The Sertoli cell tight junction （T J） is the key component of the blood-testis barrier, where it sequesters developing germ cells undergoing spermatogenesis within the seminiferous tubules. Hormonally regulated clau...The Sertoli cell tight junction （T J） is the key component of the blood-testis barrier, where it sequesters developing germ cells undergoing spermatogenesis within the seminiferous tubules. Hormonally regulated claudin-11 is a critical transmembrane protein involved in barrier function and its murine knockout results in infertility. We aimed to assess quantitatively the significance of the contribution of claudin-11 to TJ function, in vitro, using siRNA-mediated gene silencing. We also conducted an analysis of the contribution of occludin, another intrinsic transmembrane protein of the TJ. Silencing of claudin-11 and/or occludin was conducted using siRNA in an immature rat Sertoli cell culture model. Transepithelial electrical resistance was used to assess quantitatively TJ function throughout the culture. Two days after siRNA treatment, cells were fixed for immunocytochemical localization of junction proteins or lyzed for RT-PCR assessment of mRNA expression. Silencing of claudin-11, occludin, or both resulted in significant decreases in TJ function of 55% （P 〈 0.01）, 51% （P 〈 0.01）, and 62% （P 〈 0.01）, respectively. Data were concomitant with significant decreases in mRNA expression and marked reductions in the localization of targeted proteins to the Sertoli cell TJ. We provide quantitative evidence that claudin-11 contributes significantly （P 〈 0.01） to Sertoli cell TJ function in vitro. Interestingly, occludin, which is hormonally regulated but not implicated in infertility until late adulthood, is also a significant （P 〈 0.01） contributor to barrier function. Our data are consistent with in vivo studies that clearly demonstrate a role for these proteins in maintaining normal TJ barrier structure and function.展开更多
Background： Cinnamicaldehyde（CA） is a key flavor compound in cinnamon essential oil possessing various bioactivities. Tight junction（TJ） proteins are vital for the maintenance of intestinal epithelial barrier fun...Background： Cinnamicaldehyde（CA） is a key flavor compound in cinnamon essential oil possessing various bioactivities. Tight junction（TJ） proteins are vital for the maintenance of intestinal epithelial barrier function,transport, absorption and utilization of dietary amino acids and other nutrients. In this study, we tested the hypothesis that CA may regulate the expression of TJ proteins and amino acid transporters in intestinal porcine epithelial cells（IPEC-1） isolated from neonatal pigs.Results： Compared with the control, cells incubated with 25 μmol/L CA had increased transepithelial electrical resistance（TEER） and decreased paracellular intestinal permeability. The beneficial effect of CA on mucosal barrier function was associated with enhanced protein abundance for claudin-4, zonula occludens（ZO）-1, ZO-2, and ZO-3. Immunofluorescence staining showed that 25 μmol/L CA promoted the localization of claudin-1 and claudin-3 to the plasma membrane without affecting the localization of other TJ proteins, including claudin-4, occludin,ZO-1, ZO-2, and ZO-3, compared with the control cells. Moreover, protein abundances for rBAT, xCT and LAT2 in IPEC-1 cells were enhanced by 25 μmol/L CA, while that for EAAT3 was not affected.Conclusions： CA improves intestinal mucosal barrier function by regulating the distribution of claudin-1 and claudin-3 in enterocytes, as well as enhancing protein abundance for amino acid transporters rBAT, xCT and LAT2 in enterocytes. Supplementation with CA may provide an effective nutritional strategy to improve intestinal integrity and amino acid transport and absorption in piglets.展开更多
