The micro RNA（mi RNA） let-7 was one of the first mi RNAs to be discovered, and is highly conserved and widely expressed among species. let-7 expression increases in brain tissue after cerebral ischemia/reperfusion i...The micro RNA（mi RNA） let-7 was one of the first mi RNAs to be discovered, and is highly conserved and widely expressed among species. let-7 expression increases in brain tissue after cerebral ischemia/reperfusion injury; however, no studies have reported let-7 effects on nerve injury after cerebral ischemia/reperfusion injury. To investigate the effects of let-7 gene knockdown on cerebral ischemia/reperfusion injury, we established a rat model of cerebral ischemia/reperfusion injury. Quantitative reverse transcription-polymerase chain reaction demonstrated that 12 hours after cerebral ischemia/reperfusion injury, let-7 expression was up-regulated, peaked at 24 hours, and was still higher than that in control rats after 72 hours. Let-7 gene knockdown in rats suppressed microglial activation and inflammatory factor release, reduced neuronal apoptosis and infarct volume in brain tissue after cerebral ischemia/reperfusion injury. Western blot assays and luciferase assays revealed that mitogen-activated protein kinase phosphatase-1（MKP1） is a direct target of let-7. Let-7 enhanced phosphorylated p38 mitogen-activated protein kinase（MAPK） and c-Jun N-terminal kinase（JNK） expression by down-regulating MKP1. These findings suggest that knockdown of let-7 inhibited the activation of p38 MAPK and JNK signaling pathways by up-regulating MKP1 expression, reduced apoptosis and the inflammatory reaction, and exerted a neuroprotective effect following cerebral ischemia/reperfusion injury.展开更多
Human dental pulp cells （hDPCs） possess the capacity to differentiate into odontoblast-like cells and generate reparative dentin in response to exogenous stimuli or injury. Ten-eleven translocation 1 （TET1） is a n...Human dental pulp cells （hDPCs） possess the capacity to differentiate into odontoblast-like cells and generate reparative dentin in response to exogenous stimuli or injury. Ten-eleven translocation 1 （TET1） is a novel DNA methyldioxygenase that plays an important role in the promotion of DNA demethylation and transcriptional regulation in several cell lines. However, the role of TET1 in the biological functions of hDPCs is unknown. To investigate the effect of TET1 on the proliferation and odontogenic differentiation potential of hDPCs, a recombinant shRNA lentiviral vector was used to knock down TET1 expression in hDPCs. Following TET1 knockdown, TET1 was significantly downregulated at both the mRNA and protein levels. Proliferation of the hDPCs was suppressed in the TET1 knockdown groups. Alkaline phosphatase activity, the formation of mineralized nodules, and the expression levels of DSPP and DMP1 were all reduced in the TETl-knockdown hDPCs undergoing odontogenic differentiation. Based on these results, we concluded that TET1 knockdown can prevent the proliferation and odontogenic differentiation of hDPCs, which suggests that TET1 may play an important role in dental pulp repair and regeneration.展开更多
Fankl is exclusively expressed in the testis from the meiosis phase to the haploid phase of spermatogenesis. In this study, we examined the function of Fankl by establishing a Fankl-knockdown transgenic mouse model. T...Fankl is exclusively expressed in the testis from the meiosis phase to the haploid phase of spermatogenesis. In this study, we examined the function of Fankl by establishing a Fankl-knockdown transgenic mouse model. The apoptotic statuses of the testes of the transgenic mice were tested using the terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） method. The FANK1 consensus DNA-binding sequence was identified using cyclic amplification of sequence target （CAST） analysis. Differentially expressed genes were examined using microarray analysis. A reduction in sperm number and an increase in apoptotic spermatocytes were observed in Fankl-knockdown mice, and the apoptotic cells were found to be primarily spermatogonia and spermatocytes. The CAST results demonstrated that the consensus DNA-binding sequence was AAAAAG, in which the percentage occurrence of each base at each position ranged from 55 to 86%. This sequence was present in the promoter regions of 10 differentially expressed genes that were examined using microarray analysis. In total, 17 genes were differentially expressed with changes in their expression levels greater than twofold. The abnormal expression of Fankl target genes that were regulated directly