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Sprouty proteins are widely accepted modulators of receptor tyrosine kinase-associated pathways and fulfill diversified roles in cancerogenesis dependent on the originating cells. In this study we detected a high expression of Sprouty3 in osteosarcoma-derived cells and addressed the question of whether Sprouty3 and Sprouty1 influence the malignant phenotype of this bone tumor entity. By using adenoviruses, the Sprouty proteins were expressed in two different cell lines and their influence on cellular behavior was assessed. Growth curve analyses and Scratch assays revealed that Sprouty3 accelerates cell proliferation and migration. Additionally, more colonies were grown in Soft agar if the cells express Sprouty3. In parallel, Sprouty1 had no significant effect on the measured endpoints of the study in osteosarcoma-derived cells. The promotion of the tumorigenic capacities in the presence of Sprouty3 coincided with an increased activation of signaling as measured by evaluating the phosphorylation of extracellular signal-regulated kinases (ERKs). Ectopic expression of a mutated Sprouty3 protein, in which the tyrosine necessary for its activation was substituted, resulted in inhibited migration of the treated cells. Our findings identify Sprouty3 as a candidate for a tumor promoter in osteosarcoma.  相似文献   

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Retinal degenerative diseases are the major factors leading to severe visual impairment and even irreversible blindness worldwide. The therapeutic approach for retinal degenerative diseases is one extremely urgent and hot spot in science research. The sigma-1 receptor is a novel, multifunctional ligand-mediated molecular chaperone residing in endoplasmic reticulum (ER) membranes and the ER-associated mitochondrial membrane (ER-MAM); it is widely distributed in numerous organs and tissues of various species, providing protective effects on a variety of degenerative diseases. Over three decades, considerable research has manifested the neuroprotective function of sigma-1 receptor in the retina and has attempted to explore the molecular mechanism of action. In the present review, we will discuss neuroprotective effects of the sigma-1 receptor in retinal degenerative diseases, mainly in aspects of the following: the localization in different types of retinal neurons, the interactions of sigma-1 receptors with other molecules, the correlated signaling pathways, the influence of sigma-1 receptors to cellular functions, and the potential therapeutic effects on retinal degenerative diseases.  相似文献   

4.
Organic gem-dihydroperoxides (DHPs) and their derived peroxides have attracted a great deal of attention as potential anti-cancer agents. However, the precise mechanism of their inhibitory effect on tumors is unknown. To determine the mechanism of the inhibitory effects of DHPs, we examined the effects of DHPs on leukemia K562 cells. As a result, certain DHPs used in this study exhibited growth-inhibitory activity according to a clear structure-activity relationship. The most potent DHP, 12AC3O, induced apoptosis in K562 cells, but not in peripheral blood monocytes (PBMCs) or fibroblast cells. 12AC3O induced apoptosis through the intrinsic mitochondrial pathway and thereafter through the extrinsic pathway. The activity of the former pathway was partly attenuated by a JNK inhibitor. Interestingly, 12AC3O induced apoptosis by trapping a large amount of ROS, leading to an extremely lower intracellular ROS level compared with that in the cells in the steady-state condition. These results suggest that an appropriate level of intracellular ROS was necessary for the maintenance of cancer cell growth. DHPs may have a potential to be a novel anti-cancer agent with minimum adverse effects on normal cells.  相似文献   

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Despite the recurring outbreak of resistance mechanisms and adverse reactions, doxorubicin (Doxo) still remains the standard-of-care for several cancers, including osteosarcoma (OS). As an appealing source of phytochemical compounds, naturally occurring molecules have extensively been reported to overcome Doxo limitations in preclinical models. Unlike other dietary polyphenols, only few studies recognize chlorogenic acid (CGA) as a potential partner in combination therapy, while, conversely, its anticancer evidence is steadily growing, ultimately in OS. On this basis, herein we examine the cooperating effects between CGA and Doxo in U2OS and MG-63 human OS cells. With respect to Doxo alone, the concomitant administration of CGA further decreased cell viability and growth, promoting cell death potentially via apoptosis induction. Furthermore, a longer-lasting reduction in clonogenic potential deeply supported the CGA ability to improve Doxo efficacy in those cells. Remarkably, CGA treatment ameliorated Doxo-induced cytotoxicity in H9c2 rat cardiomyocyte cells instead. Although inactivation of p44/42 MAPK was detected in response to CGA plus Doxo, PD98059-mediated p44/42 MAPK impairment enhanced the combination outcome in OS cells. These findings firstly propose CGA as a promising chemosensitizer and cardioprotective agent in OS therapy, suggesting the p44/42 MAPK pathway as relevantly involved in CGA-mediated Doxo susceptibility.  相似文献   

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Oral cancer (OC) has been attracted research attention in recent years as result of its high morbidity and mortality. Costunolide (CTD) possesses potential anticancer and bioactive abilities that have been confirmed in several types of cancers. However, its effects on oral cancer remain unclear. This study investigated the potential anticancer ability and underlying mechanisms of CTD in OC in vivo and in vitro. Cell viability and anchorage-independent colony formation assays were performed to examine the antigrowth effects of CTD on OC cells; assessments for migration and invasion of OC cells were conducted by transwell; Cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. The results revealed that CTD suppressed the proliferation, migration and invasion of oral cancer cells effectively and induced cell cycle arrest and apoptosis; regarding the mechanism, CTD bound to AKT directly by binding assay and repressed AKT activities through kinase assay, which thereby downregulating the downstream of AKT. Furthermore, CTD remarkably promotes the generation of reactive oxygen species by flow cytometry assay, leading to cell apoptosis. Notably, CTD strongly suppresses cell-derived xenograft OC tumor growth in an in vivo mouse model. In conclusion, our results suggested that costunolide might prevent progression of OC and promise to be a novel AKT inhibitor.  相似文献   

