therapeutic targets to ameliorate or avoid the consequences of altered intestinal Ca2+absorption.展开更多
Glutathione(GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca2+ absorption. The use of GSH de...Glutathione(GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca2+ absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K3, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca2+ absorption. The GSH depleting drugs switch the redox state towards an oxidant condition provoking oxidative/nitrosative stress and inflammation, which lead to apoptosis and/or autophagy of the enterocytes. Either the transcellular Ca2+ transport or the paracellular Ca2+ route are altered by GSH depleting drugs. The gene and/or protein expression of transporters involved in the transcellular Ca2+ pathway are decreased. The flavonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca2+ absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca2+ transport caused by GSH depleting drugs. The use of any of these antioxidants to ameliorate the intestinal Ca2+ absorption under oxidant conditions associated with different pathologies in humans requires more investigation with regards to the safety, pharmacokinetics and pharmacodynamics of them.展开更多
Abnormal tumor microenvironment imposes barriers to tumor penetration of nanomedicine,which remains a major challenge for effective anti-tumor.Herein,we present disulfide-based nanoparticles that actively penetrate de...Abnormal tumor microenvironment imposes barriers to tumor penetration of nanomedicine,which remains a major challenge for effective anti-tumor.Herein,we present disulfide-based nanoparticles that actively penetrate deep tumors in vivo through a thiol-mediated transportation pathway.To achieve active tumor accumulation in vivo,disulfide-based nanoparticles are modified with folic acid units(FA-DBNPs).It is gratifying that FA-DBNPs still enter cells via the thiol-mediated pathway,which facilitates transcellular transportation and tumor penetration both in vitro and in vivo.Besides,FA-DBNPs exhibit GSH concentration-dependent depolymerization characterization,indicating that the GSH level in tumor tissues regulates the penetration depth of FA-DBNPs.Benefiting from these advantages,FA-DBNPs showed potent anti-tumor activity in mouse models,leading to the significant regression of tumors.The current study lays a foundation that thiol-mediated transportation is a promising approach in nanomedicine design for solid tumor therapy.展开更多
Objective：To review recent research advances on tau,a major player in Alzheimer＇s disease （AD） pathogenesis,a biomarker for AD onset,and potential target for AD therapy.Data Sources：This review was based on a com...Objective：To review recent research advances on tau,a major player in Alzheimer＇s disease （AD） pathogenesis,a biomarker for AD onset,and potential target for AD therapy.Data Sources：This review was based on a comprehensive search using online literature databases,including PubMed,Web of Science,and Google Scholar.Study Selection：Literature search was based on the following keywords：Alzheimer＇s disease,tau protein,biomarker,cerebrospinal fluid （CSF）,therapeutics,plasma,imaging,propagation,spreading,seeding,prion,conformational templating,and posttranslational modification.Relevant articles were carefully reviewed,with no exclusions applied to study design and publication type.Results：Amyloid plaques enriched with extracellular amyloid beta （Aβ） and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau proteins are the two main pathological hallmarks ofAD.Although the Aβ hypothesis has dominated AD research for many years,clinical Aβ-targeting strategies have consistently failed to effectively treat AD or prevent AD onset.The research focus in AD has recently shifted to the role oftau in AD.In addition to phosphorylation,tau is acetylated and proteolytically cleaved,which also contribute to its physiological and pathological functions.Emerging evidence characterizing pathological tau propagation and spreading provides new avenues for research into the molecular and cellular mechanisms underlying AD pathogenesis.Techniques to detect tau at minute levels in CSF and blood have been developed,and improved tracers have facilitated tau imaging in the brain.These advances have potential to accurately determine tau levels at early diagnostic stages in AD.Given that tau is a potential therapeutic target,anti-tau immunotherapy may potentially be a viable treatment strategy in AD intervention.Conclusion：Detecting changes in tau and targeting tau pathology represent a promising lead in the diagnosis and treatment of AD.展开更多
基金supported by Clinical Special Funds of China University Medical Journals(11321611)
文摘Objective:To study the various processes involved in transcellular transport(TT) of huperzine A alone or in combination with ginkgolide B in Caco-2 and Madin-Darby canine renal(MDCK)cell monolayer.Methods:The transepithelial passage was assayed in the apical-to-basolateral(AP to BL) direction and opposite direction(BL to AP) in both cell lines.The determination of huperzine A and ginkgolide B were performed by high performance liquid chromatography(HPLC).The passage rates of huperzine A and ginkgolide B were calculated.Bi-directional TT(absorption and secretion) were taken in huperzine A and ginkgolide B in Caco-2 and MDCK cell monolayer.Results:TT absorption and secretion kinetics of huperzine A and ginkgolide B across two cells existed at the same time.The passage rates of huperzine A were increased significantly with adding different concentrations of ginkgolide B.Conclusions:The compound preparations of HA in combination with CB for dementia caused by cerebral ischemic have synergistic effects on the pharmacodynamics,and improve the bioavailability through BBB.
