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1.
目的:探讨不同剂量叶酸对宫颈癌SiHa细胞自噬小体形成的影响。方法:选取处于对数生长期的SiHa细胞,将其分为5组,分别应用不同浓度叶酸(0.1 μg/ml、1.0 μg/ml、10 μg/ml、100 μg/ml、1 000 μg/ml)干预72 h,记录干预后各组SiHa细胞自噬小体数量;采用qRT-PCR法测定不同浓度叶酸干预后宫颈癌SiHa细胞自噬蛋白中Beclin1、LC3及p62 mRNA表达情况;采用Western blot法测定不同浓度叶酸干预后宫颈癌SiHa细胞自噬蛋白中Beclin1、LC3和p62蛋白表达情况。结果:不同浓度叶酸干预后自噬小体数量比较,1 000 μg/ml组明显高于其他组(P<0.05),其中0.1 μg/ml组数量最低,1.0 μg/ml组与10 μg/ml组比较差异无统计学意义(P>0.05)。qRT-PCR法测定结果显示,随干预叶酸浓度升高,宫颈癌SiHa细胞中自噬蛋白Beclin1、LC3的mRNA明显升高(P<0.05);p62 mRNA表达水平随叶酸浓度升高而降低(P<0.05)。Western blot法测定结果显示,自噬蛋白Beclin1、LC3的蛋白表达水平随叶酸浓度增高而增高(P<0.05),p62蛋白表达水平随叶酸浓度升高而下降(P<0.05)。结论:不同剂量叶酸对宫颈癌SiHa细胞自噬小体形成的抑制效果不同,剂量越低抑制效果越强,高剂量叶酸还有刺激宫颈癌SiHa细胞自噬小体形成的作用。  相似文献   
2.
Safety concerns have been raised over the extensive applications of silver nanoparticles (AgNPs) because nano dimensions make them highly bioactive, being potentially harmful to the exposed humans. Surface physico-chemistry (shape, surface charge, chemical composition, etc.) that mainly dictates nano-bio interactions is relevant for influencing their biocompatibility and toxicity. Although the hazardousness of AgNPs has been demonstrated in vitro and in vivo, mechanistic understanding of the toxicity particularly at the molecular and organismal levels, in addition to oxidative stress and silver ion dissolution, has remained unclear. A growing body of research has elucidated that autophagy, being activated in response to exposure to various nanomaterials, may serve as a cellular defense mechanism against nanotoxicity. Recently, autophagy activation was shown to correlate with AgNPs exposure; however, the subsequent autophagosome–lysosome fusion was defective. As autophagy plays a crucial role in selective removal of stress-mediated protein aggregates and injured organelles, AgNPs-induced autophagic flux defect may consequently lead to aggravated cytotoxic responses. Furthermore, we suggest that p62 accumulation resulting from defective autophagy may also potentially account for AgNPs cytotoxicity. Intriguingly, AgNPs have been shown to interfere with ubiquitin modifications, either via upregulating levels of enzymes participating in ubiquitination, or through impairing the biological reactivity of ubiquitin (due to formation of AgNPs-ubiquitin corona). Ubiquitination both confers selectivity to autophagy as well as modulates stabilization, activation, and trafficking of proteins involved in autophagic clearance pathways. In this regard, we offer a new perspective that interference of AgNPs with ubiquitination may account for AgNPs-induced defective autophagy and cytotoxic effects.  相似文献   
3.
Autophagy, also known as macroautophagy, is a tightly regulated process involved in the stress responses, such as starvation. It is a vacuolar, lysosomal pathway for the degradation of damaged proteins and organelles in eukaryotic cells. Autophagy also plays a key role in various tissue processes and immune responses and in the regulation of inflammation. Over the past decade, three levels of autophagy regulation have been identified in mammalian cells: 1) signaling, 2) autophagosome formation, and 3) autophagosome maturation and lysosomal degradation. Any deregulation of the autophagy processes can lead to the development of diverse chronic diseases, such as diabetes, obesity, cardiovascular disease, neurodegenerative disease, and malignancies. However, the potential role of autophagy in cancer is rather complex