We aimed to examine paracellular barrier function in cultured mouse lung microvascular endothelial cells (LMECs). The transcellular resistance of LMEC monolayers yielded an electrical resistance of approximately 19 Ω...We aimed to examine paracellular barrier function in cultured mouse lung microvascular endothelial cells (LMECs). The transcellular resistance of LMEC monolayers yielded an electrical resistance of approximately 19 Ω × cm<sup>2</sup> at days 6 - 7 in culture when the cells reached confluence, and paracellular permeable clearance of sodium fluorescein was the lowest on day 6 in culture, suggesting the formation of tight junctions (TJs) in cultured LMECs. Moreover, the expression of TJ-associated proteins, occludin, claudin-1 and -4 and zonula occludents 1 (ZO-1) was detected in LMECs at day 6 in culture. However, mRNAs of occludin, claudin-1 and -4 and ZO-1 were already expressed on day 1 after culture, and large variations were absent in the mRNA levels of occludin, claudin-4 and ZO-1 between days 1 and 7 in culture, when the level of each mRNA on day 1 in culture was used as a basal level. However, the claudin-1 mRNA level gradually increased up to approximately 7-fold on day 7 in culture over the basal level. These results indicate that the drastic increase in the mRNA expression level of claudin-1 leads to the strong formation of TJs.展开更多
AIM:To investigate the effect of herb-partitioned moxibustion combined with acupuncture on the expression of intestinal epithelial tight junction(TJ) proteins.METHODS:Sixty patients diagnosed with mild to moderate Cr...AIM:To investigate the effect of herb-partitioned moxibustion combined with acupuncture on the expression of intestinal epithelial tight junction(TJ) proteins.METHODS:Sixty patients diagnosed with mild to moderate Crohn’s disease(CD)were allocated into the herb-partitioned moxibustion combined with acupuncture(HMA)group(n=30)or the mesalazine(MESA)group(n=30)using a parallel control method.There were 2 sets of acupoints used alternately for HMA treatment.The following points were included in Set A:ST25(Tianshu),RN6(Qihai),and RN9(Shuifen)for herb-partitioned moxibustion and ST36(Zusanli),ST37(Shangjuxu),LI11(Quchi),and LI4(Hegu)for acupuncture.The points for Set B included BL23(Shenshu)and BL25(Dachangshu)for herb-partitioned moxibustion and EX-B2 of T6-T1(Jiajixue)fo r acupuncture.The patients received the same treatment6 times a week for 12 consecutive weeks.The MESA group received 1 g of mesalazine enteric coated tablets4 times daily for 12 consecutive weeks.Intestinaltissues were stained and examined to compare the morphological and ultrastructural changes before and after the treatment session.Immunohistochemistry and in situ hybridization assays were used to detect the expression of intestinal epithelial TJ proteins zonula occludens-1(ZO-1),occludin,and claudin-1.The m RNA levels were also evaluated.RESULTS:After the treatment,both herb-partitioned moxibustion combined with acupuncture and mesalazine improved intestinal morphology and ultrastructure of CD patients;the patients treated with HMA showed better improvement.HMA significantly increased the expression of ZO-1(P=0.000),occludin(P=0.021),and claudin-1(P=0.016).MESA significantly increased the expression of ZO-1(P=0.016)and occludin(P=0.026).However,there was no significant increase in the expression of claudin-1(P=0.935).There was no statistically significant difference between the two groups for the expression of occludin and claudin-1(P>0.05).The HMA group showed a significant improvement in ZO-1 expression compared to the MESA group(2333.34±352.51 vs 2160.38±307.08,P=0.047).HMA significantly increased the expression of ZO-1 m RNA(P=0.000),occludin m RNA(P=0.017),and claudin-1 m RNA(P=0.017).MESA significantly increased the expression of ZO-1 m RNA(P=0.000),occludin m RNA(P=0.042),and claudin-1 m RNA(P=0.041).There was no statistically significant difference between the two groups in the expression of occludin and claudin-1 m RNA(P>0.05).However,the HMA group showed a significant improvement in ZO-1 m RNA expression compared with the MESA group(2378.17±308.77 vs 2200.56±281.88,P=0.023).CONCLUSION:HMA can repair intestinal epithelial barrier lesions and relieve inflammation by upregulating the expression of TJ proteins and their m RNAs.展开更多
