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1.
《Biomaterials》2015
A combination of various therapeutic approaches has emerged as a promising strategy for cancer treatment. A safe and competent nano-delivery system is thus in urgent demand to facilitate the simultaneous transport of various therapeutic agents to cancer cells and a tumor region to achieve synergistic effect. Gold nanoparticles (GNPs) and mesoporous silica nanoparticle (MSNs) were fabricated herein as potential candidates for drug delivery. Serving as gatekeepers, GNPs (5 nm in diameter) were attached onto the amino-functionalized MSNs (denoted as NMSNs) via a relatively weak gold–nitrogen bonding. The resulting nanohybrids (denoted as GCMSNs) were uptaken by cells, and the detachment of GNPs and subsequent intracellular drug release from NMSNs were achieved by competitive binding of intracellular glutathione to GNPs. In addition to the function of gatekeeping, GNPs also play another role as the oxidative stress elicitor. Our in vitro studies revealed that GCMSNs induced higher oxidative stress in lung cancer cells (A549) than in normal cells (3T3-L1). This growth inhibitory effect found in the cancer cells was likely induced by mitochondria dysfunction originated from the GCMSN-induced, oxidative stress-triggered mitochondria-mediated autophagy. The redox-responsive nanohybrids were further loaded with camptothecin and the intensified synergistic therapeutic effects were observed associated with combined chemotherapy and oxidative stress strategy. The results clearly demonstrate that such unique nanohybrids hold great promise for selective and effective cancer treatments. 相似文献
2.
《Biomaterials》2015
Malignant glioma is the most common intracranial tumor with a dismal prognosis. The radiosensitizing effect of silver nanoparticles (AgNPs) on glioma both in vitro and in vivo had been demonstrated in the previous studies of our group. However, the underlying mechanism is still unclear. Consistent with previous studies, a size and dose dependent antitumor effect and significant radiosensitivity enhancing effect of AgNPs were observed in our experiment system. We also found that cell protective autophagy could be induced by AgNPs and/or radiation, which was verified by the use of 3-MA. The mechanism through which had autophagy and the enhancement of radiosensitivity taken place was further investigated with inhibitors of ERK and JNK pathways. We demonstrated that ERK and JNK played pivotal roles in the radiosensitivity enhancement. Inhibiting ERK and JNK with U0126 and SP600125 respectively, we found that the autophagy level of the cells treated with AgNPs and radiation were attenuated. Moreover, SP600125 down-regulated the apoptosis rate of the co-treated cells significantly. Taken together, the present study would have important impact on biomedical applications of AgNPs and clinical treatment for glioma. 相似文献
3.
《Diabetes & Metabolic Syndrome: Clinical Research & Reviews》2019,13(4):2445-2449
Diabetes mellitus is a chronic metabolic disorder that has a complex molecular and cellular pathophysiology, resulting in its dynamic progression and that may show differing responses to therapy. The incidence of diabetes mellitus increases with age and requires additive therapeutic agents for its management. SGLT2i and DPP-4 inhibitors and GLP-1 receptor agonists (GLP-1RA) are newly introduced antidiabetic drugs that work through differing mechanisms; DPP-4 inhibitors maintain the endogenous level of GLP1; GLP-1RA result in pharmacological levels of GLP1, whilst SGLT2i act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes and in contrast to other antidiabetic drugs, do not inherently cause hypoglycemia in therapeutic doses. Autophagy as a highly conserved mechanism to maintain cell survival and homeostasis by degradation of damaged or aged organelles and components, and recognised to be increasingly important in diabetes. In the present review, we discuss the modulatory effects of these newly introduced antidiabetic drugs on the autophagy process. 相似文献
4.
It has been suggested that the cytoplasmic amino-terminal tail of invariant chain (Ii) contains a sorting signal that directs trafficking of the major histocompatibility complex (MHC) class II: Ii oligomeric complex to endocytic compartments. This model is based, in part, on the observation that in the absence of MHC class II molecules, Ii is detectable in lysosomal structures, a phenotype that is dependent on an intact NH2 terminus. However, the route by which Ii gains access to endosomal compartments in the absence of class II molecules remains uncertain. Here we report a mechanism that localizes Ii in lysosomal compartments independently of class II. We show that murine Ii can be detected by immunofluorescence within late endocytic compartments of stably transfected Ltk? mouse fibroblasts. Immunochemical studies indicate that degradation of Ii in these cells is sensitive to the lysosomotropic agent ammonium chloride, yet the majority of Ii that undergoes this apparent lysosomal degradation is sensitive to the enzyme endoglycosidase H. This finding suggests that Ii may reach the lysosomal compartment by a route that bypasses the Golgi complex. Consistent with this possibility, we found that in contrast to Ii which is complexed to class II molecules, transport of free Ii to lysosomes is prevented by 3-methyladenine, an inhibitor of the autophagic pathway of protein degradation, a process which involves direct transport from the endoplasmic reticulum to lysosomes. These data suggest the route of transport that leads to endosomal localization of Ii in the absence of class II is distinct from that taken when expressed with class II. This forces a re-evaluation of the concept that the cytosolic tail of Ii contains a dominant Golgi-to-endosomal sorting signal. 相似文献
5.