文摘The blood-brain barrier is the interface through which the brain interacts with the milieu and consists mainly of a sophisticated network of brain endothelial cells that forms blood vessels and selectively moves molecules inside and outside the brain through multiple mechanisms of transport.Although brain endothelial cell function is crucial for brain homeostasis,their role in neurodegenerative diseases has historically not been considered with the same importance as other brain cells such as microglia,astroglia,neurons,or even molecules such as amyloid beta,Tau,or alpha-synuclein.Alzheimer's disease is the most common neurodegenerative disease,and brain endothelial cell dysfunction has been reported by several groups.However,its impairment has barely been considered as a potential therapeutic target.Here we review the most recent advances in the relationship between Alzheimer's disease and brain endothelial cells commitment and analyze the possible mechanisms through which their alterations contribute to this neurodegenerative disease,highlighting their inflammatory phenotype and the possibility of an impaired secretory pattern of brain endothelial cells that could contribute to the progression of this ailment.Finally,we discuss why shall brain endothelial cells be appreciated as a therapeutic target instead of solely an obstacle for delivering treatments to the injured brain in Alzheimer's disease.
基金Supported by Dr.Nori Tolosa de Talamoni from CONICET,No.PIP 2013-2015 and No.SECYT(UNC)2016,Argentina
文摘The disequilibrium between the production of reactive oxygen(ROS) and nitrogen(RNS) species and their elimination by protective mechanisms leads to oxidative stress. Mitochondria are the main source of ROS as by-products of electron transport chain. Most of the time the intestine responds adequately against the oxidative stress, but with aging or under conditions that exacerbate the ROS and/or RNS production, the defenses are not enough and contribute to developing intestinal pathologies. The endogenous antioxidant defense system in gut includes glutathione(GSH) and GSH-dependent enzymes as major components. When the ROS and/or RNS production is exacerbated, oxidative stress occurs and the intestinal Ca2+ absorption is inhibited. GSH depleting drugs such as DLbuthionine-S,R-sulfoximine, menadione and sodium deoxycholate inhibit the Ca2+ transport from lumen to blood by alteration in the protein expression and/or activity of molecules involved in the Ca2+ transcellular and paracellular pathways through mechanisms of oxidative stress, apoptosis and/or autophagy. Quercetin, melatonin, lithocholic and ursodeoxycholic acids block the effect of those drugs in experimental animals by their antioxidant, anti-apoptotic and/or anti-autophagic properties. Therefore, they may become drugs of choice for treatment of deteriorated intestinal Ca2+ absorption under oxidant conditions such as aging, diabetes, gut inflammation and other intestinal disorders.