The pathogenesis of inflammatory bowel diseases (IBDs) seems to involve a primary defect in one or more of the elements responsible for the maintenance of intestinal homeostasis and oral tolerance. The most important ...The pathogenesis of inflammatory bowel diseases (IBDs) seems to involve a primary defect in one or more of the elements responsible for the maintenance of intestinal homeostasis and oral tolerance. The most important element is represented by the intestinal barrier, a complex system formed mostly by intestinal epithelial cells (IECs). IECs have an active role in producing mucus and regulating its composition; they provide a physical barrier capable of controlling antigen traff ic through the intestinal mucosa. At the same time, they are able to play the role of non-professional antigen presenting cells, by processing and presenting antigens directly to the cells of the intestinal immune system. On the other hand, immune cells regulate epithelial growth and differentiation, producing a continuous bi-directional cross-talk within the barrier. Several alterations of the barrier function have been identif ied in IBD, starting from mucus features up to its components, from epithelial junctions up to the Toll-like receptors, and altered immune responses. It remains to be understood whether these defects are primary causes of epithelial damage or secondary effects. We review the possible role of the epithelial barrier and particularly describe the role of IECs in the pathogenesis of IBD.展开更多
Shuxuetong injection composed of leech(Hirudo nipponica Whitman) and earthworm(Pheretima aspergillum) has been used for the clinical treatment of acute stroke for many years in China. However, the precise neuroprotect...Shuxuetong injection composed of leech(Hirudo nipponica Whitman) and earthworm(Pheretima aspergillum) has been used for the clinical treatment of acute stroke for many years in China. However, the precise neuroprotective mechanism of Shuxuetong injection remains poorly understood. Here, cerebral microvascular endothelial cells(bEnd.3) were incubated in glucose-free Dulbecco's modified Eagle's medium containing 95% N_2/5% CO_2 for 6 hours, followed by high-glucose medium containing 95% O_2 and 5% CO_2 for 18 hours to establish an oxygen-glucose deprivation/reperfusion model. This in vitro cell model was administered Shuxuetong injection at 1/32, 1/64, and 1/128 concentrations(diluted 32-, 64-, and 128-times). Cell Counting Kit-8 assay was used to evaluate cell viability. A fluorescence method was used to measure lactate dehydrogenase, and a fluorescence microplate reader used to detect intracellular reactive oxygen species. A fluorescent probe was also used to measure mitochondrial superoxide production. A cell resistance meter was used to measure transepithelial resistance and examine integrity of monolayer cells. The fluorescein isothiocyanate-dextran test was performed to examine blood-brain barrier permeability. Real-time reverse transcription polymerase chain reaction was performed to analyze mRNA expression levels of tumor necrosis factor alpha, interleukin-1β, interleukin-6, and inducible nitric oxide synthase. Western blot assay was performed to analyze expression of caspase-3, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, occludin, vascular endothelial growth factor, cleaved caspase-3, B-cell lymphoma 2, phosphorylated extracellular signal-regulated protein kinase, extracellular signal-regulated protein kinase, nuclear factor-κB p65, I kappa B alpha, phosphorylated I kappa B alpha, I kappa B kinase, phosphorylated I kappa B kinase, claudin-5, and zonula occludens-1. Our results show that Shuxuetong injection increases bEnd.3 cell viability and B-cell lymphoma 2 expression, reduces cleaved caspase-3 expression, inhibits production of reactive oxygen species and mitochondrial superoxide, suppresses expression of tumor necrosis factor