Summary The ultrastructure of the physiological cell death was studied in distal ventral bulbar cushions of 15 chick embryo hearts on the 4th and 5th day of incubation. Microperfusion fixation was performed. The ultracytochemistry of a lysosomal hydrolytic enzyme acid phosphatase was also investigated in another 15 embryonic hearts.In the course of the cell degeneration an increase in cellulr autophagy was observed without previous cytoplasmic or nuclear changes or phagocyte ingestion. A cytoplasmic diffusion of acid phosphatase outside of lysosomes was observed.Besides the cell death with the marked participation of the lysosomal system, another kind of dying cells was found, characterized by their nuclear pycnosis and cytoplasmic condensation. Starting from the 5th day of incubation the dying and dead cells were found phagocytized by some of their neighbouring viable mesenchymal cells. A formation of ribosomal crystals was not observed.The formation and fate of cytolysomes as well as the fate of phagocytes are discussed. The presence of pre-necrotic cells with important autophagy and of necrotic cells with nuclear changes was related to the possibility of a dual cause of the cell death. In the case of pre-necrotic cells the epigenetic factors like the biomechanic action of hemodynamics were considered, while the necrotic cells seem to be programmed to death by their genome.Finally the uniformity of cell death ultrastructure in different organs and species was noticed. 相似文献
6.
目的:本研究旨在探究川陈皮素(NOB)保护小鼠肾缺血再灌注损伤(RIRI)的可能分子机制。方法:将Balb/c小鼠分为5组(n=6):假手术组、模型组、NOB组(50 mg/kg)、组蛋白去乙酰化酶沉默信息调节因子1(SIRT1)抑制剂EX527组(5 mg/kg)、NOB+EX527组(50 mg/kg的NOB+5 mg/kg EX527)。在建模前24 h对小鼠进行药物处理。通过阻断小鼠左肾动静脉血流建立RIRI模型。建模24 h后检测肾组织中氧化应激标志物含量。通过苏木精-伊红(HE)染色和天狼星红染色评价肾组织病变和纤维化。通过TUNEL染色检测肾细胞凋亡。通过蛋白质免疫印迹法检测肾组织中SIRT1、叉头框蛋白O3a(FOXO3a)、细胞凋亡和自噬相关蛋白表达。通过实时荧光定量PCR检测肾组织中SIRT1和FOXO3a mRNA的水平。结果:与模型组比较,NOB组小鼠肾脏病变程度减轻,肾脏纤维化面积降低(均P<0.05)。与模型组比较,NOB组肾组织抗氧化作用升高(P<0.05)。与模型组比较,NOB组肾组织中细胞凋亡减少(P<0.05)。与模型组比较,NOB组肾组织中SIRT1和FOXO3a的mRNA和蛋白相对表达量升高,微管相关蛋白轻链(LC)3Ⅱ/LC3Ⅰ蛋白相对表达量升高,而p62降低(均P<0.05)。此外,EX527逆转了NOB对肾脏的保护作用(P<0.05)。结论:NOB通过激活SIRT-1/FOXO3a信号通路介导的自噬来减轻RIRI。 相似文献
7.
目的 探讨槐定碱对胰腺癌细胞增殖及自噬的影响,并分析其机制。方法 MTT法分析Sw1990细胞增殖, MDC染色法检测细胞自噬水平,western blot检测细胞自噬相关蛋白、PI3K/Akt/mTOR信号通路相关蛋白表达水平,运用自噬抑制剂(3 - MA)研究自噬对细胞增殖的影响;裸鼠成瘤实验检测体内胰腺癌细胞增殖情况,并分析瘤组织中LC3 II、p - mTOR蛋白水平。结果 槐定碱抑制胰腺癌Sw1990细胞的增长,促进自噬小泡的形成,上调LC3 II/ LC3 I、Beclin - 1水平,下调p - PI3K、p - AKT、p - mTOR水平(P<0.05);与槐定碱40 μmol/L组比较,槐定碱40 μmol/L + 3 - MA 5 μmol/L组细胞抑制率升高,LC3 II/ LC3 I降低,p - mTOR蛋白水平升高(P<0.05); 40 mg/kg槐定碱下调裸鼠瘤体体积、瘤体质量,上调LC3 II/ LC3 I水平,下调p - mTOR蛋白水平(P<0.05)。结论 槐定碱能抑制Sw1990细胞增殖,与调控PI3K/Akt/mTOR信号通路影响自噬有关。 相似文献
8.
