Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATPbinding ...Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATPbinding cassette(ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.展开更多
Terrestrial plants have two to four times more ATP-binding cassette （ABC） transporter genes than other organisms, including their ancestral microalgae. Recent studies found that plants harboring mutations in these t...Terrestrial plants have two to four times more ATP-binding cassette （ABC） transporter genes than other organisms, including their ancestral microalgae. Recent studies found that plants harboring mutations in these transporters exhibit dramatic phenotypes, many of which are related to developmental processes and functions necessary for life on dry land. These results suggest that ABC transporters multiplied during evolution and assumed novel functions that allowed plants to adapt to terrestrial environmental conditions. Examining the literature on plant ABC transporters from this viewpoint led us to propose that diverse ABC transporters enabled many unique and essential aspects of a terrestrial plant＇s lifestyle, by transporting various compounds across specific membranes of the plant.展开更多
[A Review] LXRs,LXRα and LXRβ are ligand-activated transcription factors that are members of the nuclear receptor superfamily.LXRs preferentially bind with their heterodimeric partner,retinoid X receptor(RXR),to LXR...[A Review] LXRs,LXRα and LXRβ are ligand-activated transcription factors that are members of the nuclear receptor superfamily.LXRs preferentially bind with their heterodimeric partner,retinoid X receptor(RXR),to LXR response elements to activate gene expression.Cellular and whole-body cholesterol homeostasis is maintained through a network of transcriptional programs.Liver X receptors regulate key aspects of cellular and whole-body sterol homeostasis,including cholesterol absorption,lipoprotein synthesis and remodeling,lipoprotein uptake by peripheral tissues,reverse cholesterol transport,and bile acid synthesis and absorption.This review focuses on the role of liver X receptors in the control of cholesterol homeostasis.展开更多
AIM: To evaluate ATP-binding cassette(ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer(CRC) development. METHODS: Literature search was conducted on Pub Med using com...AIM: To evaluate ATP-binding cassette(ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer(CRC) development. METHODS: Literature search was conducted on Pub Med using combinations of the following terms: ABC transporters, ATP binding cassette transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein(P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2(MRP2) and ABCG2/breast cancer resistance protein(BCRP), Abcb1/Mdr1 a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function. RESULTS: Recently, human studies reported thatchanges in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of hostmicrobiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogenfree Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that ABCB1 expression identifies a subpopulation of pro-inflamm展开更多
目的:以THP-1源性泡沫细胞为研究对象,探讨血管紧张素Ⅱ(AngⅡ)对THP-1源性泡沫细胞ATP结合盒转运子A1(ABCA1)表达、细胞内胆固醇含量及胆固醇流出的影响。方法:运用逆转录-多聚酶链反应(RT-PCR)和W estern b lotting分别检测AngⅡ对ABC...目的:以THP-1源性泡沫细胞为研究对象,探讨血管紧张素Ⅱ(AngⅡ)对THP-1源性泡沫细胞ATP结合盒转运子A1(ABCA1)表达、细胞内胆固醇含量及胆固醇流出的影响。方法:运用逆转录-多聚酶链反应(RT-PCR)和W estern b lotting分别检测AngⅡ对ABCA1 mRNA与ABCA1蛋白表达的影响,采用酶法,通过荧光分光光度计检测细胞内胆固醇含量,应用液体闪烁计数仪检测胆固醇流出的变化。结果:AngⅡ能引起THP-1源性泡沫细胞胆固醇含量显著升高(P<0.05)、ABCA1表达显著减少(P<0.05),AngⅡ受体拮抗剂厄贝沙坦(Irb)能显著减少细胞内胆固醇含量(P<0.05)、促进细胞内胆固醇流出及减轻AngⅡ对ABCA1的抑制作用(P<0.05)。结论:AngⅡ有通过其受体抑制ABCA1表达,促进泡沫细胞形成,加速动脉粥样硬化的作用。展开更多