alpha, interleukin-1β, interleukin-6, inducible nitric oxide synthase mRNA, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, markedly increases transepithelial resistance, decreases blood-brain barrier permeability, upregulates claudin-5, occludin, and zonula occludens-1 expression, reduces nuclear factor-κB p65 and vascular endothelial growth factor expression, and reduces I kappa B alpha, extracellular signal-regulated protein kinase 1/2, and I kappa B kinase phosphorylation levels. Overall, these findings suggest that Shuxuetong injection has protective effects on brain microvascular endothelial cells after oxygen-glucose deprivation/reperfusion. Moreover, its protective effect is associated with reduction of mitochondrial superoxide production, inhibition of the inflammatory response, and inhibition of vascular endothelial growth factor, extracellular signal-regulated protein kinase 1/2, and the nuclear factor-κB p65 signaling pathway.展开更多
Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and...Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and mechanisms are often deregulated in cancer. Aberrant signaling at cell-cell and cell-matrix adhesion sites often involves downstream mediators including Rho GTPases and tyrosine kinases. This review discusses these molecules as putative mediators of cellular crosstalk between cell-cell and cell-matrix adhesion sites, in addition to their attractiveness as therapeutic targets in cancer. Interestingly, inter-junctional crosstalk mechanisms are frequently typified by the way in which bacterial and viral pathogens opportunistically infect or intoxicate mammalian cells. This review therefore also discusses the concept of learning from pathogen-host interaction studies to better understand coordinated communication between cell-cell and cell-matrix adhesion sites, in addition to highlighting the potential therapeutic usefulness of exploiting pathogens or their products to tap into inter-junctional crosstalk. Taken together, we feel that increased knowledge around mechanisms of cell-cell and cell-matrix adhesion site crosstalk and consequently a greater understanding of their therapeutic targeting offers a unique opportunity to contribute to the emerging molecular revolution in cancer biology.展开更多
文摘The Sertoli cell tight junction （T J） is the key component of the blood-testis barrier, where it sequesters developing germ cells undergoing spermatogenesis within the seminiferous tubules. Hormonally regulated claudin-11 is a critical transmembrane protein involved in barrier function and its murine knockout results in infertility. We aimed to assess quantitatively the significance of the contribution of claudin-11 to TJ function, in vitro, using siRNA-mediated gene silencing. We also conducted an analysis of the contribution of occludin, another intrinsic transmembrane protein of the TJ. Silencing of claudin-11 and/or occludin was conducted using siRNA in an immature rat Sertoli cell culture model. Transepithelial electrical resistance was used to assess quantitatively TJ function throughout the culture. Two days after siRNA treatment, cells were fixed for immunocytochemical localization of junction proteins or lyzed for RT-PCR assessment of mRNA expression. Silencing of claudin-11, occludin, or both resulted in significant decreases in TJ function of 55% （P 〈 0.01）, 51% （P 〈 0.01）, and 62% （P 〈 0.01）, respectively. Data were concomitant with significant decreases in mRNA expression and marked reductions in the localization of targeted proteins to the Sertoli cell TJ. We provide quantitative evidence that claudin-11 contributes significantly （P 〈 0.01） to Sertoli cell TJ function in vitro. Interestingly, occludin, which is hormonally regulated but not implicated in infertility until late adulthood, is also a significant （P 〈 0.01） contributor to barrier function. Our data are consistent with in vivo studies that clearly demonstrate a role for these proteins in maintaining normal TJ barrier structure and function.