目的 研究Homer1b/c蛋白在谷氨酸诱发的细胞自噬中的作用及机制。方法 选用小鼠海马细胞系HT22细胞,通过500 ?mol/L谷氨酸处理建立细胞损伤模型。用siRNA慢病毒转染方式下调Homer1b/c表达和10 ?mol/LBAPTA-AM(1,2-双(2-氨基苯氧基)乙烷-N,N,N`,N`-四乙酸四乙酸甲酯,钙离子螯合剂)、10 mmol/L4-PBA(4-苯基丁酸,内质网应激抑制剂)分别抑制细胞内钙离子释放和内质网应激后,使用蛋白质印迹法检测Homer1b/c,自噬蛋白Beclin-1、微管相关蛋白轻链3(LC3),以及内质网应激标志蛋白CHOP(人内质网应激相关蛋白)、GRP-78(葡萄糖调节蛋白78)的表达水平。每组实验均进行3次,采用独立样本t检验和单因素方差分析进行统计学分析。结果 谷氨酸处理HT22细胞12 h后,Beclin-1表达和LC3-Ⅱ/LC3-Ⅰ比值均升高(P<0.05),下调Homer1b/c表达可降低Beclin-1表达和LC3-Ⅱ/LC3-Ⅰ比值的升高程度(P<0.05)。抑制细胞内钙离子释放和抑制内质网应激均能降低Beclin-1表达和LC3-Ⅱ/LC3-Ⅰ比值的升高程度(P<0.05)。然而在下调Homer1b/c表达后,抑制细胞内钙离子释放和抑制内质网应激未能进一步降低Beclin-1表达和LC3-Ⅱ/LC3-Ⅰ比值的升高程度(P<0.05)。结论 Homer1b/c能够调节谷氨酸诱导的自噬,其调节作用可能与内质网功能有关。 相似文献
9.
《Immunobiology》2023,228(4):152386
Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon that can be influenced by microRNAs (miRNAs). This study aims to investigate the impact of miR-146a-5p on lipopolysaccharide (LPS)-induced Caco-2/HT-29 cell autophagy and NLRP3 inflammasome activation and the underlying mechanism, with the aim of identifying potential therapeutic targets. We used LPS to establish Caco-2/HT-29 cell models and measured cell viability by CCK-8. The levels of miR-146a-5p, RNF8, markers of NLRP3 inflammasome activation and autophagy, proteins involved in the Notch1/mTORC1 pathway, and inflammatory factors were assessed by RT-qPCR, Western blot, and ELISA. Intestinal epithelial barrier function was evaluated by measuring transepithelial electrical resistance. Autophagic flux was measured using tandem fluorescent-labeled LC3. miR-146a-5p was highly-expressed in LPS-induced Caco-2/HT-29 cells, and autophagy flux was blocked at the autolysosomal stage after LPS induction. Inhibition of miR-146a-5p suppressed NLRP3 inflammasome activation, reduced intestinal epithelial barrier damage, and facilitated autophagy inhibition in LPS-induced Caco-2/HT-29 cells. The autophagy inhibitor NH4Cl partially nullified the inhibitory effects of miR-146a-5p inhibition on NLRP3 inflammation activation. miR-146a-5p targeted RNF8, and silencing RNF8 partly abrogated the action of miR-146a-5p inhibition on promoting autophagy and inhibiting NLRP3 inflammasome activation. miR-146a-5p inhibition suppressed the Notch1/mTORC1 pathway activation by upregulating RNF8. Inhibition of the Notch1/mTORC1 pathway partially nullified the function of silencing RNF8 on inhibiting autophagy and bolstering NLRP3 inflammasome activation. In conclusion, miR-146a-5p inhibition may be a potential therapeutic approach for UC, as it facilitates autophagy of LPS-stimulated Caco-2/HT-29 cells, inhibits NLRP3 inflammasome activation, and reduces intestinal epithelial barrier damage by upregulating RNF8 and suppressing the Notch1/mTORC1 pathway. 相似文献
10.
骨骼肌卫星细胞(muscle satellite/stem cells, MuSCs)介导的再生和修复对骨骼肌损伤后完整肌肉功能的恢复至关重要。在多种病理生理过程中,内质网应激(endoplasmic reticulum stress, ERS)诱导的未折叠蛋白质反应(unfolded protein response, UPR)和自噬能够清除积累的错误折叠的蛋白质,是细胞维持稳态的重要机制。近年来,越来越多的研究发现在骨骼肌再生过程中内质网应激和自噬被激活,且在肌再生过程中发挥重要的调控作用,对损伤后肌肉的修复至关重要。本文主要针对近年来内质网应激和自噬在肌再生过程中的作用的研究进展做一综述,旨在为研发以内质网应激和自噬为靶点改善骨骼肌再生的药物提供理论依据。 相似文献