目的探索在人胆囊癌GBC-SD细胞系中是否存在具有干细胞特性的SP细胞（side population cells）群。方法采用荧光激活细胞分选技术（FACS）分选出人胆囊癌SP细胞、非SP细胞。培养3～5周后再次进行FACS，用以检测SP细胞的分化情况。利用...目的探索在人胆囊癌GBC-SD细胞系中是否存在具有干细胞特性的SP细胞（side population cells）群。方法采用荧光激活细胞分选技术（FACS）分选出人胆囊癌SP细胞、非SP细胞。培养3～5周后再次进行FACS，用以检测SP细胞的分化情况。利用流式细胞术检测ABCG2蛋白在SP细胞的表达。结果SP细胞群在人胆囊癌GBC-SD细胞中占（0．64±0．08）％，分离出的SP细胞在培养3～5周后会产生SP细胞和非SP细胞，而非SP细胞则不具备此特性；并且ABCG2在胆囊癌SP细胞群中呈现出高表达状态[（89．56±3．86）％]，在非SP细胞中几乎不表达[（1．32±0．49）％]，两者之间的差异具有统计学意义（P〈0．01）。结论人胆囊癌GBC-SD细胞系中存在着很少量的干细胞样SP细胞群，并且高表达ABCG2。展开更多
Objective:Side population(SP) cells may play a crucial role in tumorigenesis and the recurrence of cancer.Many kinds of cell lines and tissues have demonstrated the presence of SP cells,including several gastric cance...Objective:Side population(SP) cells may play a crucial role in tumorigenesis and the recurrence of cancer.Many kinds of cell lines and tissues have demonstrated the presence of SP cells,including several gastric cancer cell lines.This study is aimed to identify the cancer stem-like cells in the SP of gastric cancer cell line MKN-45.Methods:We used fluorescence activated cell sorting(FACS) to sort SP cells in the human gastric carcinoma cell line MKN-45(cells labeled with Hoechst 33342) and then characterized the cancer stem-like properties of SP cells.Results:This study found that the SP cells had higher clone formation efficiency than major population(MP) cells.Five stemness-related gene expression profiles,including OCT-4,SOX-2,NANOG,CD44,and adenosine triphosphate(ATP)-binding cassette transporters gene ABCG2,were tested in SP and MP cells using quantitative real-time reverse transcription polymerase chain reaction(RT-PCR).Western blot was used to show the difference of protein expression between SP and MP cells.Both results show that there was significantly higher protein expression in SP cells than in MP cells.When inoculated into non-obese diabetic/severe combined immunodeficiency(NOD/SCID) mice,SP cells show higher tumorigenesis tendency than MP cells.Conclusions:These results indicate that SP cells possess cancer stem cell properties and prove that SP cells from MKN-45 are gastric cancer stem-like cells.展开更多
AIM: To explore the micro RNA(mi RNA) profiles and to determine the key mi RNAs within the side population(SP) cells of the gastric cancer cell line MKN-45. METHODS: We used fluorescence-activated cell sorting and Hoe...AIM: To explore the micro RNA(mi RNA) profiles and to determine the key mi RNAs within the side population(SP) cells of the gastric cancer cell line MKN-45. METHODS: We used fluorescence-activated cell sorting and Hoechst 33342 labeling to obtain SP cells from the human gastric carcinoma cell line MKN-45. The mi RNA expression profiles of the SP and major population(MP) cells were examined using a mi RNA gene chip, and key mi RNAs were obtained according to aberrant expression and the mi RNAs' possible targets as predicted by bioinformatics. RESULTS: Using a significance criterion of a 1.5-fold or greater difference in expression level, we observed an increase in the expression of 34 mi RNAs and a decrease in the expression of 34 mi RNAs when comparing SP to MP cells. Using quantitative real-time reverse transcription-polymerase chain reaction to test for differentially expressed mi RNAs combined with bioinformatics results, we found that the downregulated mi RNAs, such as hsa-mi R-3175 and hsa-mi R-203, and the upregulated mi RNAs, including hsa-mi R-130 a, hsa-mi R-324-5p, hsa-mi R-34 a, and hsa-mi R-25-star, may be important in maintaining and regulating the characteristics of SP cells. CONCLUSION: There are key mi RNAs expressed within the SP cells of the gastric cancer cell line MKN-45, andinclude hsa-mi R-3175, hsa-mi R-203, hsa-mi R-130 a, hsami R-324-5p, hsa-mi R-34 a, and hsa-mi R-25-star.展开更多
Pancreatic ductal adenocarcinoma(PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasin...Pancreatic ductal adenocarcinoma(PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATPbinding cassette(ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance(MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.展开更多