or indirectly by Fankl reduced the number of sperm in the knockdown mice. Thus, FANK1 may Dlav a pivotal role in sDermato^enesis as a transcription factor.Fankl is exclusively expressed in the testis from the meiosis phase to the haploid phase of spermatogenesis. In this study, we examined the function of Fankl by establishing a Fankl-knockdown transgenic mouse model. The apoptotic statuses of the testes of the transgenic mice were tested using the terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） method. The FANK1 consensus DNA-binding sequence was identified using cyclic amplification of sequence target （CAST） analysis. Differentially expressed genes were examined using microarray analysis, A reduction in sperm number and an increase in apoptotic sperm展开更多
背景:溶质载体家族1成员5(solute carrier family 1 member 5,SLC1A5)在多种疾病中发挥了潜在作用,但确切作用机制尚不清楚。构建稳定的SLC1A5过表达和敲低细胞模型可为深入研究SLC1A5在疾病中的确切作用机制以及发现潜在治疗靶点提供...背景:溶质载体家族1成员5(solute carrier family 1 member 5,SLC1A5)在多种疾病中发挥了潜在作用,但确切作用机制尚不清楚。构建稳定的SLC1A5过表达和敲低细胞模型可为深入研究SLC1A5在疾病中的确切作用机制以及发现潜在治疗靶点提供有力的实验工具。目的:构建小鼠SLC1A5过表达和敲低的慢病毒载体,以建立稳定转染的RAW264.7细胞株,为深入探讨SLC1A5在炎症中的作用提供实验基础。方法:根据SLC1A5基因序列设计合成引物并使用聚合酶链反应扩增该基因片段。将目的基因定向接入经Age I/Nhe I酶切的载体质粒GV492中构建重组慢病毒质粒,对阳性克隆进一步筛选后测序比对结果;pHelper1.0质粒载体、pHelper2.0质粒载体、目的质粒载体与293T细胞共同培养并转染,获得慢病毒原液进行包装和滴度测定;在此基础上,通过体外培养RAW264.7细胞,确定嘌呤霉素工作质量浓度;不同滴度的慢病毒分别与RAW264.7细胞共同培养,根据荧光强度确定转染效率;用嘌呤霉素挑选出稳定转染细胞,实时荧光定量聚合酶链反应和蛋白免疫印迹方法检测稳定转染细胞株的SLC1A5基因和蛋白表达水平。结果与结论:(1)测序序列与目的序列一致提示重组慢病毒载体构建成功;(2)过表达SLC1A5慢病毒的滴度为1×10~9 TU/mL,敲低SLC1A5慢病毒的滴度为3×10~9 TU/mL;(3)确定RAW264.7细胞嘌呤霉素工作质量浓度为3μg/mL;(4)过表达/敲低SLC1A5慢病毒转染RAW264.7细胞的最佳条件皆为HiTransG P转染增强液且感染复数值等于50;(5)过表达SLC1A5稳转细胞株中SLC1A5基因和蛋白的表达量明显上调,而敲低SLC1A5稳转细胞株中SLC1A5基因和蛋白的表达量显著下调。结果表明,成功构建了小鼠SLC1A5过表达和敲低的慢病毒载体并获得稳定转染的RAW264.7细胞株。展开更多
Doxorubicin is a commonly used chemotherapy drug for cancer treatment,although its effectiveness varies across different cancer types.p53 is a key factor involved in cell death induced by therapeutic agents,and it can...Doxorubicin is a commonly used chemotherapy drug for cancer treatment,although its effectiveness varies across different cancer types.p53 is a key factor involved in cell death induced by therapeutic agents,and it can be upregulated by doxorubicin,exhibiting a function of apoptosis.To further investigate the mechanism between p53 and doxorubicin,this study explored whether p53 plays a role in doxorubicin-induced cell death in the colorectal cancer line HCT116.The findings revealed that p53 was upregulated in HCT116 cells when treated with doxorubicin,and the knockdown of p53 decreased the sensitivity of HCT116 cells to doxorubicin.These results suggest that p53 plays an important role in doxorubicin-induced cell death in HCT116 cells,potentially contributing to more effective treatment approaches.展开更多
BACKGROUND The role of Sm-like 5(LSM5)in colon cancer has not been determined.In this study,we investigated the role of LSM5 in progression of colon cancer and the potential underlying mechanism involved.AIM To determ...BACKGROUND The role of Sm-like 5(LSM5)in colon cancer has not been determined.In this study,we investigated the role of LSM5 in progression of colon cancer and the potential underlying mechanism involved.AIM To determine the role of LSM5 in the progression of colon cancer and the potential underlying mechanism involved.METHODS The Gene Expression Profiling Interactive Analysis database and the Human Protein Atlas website were used for LSM5 expression analysis and prognosis analysis.Real-time quantitative polymerase chain reaction and Western blotting were utilized to detect the expression of mRNAs and proteins.A lentivirus targeting LSM5 was constructed and transfected into colon cancer cells to silence LSM5 expression.Proliferation and apoptosis assays were also conducted to evaluate the growth of the colon cancer cells.Human GeneChip assay and bioinformatics analysis were performed to identify the potential underlying mechanism of LSM5 in colon cancer.RESULTS LSM5 was highly expressed in tumor tissue and colon cancer cells.A high expression level of LSM5 was related to poor prognosis in patients with colon cancer.Knockdown of LSM5 suppressed proliferation and promoted apoptosis in colon cancer cells.Silencing of LSM5 also facilitates the expression of p53,cyclin-dependent kinase inhibitor 1A(CDKN1A)and tumor necrosis factor receptor superfamily 10B(TNFRSF10B).The inhibitory effect of LSM5 knockdown on the growth of colon cancer cells was associated with the upregulation of p53,CDKN1A and TNFRSF10B.CONCLUSION LSM5 knockdown inhibited the proliferation and facilitated the apoptosis of colon cancer cells by upregulating p53,CDKN1A and TNFRSF10B.展开更多