基金supported the National Natural Science Foundation of China(31572410,31572412,31625025)the 111 Project(B16044)+2 种基金the Program for New Century Excellent Talents in University(NCET-12-0522)the Agriculture and Food Research Initiative Competitive Grant from the USDA National Institute of Food and Agriculture(No.2014-6701521770)Texas A&M Agri Life Research(H-8200)
文摘Background： Cinnamicaldehyde（CA） is a key flavor compound in cinnamon essential oil possessing various bioactivities. Tight junction（TJ） proteins are vital for the maintenance of intestinal epithelial barrier function,transport, absorption and utilization of dietary amino acids and other nutrients. In this study, we tested the hypothesis that CA may regulate the expression of TJ proteins and amino acid transporters in intestinal porcine epithelial cells（IPEC-1） isolated from neonatal pigs.Results： Compared with the control, cells incubated with 25 μmol/L CA had increased transepithelial electrical resistance（TEER） and decreased paracellular intestinal permeability. The beneficial effect of CA on mucosal barrier function was associated with enhanced protein abundance for claudin-4, zonula occludens（ZO）-1, ZO-2, and ZO-3. Immunofluorescence staining showed that 25 μmol/L CA promoted the localization of claudin-1 and claudin-3 to the plasma membrane without affecting the localization of other TJ proteins, including claudin-4, occludin,ZO-1, ZO-2, and ZO-3, compared with the control cells. Moreover, protein abundances for rBAT, xCT and LAT2 in IPEC-1 cells were enhanced by 25 μmol/L CA, while that for EAAT3 was not affected.Conclusions： CA improves intestinal mucosal barrier function by regulating the distribution of claudin-1 and claudin-3 in enterocytes, as well as enhancing protein abundance for amino acid transporters rBAT, xCT and LAT2 in enterocytes. Supplementation with CA may provide an effective nutritional strategy to improve intestinal integrity and amino acid transport and absorption in piglets.
文摘We aimed to examine paracellular barrier function in cultured mouse lung microvascular endothelial cells (LMECs). The transcellular resistance of LMEC monolayers yielded an electrical resistance of approximately 19 Ω × cm<sup>2</sup> at days 6 - 7 in culture when the cells reached confluence, and paracellular permeable clearance of sodium fluorescein was the lowest on day 6 in culture, suggesting the formation of tight junctions (TJs) in cultured LMECs. Moreover, the expression of TJ-associated proteins, occludin, claudin-1 and -4 and zonula occludents 1 (ZO-1) was detected in LMECs at day 6 in culture. However, mRNAs of occludin, claudin-1 and -4 and ZO-1 were already expressed on day 1 after culture, and large variations were absent in the mRNA levels of occludin, claudin-4 and ZO-1 between days 1 and 7 in culture, when the level of each mRNA on day 1 in culture was used as a basal level. However, the claudin-1 mRNA level gradually increased up to approximately 7-fold on day 7 in culture over the basal level. These results indicate that the drastic increase in the mRNA expression level of claudin-1 leads to the strong formation of TJs.
基金Supported by National Natural Science Foundation of China,No.30772831,No.81473757the National Basic Research Program of China,973 Program,No.2009CB522900
文摘AIM:To investigate the effect of herb-partitioned moxibustion combined with acupuncture on the expression of intestinal epithelial tight junction(TJ) proteins.METHODS:Sixty patients diagnosed with mild to moderate Crohn’s disease(CD)were allocated into the herb-partitioned moxibustion combined with acupuncture(HMA)group(n=30)or the mesalazine(MESA)group(n=30)using a parallel control method.There were 2 sets of acupoints used alternately for HMA treatment.The following points were included in Set A:ST25(Tianshu),RN6(Qihai),and RN9(Shuifen)for herb-partitioned moxibustion and ST36(Zusanli),ST37(Shangjuxu),LI11(Quchi),and LI4(Hegu)for acupuncture.The points for Set B included BL23(Shenshu)and BL25(Dachangshu)for herb-partitioned moxibustion and EX-B2 of T6-T1(Jiajixue)fo r acupuncture.The patients received the same treatment6 times a week for 12 consecutive weeks.The MESA group received 1 g of mesalazine enteric coated tablets4 times daily for 12 consecutive weeks.Intestinaltissues were stained and examined