OBJECTIVE: To evaluate the efficacy of Shoushen granule, prepared with four Chinese medicinals, on the targeted regulation of adenosine triphosphate binding cassette transporter A1(ABCA1) through proprotein convertase...OBJECTIVE: To evaluate the efficacy of Shoushen granule, prepared with four Chinese medicinals, on the targeted regulation of adenosine triphosphate binding cassette transporter A1(ABCA1) through proprotein convertase subtilisin/kexin type 9(PCSK9) and toll-like receptor 4(TLR4)/nuclear factor kappa-B(NF-κB) signaling pathway to affect atherosclerosis(AS) in ApoE-knockout(ApoE-/-) mice.METHODS: ApoE-/-mice fed with a high-fat diet were used for AS modeling and divided into Model,Shoushen, and Atorvastatin groups. C57 BL/6 J mice at the same age and background strain were included in the Control group. Western blot and immunohistochemistry were used to measure ABCA1, PCSK9, TLR4, and NF-κB protein expression in mouse aortas. Enzyme-linked immuno sorbent assay was used to measure mouse serum tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), monocyte chemoattractant protein 1(MCP-1), and intercellular cell adhesion molecule-1(ICAM-1) expression. Serum lipid profiles and histopathology were also assessed. Shoushen granule were composed of Heshouwu(Radix Polygoni Multiflori) 15 g, Gouqizi(Fructus Lycii) 15 g, Sheng shanzha(Raw Fructus Crataegus Pinnatifidae) 10 g, and Sanqi(Radix Notoginseng) 3 g.RESULTS: ApoE-/-mice fed with a high-fat diet had notable AS lesions, with reduced ABCA1 and IL-10 levels, elevated PCSK9, TLR4, NF-κB, TNF-α, MCP-1,and ICAM-1 expression, and increased total cholesterol(TC) and low density lipoprotein cholesterol(LDL-C) contents. With drug interventions, the areas of AS plaques were significantly reduced,the ABCA1 and IL-10 levels were increase, while the PCSK9, TLR4, NF-κB, TC, and LDL-C contents,and the TNF-α, MCP-1, and ICAM-1 expression were reduced.CONCLUSION: Shoushen granule effectively interfered with AS development by antagonizing the expression of key factors of the PCSK9 and TLR4/NF-κB signaling pathway to upregulate ABCA1 expression.展开更多
文摘Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATPbinding cassette(ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.
文摘Terrestrial plants have two to four times more ATP-binding cassette （ABC） transporter genes than other organisms, including their ancestral microalgae. Recent studies found that plants harboring mutations in these transporters exhibit dramatic phenotypes, many of which are related to developmental processes and functions necessary for life on dry land. These results suggest that ABC transporters multiplied during evolution and assumed novel functions that allowed plants to adapt to terrestrial environmental conditions. Examining the literature on plant ABC transporters from this viewpoint led us to propose that diverse ABC transporters enabled many unique and essential aspects of a terrestrial plant＇s lifestyle, by transporting various compounds across specific membranes of the plant.
文摘[A Review] LXRs,LXRα and LXRβ are ligand-activated transcription factors that are members of the nuclear receptor superfamily.LXRs preferentially bind with their heterodimeric partner,retinoid X receptor(RXR),to LXR response elements to activate gene expression.Cellular and whole-body cholesterol homeostasis is maintained through a network of transcriptional programs.Liver X receptors regulate key aspects of cellular and whole-body sterol homeostasis,including cholesterol absorption,lipoprotein synthesis and remodeling,lipoprotein uptake by peripheral tissues,reverse cholesterol transport,and bile acid synthesis and absorption.This review focuses on the role of liver X receptors in the control of cholesterol homeostasis.
