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Suppressing Wnt signaling of the blood-tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2716-2731页

作者： Yang Tong Pei An Puxian Tang Rui Mu Yuteng Zeng Hang Sun Mei Zhao Ziyan Lv Pan Wang Wanjun Han Chunshan Gui Xuechu Zhen Liang Han Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences Soochow UniversitySuzhou 215123China Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development Soochow UniversitySuzhou 215123China

Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid *** inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low ***,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@*** the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model *** combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy *** Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

关键词： Lipogenesis Brain metastases blood-tumor barrier Wnt signaling Drug delivery Fatty acid synthase Nanoparticles Combination therapy

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Roles of protein kinase C and RhoA in the opening of blood-tumor barrier induced by low-dose endothelial monocyte-activating polypeptide-Ⅱ

Roles of protein kinase C and RhoA in the opening of blood-t...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Li-Bo LIU~1,Li ZHEN~2,Yun-Hui LIU~2,Yi-Xue XUE~(1,*) 1 Department of Neurobiology,College of Basic Medicine,China Medical University,Shenyang 110001,China 2 Department of Neurosurgery,Shengjing Hospital,China Medical University,Shenyang 110004,China

＜正＞Objective This study was performed with an in vitro blood-tumor barrier（BTB） model to investigate whether protein kinase C（PKC） and RhoA are involved in the low-dose endothelial monocyte-activating polypeptide-Ⅱ（EMAP-Ⅱ）-induced BTB *** The permeability of BTB model was detected by transendothelial electric resistance（TEER） and Horseradish peroxidase（HRP） *** total PKC activity was measured by using PKC Assay *** blot assay was used to test the protein expression of total PKC,PKC isoforms(a,p,y,e, 8,and Q,Rho A and tight junction（TJ）-associated proteins（occludin,cluadin-5 and ZO-1）.The distribution and expression changes of TJ associated proteins and cytoskeleton protein（F-actin） were tested by immunofluorescence *** In BMECs treated with EMAP-II（0.05 nmol/L） for 0.5 h and 1 h,the significant increases in total PKC activity and the protein expression of total PKC were ***,the protein expression of 3 PKC isoforms(PKC-a,P and Q and RhoA significantly increased at 0.5 h and 1 h after EMAP-Ⅱadministration and then recovered at 4 *** and HRP flux assays revealed that pretreatment with PKC inhibitor H7,RhoA inhibitor C3 exoenzyme or a combination of the two inhibitors significantly blocked the EMAP-Ⅱ-induced BTB permeability ***,our data showed that the EMAP-Ⅱ-induced downregulation of occludin,claudin-5,ZO-1 as well as F-actin was also significantly inhibited by pretreatment with H7,C3 exoenzyme or a combination of H7 and C3 *** In summary,our present study suggests that PKC and RhoA play crucial roles in the process of EMAP-Ⅱinducing progressive changes to BMECs of BTB,including downregulation of tight junction proteins, reorganization of actin cytoskeleton,and increasing of BTB permeability.

关键词： endothelial monocyte-activating polypeptide-Ⅱ blood-tumor barrier permeability protein kinase C RhoA

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Bradykinin down-regulating the expression levels of ZO-1,occludin and disrupting actin cytoskeleton in experimental gliom rats

Bradykinin down-regulating the expression levels of ZO-1,occ...

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中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Li-Bo LIU,Yi-XueXUE Department of Neurobiology,College of Basic Medicine,China Medical University,Shenyang 110001,China

＜正＞Objective Tight junction（TJ） is an important structural and functional basis of maintaining blood-brain barrier （BBB） ***（BK） has been shown to selectively open blood-tumor barrier（BTB） and increase permeability of the BTB transiently,but the identified mechanism is unclear and little is known about the changes of zonula occluden- 1（ZO-1）,occludin and filamentous-actin（F-actin） expression after bradykinin *** study is performed to determine whether bradykinin opens the BTB by affecting TJ associated proteins ZO-1,occludin and cytoskeleton protein Factin. Methods Experimental rat brain glioma models were established by injecting C6 glioma cells through a Hamilton syringe and the stereotaxic *** were divided into seven groups randomly（n = 8 per group）:control group,BK 0 min group,BK 5 min group,BK 10 min group,BK 15 min group,BK 30 min group and BK 60 min *** control groups, rats were given the same amount of sterile saline（10μg/kg per minute） for 15 *** permeability of blood-brain barrier （BBB） and blood-tumor barrier（BTB） were quantitatively evaluated by extravasation of Evans blue after BK infusion. Immunohistochemistry assay was used to analyze the distribution and expression levels of ZO-1 and occludin in tumor *** immunolocalization and protein expression levels of ZO-1,occludin and F-actin in tumor capillaries were determined by indirect and direct *** blot assay was used to detect the change of protein expression levels of ZO-1 and occludin in tumor *** In rat brain glioma model,we found that extravasation content and blue-staining of Evans blue were significantly increased selectively and BTB function was attenuated after BK infusion,and the most obviously change appeared at 15 min（BK 15 min group vs control group and BK 0 min group,respectively,P＜0.01）.Immunohistochemistry and immunofluorescence assays show that BK changes the distribution and down-regulates

关键词： blood-brain barrier blood-tumor barrier tight junction bradykinin glioma

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