Accumulation of float coal dust(FCD)in underground mines is an explosion hazard that affects all underground coal mine workers.While this hazard is addressed by the application of rock dust,inadequate rock dusting pra...Accumulation of float coal dust(FCD)in underground mines is an explosion hazard that affects all underground coal mine workers.While this hazard is addressed by the application of rock dust,inadequate rock dusting practices can leave miners exposed to an explosion risk.Researchers at the National Institute for Occupational Safety and Health(NIOSH)have focused on developing a water curtain that removes FCD from the airstream,thereby reducing the buildup of FCD in mine airways.In this study,the number and spacing of the active sprays in the water curtain were varied to determine the optimal configuration to obtain peak knockdown efficiency(KE)while minimizing water consumption.展开更多
The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side effects.RNA interference(RNAi)targeting PD-L...The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side effects.RNA interference(RNAi)targeting PD-L1 via inhibiting novo production of PD-L1 will overcome the innate and adaptive PD-L1 expression during chemotherapy,thus enable sustained and efficient immune checkpoint blockade(ICB)to active antitumor immune response.Herein,we designed a glutathione(GSH)-responsive camptothecin(CPT)prodrug-based hybrid micellar nanoparticles(siPD-L1@HM-CPT)to achieve synergistic antitumor chemoimmunotherapy by PD-L1 knockdown.siPD-L1@HM-CPT derived from the one-step loading PD-L1 siRNA(siPD-L1)into the CPT prodrug-based hybrid micelles(HM-CPT)which were co-assembled from biodegradable polyphosphoesters-based prodrug CPT-ss-PAEEP15 and stabilizer DSPE-PEG,showed high loading efficiency,GSH-responsive drug release,and excellent stability and biosafety.siPD-L1@HM-CPT achieved simultaneously the co-delivery of CPT and siPD-L1 in vitro and in vivo,high accumulation at the tumor sites,and rapid intracellular release to promote antitumor efficacy via sensitizing CPT chemotherapy,inducing strong immunogenic cell death(ICD)and sustained ICB to improve intratumoral CD8+T cells infiltration.In addition,the antitumor immunity response limited by the differentiated immunogenicity,intrinsic PD-L1 expression,and intracellular GSH level was facilitated by efficient ICD and ICB from silencing PD-L1 and synergistic CPT chemosensitization in our experimental B16-F10 and 4T1 tumor models.Our study might offer a perspective on designing novel co-delivery nanoparticles by convenient and controllable preparation for antitumor chemo-immunotherapy.展开更多
Axially loaded tubular structures are known to be highly sensitive to initial geometric imperfections,which can significantly reduce their design bearing capacity.To address this issue,this study explores the potentia...Axially loaded tubular structures are known to be highly sensitive to initial geometric imperfections,which can significantly reduce their design bearing capacity.To address this issue,this study explores the potential of an origami-inspired design for tubular structures to achieve a lower sensitivity to imperfections.The study considers various designs,including diamond-shaped,pyramid-shaped,new Kresling,and pre-embedded rhombic origami tubes,and employs knockdown factors(KDFs)to illustrate the reduction of the design bearing capacity of these structures with initial geometric imperfections for safety purposes.Finite element analysis shows that some of the origami tubes have superior design bearing capacity,mass efficiency,and KDFs when compared to standard circular tubes.Among the origami tubes considered,the rhombic tube demonstrates the best performance and is further studied through parametric analyses of geometric design,aspect ratio,and wall thickness to achieve additional performance enhancements.Furthermore,the superior performance of the rhombic tube is evaluated and verified for various loading scenarios,including eccentric compression and compression-torsion combination.The findings of this study provide a promising approach to designing and fabricating imperfection-insensitive tubes using advanced processing technologies such as additive manufacturing.This work can potentially lead to the development of innovative tubular structures with enhanced safety and reliability in various engineering applications.展开更多