to compare the morphological and ultrastructural changes before and after the treatment session.Immunohistochemistry and in situ hybridization assays were used to detect the expression of intestinal epithelial TJ proteins zonula occludens-1(ZO-1),occludin,and claudin-1.The m RNA levels were also evaluated.RESULTS:After the treatment,both herb-partitioned moxibustion combined with acupuncture and mesalazine improved intestinal morphology and ultrastructure of CD patients;the patients treated with HMA showed better improvement.HMA significantly increased the expression of ZO-1(P=0.000),occludin(P=0.021),and claudin-1(P=0.016).MESA significantly increased the expression of ZO-1(P=0.016)and occludin(P=0.026).However,there was no significant increase in the expression of claudin-1(P=0.935).There was no statistically significant difference between the two groups for the expression of occludin and claudin-1(P>0.05).The HMA group showed a significant improvement in ZO-1 expression compared to the MESA group(2333.34±352.51 vs 2160.38±307.08,P=0.047).HMA significantly increased the expression of ZO-1 m RNA(P=0.000),occludin m RNA(P=0.017),and claudin-1 m RNA(P=0.017).MESA significantly increased the expression of ZO-1 m RNA(P=0.000),occludin m RNA(P=0.042),and claudin-1 m RNA(P=0.041).There was no statistically significant difference between the two groups in the expression of occludin and claudin-1 m RNA(P>0.05).However,the HMA group showed a significant improvement in ZO-1 m RNA expression compared with the MESA group(2378.17±308.77 vs 2200.56±281.88,P=0.023).CONCLUSION:HMA can repair intestinal epithelial barrier lesions and relieve inflammation by upregulating the expression of TJ proteins and their m RNAs.
文摘The pathogenesis of inflammatory bowel diseases (IBDs) seems to involve a primary defect in one or more of the elements responsible for the maintenance of intestinal homeostasis and oral tolerance. The most important element is represented by the intestinal barrier, a complex system formed mostly by intestinal epithelial cells (IECs). IECs have an active role in producing mucus and regulating its composition; they provide a physical barrier capable of controlling antigen traff ic through the intestinal mucosa. At the same time, they are able to play the role of non-professional antigen presenting cells, by processing and presenting antigens directly to the cells of the intestinal immune system. On the other hand, immune cells regulate epithelial growth and differentiation, producing a continuous bi-directional cross-talk within the barrier. Several alterations of the barrier function have been identif ied in IBD, starting from mucus features up to its components, from epithelial junctions up to the Toll-like receptors, and altered immune responses. It remains to be understood whether these defects are primary causes of epithelial damage or secondary effects. We review the possible role of the epithelial barrier and particularly describe the role of IECs in the pathogenesis of IBD.
基金supported in part by the National Natural Science Foundation of China,No.81573644(to LMH),81573733(to SWX)the Tianjin 131 Innovative Team Project,China(to HW)+5 种基金the National Major Science and Technology Project of China,No.2012ZX09101201-004(to SWX)the Science and Technology Plan Project of Tianjin of China,No.16PTSYJC00120(to LMH)the Applied Foundation and Frontier Technology Research Program of Tianjin of China(General Project),No.14JCYBJC28900(to SXW)the National International Science and Technology Cooperation Project of China,No.2015DFA30430(to HW)the Key Program of the Natural Science Foundation of Tianjin of China,No.16ICZDJC36300(to HW)the Scientific Research and Technology Development Plan Project of Guangxi Zhuang Autonomous Region of China,No.14125008-2-5(to SXW)