and has been associated with both the induction and the inhibition of neoplasia. Several synthetic autophagy modulators have been identified as promising candidates for cancer therapy. In addition, diverse phytochemicals derived from natural sources, such as curcumin, ursolic acid, resveratrol, thymoquinone, and γ-tocotrienol, also have attracted attention as promising autophagy modulators with minimal side effects. In this review, the authors discuss the importance of autophagy regulators and various natural compounds that induce and/or inhibit autophagy in the prevention and therapy of cancer.  相似文献   
4.
目的 探讨mTOR通路抑制剂雷帕霉素对真菌性角膜炎小鼠角膜瘢痕化的影响。方法 取96只SPF级C57BL/6J雄性小鼠,随机分为雷帕霉素组和对照组,每组各48只。两组小鼠同时建立真菌性角膜炎模型。雷帕霉素组模型制作前1 d按6.0 mg·kg-1雷帕霉素对小鼠进行腹腔注射预处理,之后按0.2 g·L-1浓度在结膜下注射5 μL,持续3 d;对照组注射PBS溶液。造模后对各组小鼠进行角膜临床评分,Western blot和实时荧光定量PCR分别检测造模后各组小鼠不同时间角膜LC-3Ⅱ、α-SMA和 TGF-β1表达情况。结果 造模后24 h、48 h、72 h、96 h、120 h、144 h、336 h,对照组小鼠角膜临床评分均明显高于雷帕霉素组,差异均有统计学意义(均为P<0.05) 。造模后144 h、216 h雷帕霉素组小鼠角膜LC-3Ⅱ表达上调,LC-3Ⅱ蛋白和mRNA相对表达量与对照组相比,差异均有统计学意义(均为P<0.05);而在造模后72 h及336 h两组LC-3Ⅱ蛋白和mRNA相对表达量差异均无统计学意义(均为P>0.05)。与对照组相比,造模后144 h、216 h雷帕霉素组小鼠角膜α-SMA蛋白及 mRNA相对表达量下降,差异均有统计学意义(均为P<0.05);造模后144 h、336 h雷帕霉素组TGF-β1 mRNA相对表达量亦下降,与对照组相比,差异均有统计学意义(均为P<0.05)。结论 雷帕霉素通过促进自噬作用下调角膜瘢痕化相关因子的表达,减轻了真菌性角膜炎模型小鼠角膜瘢痕化程度。  相似文献   
5.
It is predicted that the toxicity of nanoparticles may be different depending on the properties of the nanoparticles and biological system being tested. However, the factors that influence the toxicity of nanoparticles have not been adequately investigated. In this study, we characterized two types of TiO2 nanorods, anatase (ATO) and brookite (BTO), and compared their toxicity in vivo and in vitro. ATO and BTO differed from each other most notably in their surface areas. Treatment with the two TiO2 nanorods (10 µg ml–1) produced similar effects on the cell cycle in eight cell lines which are derived from potential target organs of nanoparticles, with the BTO eliciting stronger responses than ATO in all cell lines, among the cell lines, H9C2 showed the maximal change. Similarly, when mice were exposed to two TiO2 nanorods (1 mg kg–1), BTO induced clearer histopathological lesions and triggered a more robust secretion of inflammatory cytokines than ATO. Furthermore, we compared the cellular response of both TiO2 nanorods using BEAS‐2B cells, the human bronchial epithelial cell line. Both nanorods induced cell death by increasing the formation of autophagosome‐like vacuoles. The mitochondrial calcium concentration decreased by exposure of both types, but the distribution of lysosome and endoplasmic reticulum (ER) showed a clear difference between the two nanorods. Thus, we conclude that the surface area acts as an important factor which depends on toxicity of nanorod type‐TiO2 nanoparticles. Furthermore, the toxicity of nanoparticles varies according to the type of cells tested, and that the assembly of autophagosome‐like vacuoles is a critical part of the cellular response to nanoparticle exposure. Copyright © 2013 John Wiley & Sons, Ltd.  相似文献   
6.
Evidence suggests that autophagy may be a new therapeutic target for stroke, but whether acti- vation of autophagy increases or decreases the rate of neuronal death is still under debate. This review summarizes the potential role and possible signaling pathway of autophagy in neuronal survival after cerebral ischemia and proposes that autophagy has dual effects.  相似文献   
7.