RNA interference(RNAi)using small interfering RNA(siRNA)has shown potential as a therapeutic option for the treatment of arthritis by silencing specific genes.However,siRNA delivery faces several challenges,including ...RNA interference(RNAi)using small interfering RNA(siRNA)has shown potential as a therapeutic option for the treatment of arthritis by silencing specific genes.However,siRNA delivery faces several challenges,including stability,targeting,off-target effects,endosomal escape,immune response activation,intravascular degradation,and renal clearance.A variety of nanotherapeutics like lipidic nanoparticles,liposomes,polymeric nanoparticles,and solid lipid nanoparticles have been developed to improve siRNA cellular uptake,protect it from degradation,and enhance its therapeutic efficacy.Researchers are also investigating chemical modifications and bioconjugation to reduce its immunogenicity.This review discusses the potential of siRNA nanotherapeutics as a therapeutic option for various immune-mediated diseases,including rheumatoid arthritis,osteoarthritis,etc.siRNA nanotherapeutics have shown an upsurge of interest and the future looks promising for such interdisciplinary approach-based modalities that combine the principles of molecular biology,nanotechnology,and formulation sciences.展开更多
Background：Overexpression of G-protein coupled receptor 34 （GPR34） affects the progression and prognosis of human gastric adenocarcinoma,however,the role of GPR34 in gastric cancer development and progression has n...Background：Overexpression of G-protein coupled receptor 34 （GPR34） affects the progression and prognosis of human gastric adenocarcinoma,however,the role of GPR34 in gastric cancer development and progression has not been well-determined.The current study aimed to investigate the effect of GPR34 knockdown on the proliferation,migration,and apoptosis of HGC-27 gastric cancer cells and the underlying mechanisms.Methods：The expression of GPR34 in gastric cancer cell line HGC-27 was detected by quantitative real-time reverse transcription-polymerase chain reaction （RT-PCR） and Western blotting.HGC-27 cells were employed to construct the stable GPR34 knockdown cell model in this study.Real-time RT-PCR and Western blotting were applied to validate the effect of short hairpin RNA （ShRNA） on the expression of GPR34 in HGC-27 gastric cells.The proliferation,migration of these cells were examined by Cell Counting Kit-8 and transwell.We also measured expression profile of PI3K/PDK1/AKT and ERK using Western blotting.Results：The ShRNA directed against GPR34 effectively inhibited both endogenous mRNA and protein expression levels of GPR34,and significantly down-regulated the expression of PIK3CB （P ＜ 0.01）,PIK3CD （P ＜ 0.01）,PDK1 （P ＜ 0.01）,phosphorylation of PDK1 （P ＜ 0.01）,Akt （P ＜ 0.01）,and ERK （P ＜ 0.01）.Furthermore,GPR34 knockdown resulted in an obvious reduction in HGC-27 cancer cell proliferation and migration activity （P ＜ 0.01）.Conclusions：GPR34 knockdown impairs the proliferation and migration of HGC-27 gastric cancer cells in vitro and provides a potential implication for therapy of gastric cancer.展开更多
基金supported by the National Natural Science Foundation of China,No.81460193
文摘The micro RNA（mi RNA） let-7 was one of the first mi RNAs to be discovered, and is highly conserved and widely expressed among species. let-7 expression increases in brain tissue after cerebral ischemia/reperfusion injury; however, no studies have reported let-7 effects on nerve injury after cerebral ischemia/reperfusion injury. To investigate the effects of let-7 gene knockdown on cerebral ischemia/reperfusion injury, we established a rat model of cerebral ischemia/reperfusion injury. Quantitative reverse transcription-polymerase chain reaction demonstrated that 12 hours after cerebral ischemia/reperfusion injury, let-7 expression was up-regulated, peaked at 24 hours, and was still higher than that in control rats after 72 hours. Let-7 gene knockdown in rats suppressed microglial activation and inflammatory factor release, reduced neuronal apoptosis and infarct volume in brain tissue after cerebral ischemia/reperfusion injury. Western blot assays and luciferase assays revealed that mitogen-activated protein kinase phosphatase-1（MKP1） is a direct target of let-7. Let-7 enhanced phosphorylated p38 mitogen-activated protein kinase（MAPK） and c-Jun N-terminal kinase（JNK） expression by down-regulating MKP1. These findings suggest that knockdown of let-7 inhibited the activation of p38 MAPK and JNK signaling pathways by up-regulating MKP1 expression, reduced apoptosis and the inflammatory reaction, and exerted a neuroprotective effect following cerebral ischemia/reperfusion injury.