文摘Intestinal Ca2+ absorption is a crucial physiological process for maintaining bone mineralization and Ca2+ homeostasis. It occurs through the transcellular and paracellular pathways. The first route comprises 3steps: the entrance of Ca2+ across the brush border membranes(BBM) of enterocytes through epithelial Ca2+ channels TRPV6, TRPV5, and Cav1.3; Ca2+ movement from the BBM to the basolateral membranes by binding proteins with high Ca2+ affinity(such as CB9k); and Ca2+ extrusion into the blood. Plasma membrane Ca2+ ATPase(PMCA1b) and sodium calcium exchanger(NCX1) are mainly involved in the exit of Ca2+ from enterocytes. A novel molecule, the 4.1R protein, seems to be a partner of PMCA1 b, since both molecules colocalize and interact. The paracellular pathway consists of Ca2+ transport through transmembrane proteins of tight junction structures, such as claudins 2, 12, and 15. There is evidence of crosstalk between the transcellular and paracellular pathways in intestinal Ca2+ transport. When intestinal oxidative stress is triggered, there is a decrease in the expression of several molecules of both pathways that inhibit intestinal Ca2+ absorption. Normalization of redox status in the intestine with drugs such as quercetin, ursodeoxycholic acid, or melatonin return intestinal Ca2+ transport to control values. Calcitriol [1,25(OH)2D3] is the major controlling hormone of intestinal Ca2+ transport. It increases the gene and protein expression of most of the molecules involved in both pathways. PTH, thyroid hormones, estrogens, p ro l a c t i n, g ro w t h h o r m o n e, a n d g l u c o c o r t i c o i d s apparently also regulate Ca2+ transport by direct action, indirect mechanism mediated by the increase of renal 1,25(OH)2D3 production, or both. Different physiological conditions, such as growth, pregnancy, lactation, and aging, adjust intestinal Ca2+ absorption according to Ca2+ demands. Better knowledge of the molecular details of intestinal Ca2+ absorption could lead to the development of nutritional and medical strategies for optimizing the efficiency of intestinal Ca2+ absorption and preventing osteoporosis and other pathologies related to Ca2+ metabolism.
基金Supported by Consejo Nacional de Investigaciones Científicas y Tecnológicas,Argentina PIP 2017-2019,No.11220170100012COSecretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba,Argentina(Programa 2018-2019),No.30920180100056CB。
文摘Ca2+has an important role in the maintenance of the skeleton and is involved in the main physiological processes.Its homeostasis is controlled by the intestine,kidney,bone and parathyroid glands.The intestinal Ca2+absorption occurs mainly via the paracellular and the transcellular pathways.The proteins involved in both ways are regulated by calcitriol and other hormones as well as dietary factors.Fibroblast growth factor 23(FGF-23)is a strong antagonist of vitamin D action.Part of the intestinal Ca2+movement seems to be vitamin D independent.Intestinal Ca2+absorption changes according to different physiological conditions.It is promoted under high Ca2+demands such as growth,pregnancy,lactation,dietary Ca2+deficiency and high physical activity.In contrast,the intestinal Ca2+transport decreases with aging.Oxidative stress inhibits the intestinal Ca2+absorption whereas the antioxidants counteract the effects of prooxidants leading to the normalization of this physiological process.Several pathologies such as celiac disease,inflammatory bowel diseases,Turner syndrome and others occur with inhibition of intestinal Ca2+absorption,some hypercalciurias show Ca2+hyperabsorption,most of these alterations are related to the vitamin D endocrine system.Further research work should be accomplished in order not only to know more molecular details but also to detect possible therapeutic targets to ameliorate or avoid the consequences of altered intestinal Ca2+absorption.
文摘Glutathione(GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca2+ absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K3, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca2+ absorption. The GSH depleting drugs switch the redox state towards an oxidant condition provoking oxidative/nitrosative stress and inflammation, which lead to apoptosis and/or autophagy of the enterocytes. Either the transcellular Ca2+ transport or the paracellular Ca2+ route are altered by GSH depleting drugs. The gene and/or protein expression of transporters involved in the transcellular Ca2+ pathway are decreased. The flavonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca2+ absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca2+ transport caused by GSH depleting drugs. The use of any of these antioxidants to ameliorate the intestinal Ca2+ absorption under oxidant conditions associated with different pathologies in humans requires more investigation with regards to the safety, pharmacokinetics and pharmacodynamics of them.