Aim:

Ubiquitin-proteasome system (UPS) and autophagosome-lysosome pathway (ALP) are the most important machineries responsible for protein degradation in Parkinson''s disease (PD). The aim of this study is to investigate the adaptive alterations in autophagy upon proteasome inhibition in dopaminergic neurons in vitro and in vivo.

Methods:

Human dopaminergic neuroblastoma SH-SY5Y cells were treated with the proteasome inhibitor lactacystin (5 μmol/L) for 5, 12, or 24 h. The expression of autophagy-related proteins in the cells was detected with immunoblotting. UPS-impaired mouse model of PD was established by microinjection of lactacystin (2 μg) into the left hemisphere of C57BL/6 mice that were sacrificed 2 or 4 weeks later. The midbrain tissues were dissected to assess alterations in autophagy using immunofluorescence, immunoblotting and electron microscopy assays.

Results:

Both in SH-SY5Y cells and in the midbrain of UPS-impaired mouse model of PD, treatment with lactacystin significantly increased the expression levels of LC3-I/II and Beclin 1, and reduced the levels of p-mTOR, mTOR and p62/SQSTM1. Furthermore, lactacystin treatment in UPS-impaired mouse model of PD caused significant loss of TH-positive neurons in the substantia nigra, and dramatically increased the number of autophagosomes in the left TH-positive neurons.

Conclusion:

Inhibition of UPS by lactacystin in dopaminergic neurons activates another protein degradation system, the ALP, which includes both the mTOR signaling pathway and Beclin 1-associated pathway.  相似文献   
8.
Autophagy has multiple physiological functions, including protein degradation, organelle turnover and the response of cancer cells to chemotherapy. Because autophagy is implicated in a number of diseases, a better understanding of the molecular mechanisms of autophagy is needed for therapeutic purposes, including rational design of drugs. Autophagy is a process that occurs in several steps as follows: formation of phagophores, formation of mature autophagosomes, targeting and trafficking of autophagosomes to lysosomes, formation of autolysosomes by fusion between autophagosomes and lysosomes, and finally, degradation of the autophagic bodies within the lysosomes. It has been suggested that autophagosome formation is driven by molecular motor machineries, and, once formed, autophagosomes need to reach lysosomes, enriched perinuclearly around the microtubule‐organizing centre. While it is recognized that all these steps require the cytoskeletal network, little is known about the mechanisms involved. Here we assessed the role of cytoplasmic dynein in the autophagic process of human glioma cells to determine the part played by dynein in autophagy. We observed that chemical interference with dynein function led to an accumulation of autophagosomes, suggesting impaired autophagosome‐lysosome fusion. In contrast, we found that overexpression of dynamitin, which disrupts the dynein complex, reduced the number of autophagosomes, suggesting the requirement of the dynein‐dynactin interaction in the early membrane trafficking step in autophagosome formation. These results suggest that dynein plays a variety of crucial roles during the autophagic process in glioma cells.  相似文献   
9.
In addition to its cellular homeostasis function, autophagy is emerging as a central component of antimicrobial host defense against diverse infections. To counteract this mechanism, many pathogens have evolved to evade, subvert, or exploit autophagy. Here, we report that autophagy proteins (i.e., Beclin-1, Atg4B, Atg5, and Atg12) are proviral factors required for translation of incoming hepatitis C virus (HCV) RNA and, thereby, for initiation of HCV replication, but they are not required once infection is established. These results illustrate a previously unappreciated role for autophagy in the establishment of a viral infection and they suggest that different host factors regulate the translation of incoming viral genome and translation of progeny HCV RNA once replication is established.  相似文献   
10.
In the search for antidepressants'' (ADs'') mechanisms of action beyond their influence on monoaminergic neurotransmission, we analyzed the effects of three structurally and pharmacologically different ADs on autophagic processes in rat primary astrocytes and neurons. Autophagy has a significant role in controlling protein turnover and energy supply. Both, the tricyclic AD amitriptyline (AMI) and the selective serotonin re-uptake inhibitor citalopram (CIT) induced autophagy as mirrored by pronounced upregulation and cellular redistribution of the marker LC3B-II. Redistribution was characterized by formation of LC3B-II-positive structures indicative of autophagosomes, which associated with AVs in a time-dependent manner. Deletion of Atg5, representing a central mediator of autophagy in MEFs, led to abrogation of AMI-induced LC3B-I/II conversion. By contrast, VEN, a selective serotonin and noradrenaline reuptake inhibitor, did not promote autophagic processes in either cell type. The stimulatory impact of AMI on autophagy partly involved class-III PI3 kinase-dependent pathways as 3-methyladenine slightly diminished the effects of AMI. Autophagic flux as defined by autophagosome turnover was vastly undisturbed, and degradation of long-lived proteins was augmented upon AMI treatment. Enhanced autophagy was dissociated from drug-induced alterations in cholesterol homeostasis. Subsequent to AMI- and CIT-mediated autophagy induction, neuronal and glial viability decreased, with neurons showing signs of apoptosis. In conclusion, we report that distinct ADs promote autophagy in neural cells, with important implications on energy homeostasis.  相似文献   
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