文摘Shuxuetong injection composed of leech(Hirudo nipponica Whitman) and earthworm(Pheretima aspergillum) has been used for the clinical treatment of acute stroke for many years in China. However, the precise neuroprotective mechanism of Shuxuetong injection remains poorly understood. Here, cerebral microvascular endothelial cells(bEnd.3) were incubated in glucose-free Dulbecco's modified Eagle's medium containing 95% N_2/5% CO_2 for 6 hours, followed by high-glucose medium containing 95% O_2 and 5% CO_2 for 18 hours to establish an oxygen-glucose deprivation/reperfusion model. This in vitro cell model was administered Shuxuetong injection at 1/32, 1/64, and 1/128 concentrations(diluted 32-, 64-, and 128-times). Cell Counting Kit-8 assay was used to evaluate cell viability. A fluorescence method was used to measure lactate dehydrogenase, and a fluorescence microplate reader used to detect intracellular reactive oxygen species. A fluorescent probe was also used to measure mitochondrial superoxide production. A cell resistance meter was used to measure transepithelial resistance and examine integrity of monolayer cells. The fluorescein isothiocyanate-dextran test was performed to examine blood-brain barrier permeability. Real-time reverse transcription polymerase chain reaction was performed to analyze mRNA expression levels of tumor necrosis factor alpha, interleukin-1β, interleukin-6, and inducible nitric oxide synthase. Western blot assay was performed to analyze expression of caspase-3, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, occludin, vascular endothelial growth factor, cleaved caspase-3, B-cell lymphoma 2, phosphorylated extracellular signal-regulated protein kinase, extracellular signal-regulated protein kinase, nuclear factor-κB p65, I kappa B alpha, phosphorylated I kappa B alpha, I kappa B kinase, phosphorylated I kappa B kinase, claudin-5, and zonula occludens-1. Our results show that Shuxuetong injection increases bEnd.3 cell viability and B-cell lymphoma 2 expression, reduces cleaved caspase-3 expression, inhibits production of reactive oxygen species and mitochondrial superoxide, suppresses expression of tumor necrosis factor alpha, interleukin-1β, interleukin-6, inducible nitric oxide synthase mRNA, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, markedly increases transepithelial resistance, decreases blood-brain barrier permeability, upregulates claudin-5, occludin, and zonula occludens-1 expression, reduces nuclear factor-κB p65 and vascular endothelial growth factor expression, and reduces I kappa B alpha, extracellular signal-regulated protein kinase 1/2, and I kappa B kinase phosphorylation levels. Overall, these findings suggest that Shuxuetong injection has protective effects on brain microvascular endothelial cells after oxygen-glucose deprivation/reperfusion. Moreover, its protective effect is associated with reduction of mitochondrial superoxide production, inhibition of the inflammatory response, and inhibition of vascular endothelial growth factor, extracellular signal-regulated protein kinase 1/2, and the nuclear factor-κB p65 signaling pathway.
基金Supported by Past and present funding in the senior author’s laboratory as follows--Health Research Board of Ireland(HRA--POR-2014-545HRA/2009/49+6 种基金RP/2006/95,to Hopkins AM)Science Foundation Ireland(13/IA/19942008/RFP/NSC14272008/RFP/NSC1427 TIDA Feasibility 10,to Hopkins AM)Cancer Research Ireland,Breast Cancer IrelandBrazil Science Without Borders(CAPES-13306-13-8)the Beaumont Hospital Cancer Research and Development Trust
文摘Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and mechanisms are often deregulated in cancer. Aberrant signaling at cell-cell and cell-matrix adhesion sites often involves downstream mediators including Rho GTPases and tyrosine kinases. This review discusses these molecules as putative mediators of cellular crosstalk between cell-cell and cell-matrix adhesion sites, in addition to their attractiveness as therapeutic targets in cancer. Interestingly, inter-junctional crosstalk mechanisms are frequently typified by the way in which bacterial and viral pathogens opportunistically infect or intoxicate mammalian cells. This review therefore also discusses the concept of learning from pathogen-host interaction studies to better understand coordinated communication between cell-cell and cell-matrix adhesion sites, in addition to highlighting the potential therapeutic usefulness of exploiting pathogens or their products to tap into inter-junctional crosstalk. Taken together, we feel that increased knowledge around mechanisms of cell-cell and cell-matrix adhesion site crosstalk and consequently a greater understanding of their therapeutic targeting offers a unique opportunity to contribute to the emerging molecular revolution in cancer biology.