基金supported by the National Key R&D Program of China(2020YFA0210800)the National Natural Science Foundation of China(21974022,22027805)the Major Project of Science and Technology of Fujian Province(2020HZ06006)。
文摘Abnormal tumor microenvironment imposes barriers to tumor penetration of nanomedicine,which remains a major challenge for effective anti-tumor.Herein,we present disulfide-based nanoparticles that actively penetrate deep tumors in vivo through a thiol-mediated transportation pathway.To achieve active tumor accumulation in vivo,disulfide-based nanoparticles are modified with folic acid units(FA-DBNPs).It is gratifying that FA-DBNPs still enter cells via the thiol-mediated pathway,which facilitates transcellular transportation and tumor penetration both in vitro and in vivo.Besides,FA-DBNPs exhibit GSH concentration-dependent depolymerization characterization,indicating that the GSH level in tumor tissues regulates the penetration depth of FA-DBNPs.Benefiting from these advantages,FA-DBNPs showed potent anti-tumor activity in mouse models,leading to the significant regression of tumors.The current study lays a foundation that thiol-mediated transportation is a promising approach in nanomedicine design for solid tumor therapy.
基金This work was supported by grants from the National Natural Science Foundation of China （No. 81671352, 91232709）, the National Key Project of Research and Development Plan （No. 2016YFC1306404）, the National Institute of Health （No. R21 AG048519, R01 AG021173, R01 AG038710, R01 AG044420, R01 NS046673, RF1 AG056130, and RF1 AG056114）, the Tanz Family Fund as well as scholarship from China Scholarship Council （No. 201608350068）.
文摘Objective：To review recent research advances on tau,a major player in Alzheimer＇s disease （AD） pathogenesis,a biomarker for AD onset,and potential target for AD therapy.Data Sources：This review was based on a comprehensive search using online literature databases,including PubMed,Web of Science,and Google Scholar.Study Selection：Literature search was based on the following keywords：Alzheimer＇s disease,tau protein,biomarker,cerebrospinal fluid （CSF）,therapeutics,plasma,imaging,propagation,spreading,seeding,prion,conformational templating,and posttranslational modification.Relevant articles were carefully reviewed,with no exclusions applied to study design and publication type.Results：Amyloid plaques enriched with extracellular amyloid beta （Aβ） and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau proteins are the two main pathological hallmarks ofAD.Although the Aβ hypothesis has dominated AD research for many years,clinical Aβ-targeting strategies have consistently failed to effectively treat AD or prevent AD onset.The research focus in AD has recently shifted to the role oftau in AD.In addition to phosphorylation,tau is acetylated and proteolytically cleaved,which also contribute to its physiological and pathological functions.Emerging evidence characterizing pathological tau propagation and spreading provides new avenues for research into the molecular and cellular mechanisms underlying AD pathogenesis.Techniques to detect tau at minute levels in CSF and blood have been developed,and improved tracers have facilitated tau imaging in the brain.These advances have potential to accurately determine tau levels at early diagnostic stages in AD.Given that tau is a potential therapeutic target,anti-tau immunotherapy may potentially be a viable treatment strategy in AD intervention.Conclusion：Detecting changes in tau and targeting tau pathology represent a promising lead in the diagnosis and treatment of AD.
基金supported by the National Natural Science Foundation of China (21874078 and 22074072)Taishan Young Scholar Program of Shandong Province (tsqn20161027)+2 种基金the Natural Science Foundation of Shandong Province (ZR2019BH032)the People’s Livelihood Science and Technology Project of Qingdao (166257nsh and 173378nsh)the First-Class Discipline Project of Shandong Province。