文摘AIM: To evaluate ATP-binding cassette(ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer(CRC) development. METHODS: Literature search was conducted on Pub Med using combinations of the following terms: ABC transporters, ATP binding cassette transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein(P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2(MRP2) and ABCG2/breast cancer resistance protein(BCRP), Abcb1/Mdr1 a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function. RESULTS: Recently, human studies reported thatchanges in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of hostmicrobiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogenfree Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that ABCB1 expression identifies a subpopulation of pro-inflamm
文摘目的:以THP-1源性泡沫细胞为研究对象,探讨血管紧张素Ⅱ(AngⅡ)对THP-1源性泡沫细胞ATP结合盒转运子A1(ABCA1)表达、细胞内胆固醇含量及胆固醇流出的影响。方法:运用逆转录-多聚酶链反应(RT-PCR)和W estern b lotting分别检测AngⅡ对ABCA1 mRNA与ABCA1蛋白表达的影响,采用酶法,通过荧光分光光度计检测细胞内胆固醇含量,应用液体闪烁计数仪检测胆固醇流出的变化。结果:AngⅡ能引起THP-1源性泡沫细胞胆固醇含量显著升高(P<0.05)、ABCA1表达显著减少(P<0.05),AngⅡ受体拮抗剂厄贝沙坦(Irb)能显著减少细胞内胆固醇含量(P<0.05)、促进细胞内胆固醇流出及减轻AngⅡ对ABCA1的抑制作用(P<0.05)。结论:AngⅡ有通过其受体抑制ABCA1表达,促进泡沫细胞形成,加速动脉粥样硬化的作用。
文摘目的探索在人胆囊癌GBC-SD细胞系中是否存在具有干细胞特性的SP细胞（side population cells）群。方法采用荧光激活细胞分选技术（FACS）分选出人胆囊癌SP细胞、非SP细胞。培养3～5周后再次进行FACS，用以检测SP细胞的分化情况。利用流式细胞术检测ABCG2蛋白在SP细胞的表达。结果SP细胞群在人胆囊癌GBC-SD细胞中占（0．64±0．08）％，分离出的SP细胞在培养3～5周后会产生SP细胞和非SP细胞，而非SP细胞则不具备此特性；并且ABCG2在胆囊癌SP细胞群中呈现出高表达状态[（89．56±3．86）％]，在非SP细胞中几乎不表达[（1．32±0．49）％]，两者之间的差异具有统计学意义（P〈0．01）。结论人胆囊癌GBC-SD细胞系中存在着很少量的干细胞样SP细胞群，并且高表达ABCG2。
基金Project (Nos.81000706/H1108 and 81172368) supported by the National Natural Science Foundation of China
文摘Objective:Side population(SP) cells may play a crucial role in tumorigenesis and the recurrence of cancer.Many kinds of cell lines and tissues have demonstrated the presence of SP cells,including several gastric cancer cell lines.This study is aimed to identify the cancer stem-like cells in the SP of gastric cancer cell line MKN-45.Methods:We used fluorescence activated cell sorting(FACS) to sort SP cells in the human gastric carcinoma cell line MKN-45(cells labeled with Hoechst 33342) and then characterized the cancer stem-like properties of SP cells.Results:This study found that the SP cells had higher clone formation efficiency than major population(MP) cells.Five stemness-related gene expression profiles,including OCT-4,SOX-2,NANOG,CD44,and adenosine triphosphate(ATP)-binding cassette transporters gene ABCG2,were tested in SP and MP cells using quantitative real-time reverse transcription polymerase chain reaction(RT-PCR).Western blot was used to show the difference of protein expression between SP and MP cells.Both results show that there was significantly higher protein expression in SP cells than in MP cells.When inoculated into non-obese diabetic/severe combined immunodeficiency(NOD/SCID) mice,SP cells show higher tumorigenesis tendency than MP cells.Conclusions:These results indicate that SP cells possess cancer stem cell properties and prove that SP cells from MKN-45 are gastric cancer stem-like cells.
基金Supported by National Natural Science Fund,No.81000706/H1108National Key Technology Research and Development Program,No.2012BA141B01the Air Force General Hospital of Chinese PLA Innovation Fund,No.KZ2013035
文摘AIM: To explore the micro RNA(mi RNA) profiles and to determine the key mi RNAs within the side population(SP) cells of the gastric cancer cell line MKN-45. METHODS: We used fluorescence-activated cell sorting and Hoechst 33342 labeling to obtain SP cells from the human gastric carcinoma cell line MKN-45. The mi RNA expression profiles of the SP and major population(MP) cells were examined using a mi RNA gene chip, and key mi RNAs were obtained according to aberrant expression and the mi RNAs' possible targets as predicted by bioinformatics. RESULTS: Using a significance criterion of a 1.5-fold or greater difference in expression level, we observed an increase in the expression of 34 mi RNAs and a decrease in the expression of 34 mi RNAs when comparing SP to MP cells. Using quantitative real-time reverse transcription-polymerase chain reaction to test for differentially expressed mi RNAs combined with bioinformatics results, we found that the downregulated mi RNAs, such as hsa-mi R-3175 and hsa-mi R-203, and the upregulated mi RNAs, including hsa-mi R-130 a, hsa-mi R-324-5p, hsa-mi R-34 a, and hsa-mi R-25-star, may be important in maintaining and regulating the characteristics of SP cells. CONCLUSION: There are key mi RNAs expressed within the SP cells of the gastric cancer cell line MKN-45, andinclude hsa-mi R-3175, hsa-mi R-203, hsa-mi R-130 a, hsami R-324-5p, hsa-mi R-34 a, and hsa-mi R-25-star.