基金supported by the National Nature Science Foundation of China (grant no.81570971)
文摘Human dental pulp cells （hDPCs） possess the capacity to differentiate into odontoblast-like cells and generate reparative dentin in response to exogenous stimuli or injury. Ten-eleven translocation 1 （TET1） is a novel DNA methyldioxygenase that plays an important role in the promotion of DNA demethylation and transcriptional regulation in several cell lines. However, the role of TET1 in the biological functions of hDPCs is unknown. To investigate the effect of TET1 on the proliferation and odontogenic differentiation potential of hDPCs, a recombinant shRNA lentiviral vector was used to knock down TET1 expression in hDPCs. Following TET1 knockdown, TET1 was significantly downregulated at both the mRNA and protein levels. Proliferation of the hDPCs was suppressed in the TET1 knockdown groups. Alkaline phosphatase activity, the formation of mineralized nodules, and the expression levels of DSPP and DMP1 were all reduced in the TETl-knockdown hDPCs undergoing odontogenic differentiation. Based on these results, we concluded that TET1 knockdown can prevent the proliferation and odontogenic differentiation of hDPCs, which suggests that TET1 may play an important role in dental pulp repair and regeneration.
文摘Fankl is exclusively expressed in the testis from the meiosis phase to the haploid phase of spermatogenesis. In this study, we examined the function of Fankl by establishing a Fankl-knockdown transgenic mouse model. The apoptotic statuses of the testes of the transgenic mice were tested using the terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） method. The FANK1 consensus DNA-binding sequence was identified using cyclic amplification of sequence target （CAST） analysis. Differentially expressed genes were examined using microarray analysis. A reduction in sperm number and an increase in apoptotic spermatocytes were observed in Fankl-knockdown mice, and the apoptotic cells were found to be primarily spermatogonia and spermatocytes. The CAST results demonstrated that the consensus DNA-binding sequence was AAAAAG, in which the percentage occurrence of each base at each position ranged from 55 to 86%. This sequence was present in the promoter regions of 10 differentially expressed genes that were examined using microarray analysis. In total, 17 genes were differentially expressed with changes in their expression levels greater than twofold. The abnormal expression of Fankl target genes that were regulated directly or indirectly by Fankl reduced the number of sperm in the knockdown mice. Thus, FANK1 may Dlav a pivotal role in sDermato^enesis as a transcription factor.Fankl is exclusively expressed in the testis from the meiosis phase to the haploid phase of spermatogenesis. In this study, we examined the function of Fankl by establishing a Fankl-knockdown transgenic mouse model. The apoptotic statuses of the testes of the transgenic mice were tested using the terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） method. The FANK1 consensus DNA-binding sequence was identified using cyclic amplification of sequence target （CAST） analysis. Differentially expressed genes were examined using microarray analysis, A reduction in sperm number and an increase in apoptotic sperm
文摘Doxorubicin is a commonly used chemotherapy drug for cancer treatment,although its effectiveness varies across different cancer types.p53 is a key factor involved in cell death induced by therapeutic agents,and it can be upregulated by doxorubicin,exhibiting a function of apoptosis.To further investigate the mechanism between p53 and doxorubicin,this study explored whether p53 plays a role in doxorubicin-induced cell death in the colorectal cancer line HCT116.The findings revealed that p53 was upregulated in HCT116 cells when treated with doxorubicin,and the knockdown of p53 decreased the sensitivity of HCT116 cells to doxorubicin.These results suggest that p53 plays an important role in doxorubicin-induced cell death in HCT116 cells,potentially contributing to more effective treatment approaches.