文摘Pancreatic ductal adenocarcinoma(PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATPbinding cassette(ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance(MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.
基金Supported by the National Natural Science Foundation of China(The Role of TLR4/MyD88/NF-κB Signal Transduction Pathway and Expression of miRNA-146a in Atherosclerosis and the Intervention Mechanism of Shen Invigorating Compounds,No.81202731Bushen Jiangzhi Recipe Protects Against Atherosclerosis via miR-27a-mediated PCSK9/ABCA1 Pathway,No.81873348)+2 种基金the Shanghai Natural Science Found(Inhibitory Mechanism of Chinese Herbal Compound,Shoushen Granule,for Invigorating Kidney in ApoE-/-Atherosclerosis Mouse Model by mir-19b Target Regulating ABCA1,No.16ZR1433900)the Shanghai Municipal Commission of Health and Family Planning Found(Effect of Kidney Invigoration and Lipid Intervention on the Atherosclerosis in ApoE-knockout Mice Based on mT OR signaling pathway of Autophagy System,No.201640217)Shanghai University of Traditional Chinese Medicine graduate"innovation ability training"special research projects(Mechanism of Bushen Jiangzhi Recipe Regulating TLR4/NF-κB Signaling Pathway Mediated by CD36 Through PCSK9 Targeted Regulation of apoE-/-mice Atherosclerosis,No.Y201858)
文摘OBJECTIVE: To evaluate the efficacy of Shoushen granule, prepared with four Chinese medicinals, on the targeted regulation of adenosine triphosphate binding cassette transporter A1(ABCA1) through proprotein convertase subtilisin/kexin type 9(PCSK9) and toll-like receptor 4(TLR4)/nuclear factor kappa-B(NF-κB) signaling pathway to affect atherosclerosis(AS) in ApoE-knockout(ApoE-/-) mice.METHODS: ApoE-/-mice fed with a high-fat diet were used for AS modeling and divided into Model,Shoushen, and Atorvastatin groups. C57 BL/6 J mice at the same age and background strain were included in the Control group. Western blot and immunohistochemistry were used to measure ABCA1, PCSK9, TLR4, and NF-κB protein expression in mouse aortas. Enzyme-linked immuno sorbent assay was used to measure mouse serum tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), monocyte chemoattractant protein 1(MCP-1), and intercellular cell adhesion molecule-1(ICAM-1) expression. Serum lipid profiles and histopathology were also assessed. Shoushen granule were composed of Heshouwu(Radix Polygoni Multiflori) 15 g, Gouqizi(Fructus Lycii) 15 g, Sheng shanzha(Raw Fructus Crataegus Pinnatifidae) 10 g, and Sanqi(Radix Notoginseng) 3 g.RESULTS: ApoE-/-mice fed with a high-fat diet had notable AS lesions, with reduced ABCA1 and IL-10 levels, elevated PCSK9, TLR4, NF-κB, TNF-α, MCP-1,and ICAM-1 expression, and increased total cholesterol(TC) and low density lipoprotein cholesterol(LDL-C) contents. With drug interventions, the areas of AS plaques were significantly reduced,the ABCA1 and IL-10 levels were increase, while the PCSK9, TLR4, NF-κB, TC, and LDL-C contents,and the TNF-α, MCP-1, and ICAM-1 expression were reduced.CONCLUSION: Shoushen granule effectively interfered with AS development by antagonizing the expression of key factors of the PCSK9 and TLR4/NF-κB signaling pathway to upregulate ABCA1 expression.