基金Supported by Natural Science Basic Research Program of Shaanxi Province,No.2021JM-256.
文摘BACKGROUND The role of Sm-like 5(LSM5)in colon cancer has not been determined.In this study,we investigated the role of LSM5 in progression of colon cancer and the potential underlying mechanism involved.AIM To determine the role of LSM5 in the progression of colon cancer and the potential underlying mechanism involved.METHODS The Gene Expression Profiling Interactive Analysis database and the Human Protein Atlas website were used for LSM5 expression analysis and prognosis analysis.Real-time quantitative polymerase chain reaction and Western blotting were utilized to detect the expression of mRNAs and proteins.A lentivirus targeting LSM5 was constructed and transfected into colon cancer cells to silence LSM5 expression.Proliferation and apoptosis assays were also conducted to evaluate the growth of the colon cancer cells.Human GeneChip assay and bioinformatics analysis were performed to identify the potential underlying mechanism of LSM5 in colon cancer.RESULTS LSM5 was highly expressed in tumor tissue and colon cancer cells.A high expression level of LSM5 was related to poor prognosis in patients with colon cancer.Knockdown of LSM5 suppressed proliferation and promoted apoptosis in colon cancer cells.Silencing of LSM5 also facilitates the expression of p53,cyclin-dependent kinase inhibitor 1A(CDKN1A)and tumor necrosis factor receptor superfamily 10B(TNFRSF10B).The inhibitory effect of LSM5 knockdown on the growth of colon cancer cells was associated with the upregulation of p53,CDKN1A and TNFRSF10B.CONCLUSION LSM5 knockdown inhibited the proliferation and facilitated the apoptosis of colon cancer cells by upregulating p53,CDKN1A and TNFRSF10B.
文摘Accumulation of float coal dust(FCD)in underground mines is an explosion hazard that affects all underground coal mine workers.While this hazard is addressed by the application of rock dust,inadequate rock dusting practices can leave miners exposed to an explosion risk.Researchers at the National Institute for Occupational Safety and Health(NIOSH)have focused on developing a water curtain that removes FCD from the airstream,thereby reducing the buildup of FCD in mine airways.In this study,the number and spacing of the active sprays in the water curtain were varied to determine the optimal configuration to obtain peak knockdown efficiency(KE)while minimizing water consumption.
基金The authors acknowledge the support by the National Basic Research Program of China(Nos.2020YFA0710700 and 2018YFA0208900)the National Natural Science Foundation of China(No.31470968).
文摘The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side effects.RNA interference(RNAi)targeting PD-L1 via inhibiting novo production of PD-L1 will overcome the innate and adaptive PD-L1 expression during chemotherapy,thus enable sustained and efficient immune checkpoint blockade(ICB)to active antitumor immune response.Herein,we designed a glutathione(GSH)-responsive camptothecin(CPT)prodrug-based hybrid micellar nanoparticles(siPD-L1@HM-CPT)to achieve synergistic antitumor chemoimmunotherapy by PD-L1 knockdown.siPD-L1@HM-CPT derived from the one-step loading PD-L1 siRNA(siPD-L1)into the CPT prodrug-based hybrid micelles(HM-CPT)which were co-assembled from biodegradable polyphosphoesters-based prodrug CPT-ss-PAEEP15 and stabilizer DSPE-PEG,showed high loading efficiency,GSH-responsive drug release,and excellent stability and biosafety.siPD-L1@HM-CPT achieved simultaneously the co-delivery of CPT and siPD-L1 in vitro and in vivo,high accumulation at the tumor sites,and rapid intracellular release to promote antitumor efficacy via sensitizing CPT chemotherapy,inducing strong immunogenic cell death(ICD)and sustained ICB to improve intratumoral CD8+T cells infiltration.In addition,the antitumor immunity response limited by the differentiated immunogenicity,intrinsic PD-L1 expression,and intracellular GSH level was facilitated by efficient ICD and ICB from silencing PD-L1 and synergistic CPT chemosensitization in our experimental B16-F10 and 4T1 tumor models.Our study might offer a perspective on designing novel co-delivery nanoparticles by convenient and controllable preparation for antitumor chemo-immunotherapy.
基金supported by the National Natural Science Foundation of China(Grant No.U1937202)Key Industrial Technology Research&Development Cooperation Projects of Jiangsu Province(BZ2021036)Basic Research Projects on Free Exploration of Funds for Local Scientific and Technological Development Guided by the Central Government(2021Szvup027).
文摘Axially loaded tubular structures are known to be highly sensitive to initial geometric imperfections,which can significantly reduce their design bearing capacity.To address this issue,this study explores the potential of an origami-inspired design for tubular structures to achieve a lower sensitivity to imperfections.The study considers various designs,including diamond-shaped,pyramid-shaped,new Kresling,and pre-embedded rhombic origami tubes,and employs knockdown factors(KDFs)to illustrate the reduction of the design bearing capacity of these structures with initial geometric imperfections for safety purposes.Finite element analysis shows that some of the origami tubes have superior design bearing capacity,mass efficiency,and KDFs when compared to standard circular tubes.Among the origami tubes considered,the rhombic tube demonstrates the best performance and is further studied through parametric analyses of geometric design,aspect ratio,and wall thickness to achieve additional performance enhancements.Furthermore,the superior performance of the rhombic tube is evaluated and verified for various loading scenarios,including eccentric compression and compression-torsion combination.The findings of this study provide a promising approach to designing and fabricating imperfection-insensitive tubes using advanced processing technologies such as additive manufacturing.This work can potentially lead to the development of innovative tubular structures with enhanced safety and reliability in various engineering applications.
文摘RNA interference(RNAi)using small interfering RNA(siRNA)has shown potential as a therapeutic option for the treatment of arthritis by silencing specific genes.However,siRNA delivery faces several challenges,including stability,targeting,off-target effects,endosomal escape,immune response activation,intravascular degradation,and renal clearance.A variety of nanotherapeutics like lipidic nanoparticles,liposomes,polymeric nanoparticles,and solid lipid nanoparticles have been developed to improve siRNA cellular uptake,protect it from degradation,and enhance its therapeutic efficacy.Researchers are also investigating chemical modifications and bioconjugation to reduce its immunogenicity.This review discusses the potential of siRNA nanotherapeutics as a therapeutic option for various immune-mediated diseases,including rheumatoid arthritis,osteoarthritis,etc.siRNA nanotherapeutics have shown an upsurge of interest and the future looks promising for such interdisciplinary approach-based modalities that combine the principles of molecular biology,nanotechnology,and formulation sciences.
基金This study was supported by grants from the National Natural Science Foundation of China，the Peking University People＇s Hospital Research and Development Foundations
文摘Background：Overexpression of G-protein coupled receptor 34 （GPR34） affects the progression and prognosis of human gastric adenocarcinoma,however,the role of GPR34 in gastric cancer development and progression has not been well-determined.The current study aimed to investigate the effect of GPR34 knockdown on the proliferation,migration,and apoptosis of HGC-27 gastric cancer cells and the underlying mechanisms.Methods：The expression of GPR34 in gastric cancer cell line HGC-27 was detected by quantitative real-time reverse transcription-polymerase chain reaction （RT-PCR） and Western blotting.HGC-27 cells were employed to construct the stable GPR34 knockdown cell model in this study.Real-time RT-PCR and Western blotting were applied to validate the effect of short hairpin RNA （ShRNA） on the expression of GPR34 in HGC-27 gastric cells.The proliferation,migration of these cells were examined by Cell Counting Kit-8 and transwell.We also measured expression profile of PI3K/PDK1/AKT and ERK using Western blotting.Results：The ShRNA directed against GPR34 effectively inhibited both endogenous mRNA and protein expression levels of GPR34,and significantly down-regulated the expression of PIK3CB （P ＜ 0.01）,PIK3CD （P ＜ 0.01）,PDK1 （P ＜ 0.01）,phosphorylation of PDK1 （P ＜ 0.01）,Akt （P ＜ 0.01）,and ERK （P ＜ 0.01）.Furthermore,GPR34 knockdown resulted in an obvious reduction in HGC-27 cancer cell proliferation and migration activity （P ＜ 0.01）.Conclusions：GPR34 knockdown impairs the proliferation and migration of HGC-27 gastric cancer cells in vitro and provides a potential implication for therapy of gastric cancer.