7.
相较于其他传统的脱氮技术,厌氧氨氧化(Anaerobic ammonium oxidation,Anammox)工艺作为目前新型的脱氮工艺具有无需外加碳源、节能、减排等优点。然而,在实际应用过程中却因污泥流失而无法快速培养启动。厌氧氨氧化颗粒污泥(Anammox granular sludge,AnGS)可以提高Anammox工艺脱氮效能并保障长期稳定运行,其中通过外加铁强化AnGS是当前研究最为广泛且具经济性和实用性的一种措施。该文简述了厌氧氨氧化菌(Anaerobic ammonium oxidation bacteria,AnAOB)的特性、代谢途径及AnGS的聚集机制,重点从调控酶的合成和功能基因的表达、加速功能菌群的富集、供给颗粒污泥凝结核、促进胞外聚合物(EPS)分泌以及加强系统群体感应等方面对铁调控AnGS的机制进行梳理,为铁强化Anammox技术的发展与应用提供理论指导。  相似文献   

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Ferroptosis is a cell death event caused by increased lipid peroxidation leading to iron-dependent oxidative stress and is associated with a wide variety of diseases. In recent years, ferroptosis inhibition has emerged as a novel strategy to target different pathologies. Here, we report the synthesis of two purine derivatives, 1 and 2 , for iron chelation strategy and evaluate their potency to inhibit erastin-induced ferroptosis. Both compounds showed efficient iron chelation in solution as well as in cellular environment. The crystal structure of the purine derivatives with iron demonstrated a 2 : 1 (ligand to metal center) stoichiometry for iron and purine derivative complexation. The synthesized compounds also decrease the reactive oxygen species concentration in cell cultures. Compound 2 showed better potency towards the prevention of ferroptotic cell death as compared to commercially available iron chelator in the erastin-induced ferroptosis cell culture model. Such purine analogues are potential functional scaffolds for the development of target molecules for ferroptosis inhibition.  相似文献   

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Enteroviruses (EVs) are common RNA viruses that can cause various types of human diseases and conditions such as hand, foot, and mouth disease (HFMD), myocarditis, meningitis, sepsis, and respiratory disorders. Although EV infections in most patients are generally mild and self-limiting, a small number of young children can develop serious complications such as encephalitis, acute flaccid paralysis, myocarditis, and cardiorespiratory failure, resulting in fatalities. Established evidence has suggested that certain non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs) are involved in the occurrence and progression of many human diseases. Recently, the involvement of ncRNAs in the course of EV infection has been reported. Herein, the authors focus on recent advances in the understanding of ncRNAs in EV infection from basic viral pathogenesis to clinical prospects, providing a reference basis and new ideas for disease prevention and research directions.  相似文献   

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Pro-inflammatory cytokines promote cellular iron-import through enhanced divalent metal transporter-1 (DMT1) expression in pancreatic β-cells, consequently cell death. Inhibition of β-cell iron-import by DMT1 silencing protects against apoptosis in animal models of diabetes. However, how alterations of signaling networks contribute to the protective action of DMT1 knock-down is unknown. Here, we performed phosphoproteomics using our sequential enrichment strategy of mRNA, protein, and phosphopeptides, which enabled us to explore the concurrent molecular events in the same set of wildtype and DMT1-silenced β-cells during IL-1β exposure. Our findings reveal new phosphosites in the IL-1β-induced proteins that are clearly reverted by DMT1 silencing towards their steady-state levels. We validated the levels of five novel phosphosites of the potential protective proteins using parallel reaction monitoring. We also confirmed the inactivation of autophagic flux that may be relevant for cell survival induced by DMT1 silencing during IL-1β exposure. Additionally, the potential protective proteins induced by DMT1 silencing were related to insulin secretion that may lead to improving β-cell functions upon exposure to IL-1β. This global profiling has shed light on the signal transduction pathways driving the protection against inflammation-induced cell death in β-cells after DMT1 silencing.  相似文献   

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Hydroxytyrosol (HT), the main representative of polyphenols of olive oil, has been described as one of the most powerful natural antioxidants, also showing anti-inflammatory, antimicrobial, cardioprotective and anticancer activity in different type of cancers, but has been little studied in hematological neoplasms. The objective of this work was to evaluate the anticancer potential of HT in acute human leukemia T cells (Jurkat and HL60) and the anti-inflammatory potential in murine macrophages (Raw264.7). For this, cytotoxicity tests were performed for HT, showing IC50 values, at 24 h, for Jurkat, HL60 and Raw264.7 cells, of 27.3 µg·mL−1, 109.8 µg·mL−1 and 45.7 µg·mL−1, respectively. At the same time, HT caused cell arrest in G0/G1 phase in both Jurkat and HL60 cells by increasing G0/G1 phase and significantly decreasing S phase. Apoptosis and cell cycle assays revealed an antiproliferative effect of HT, decreasing the percentage of dividing cells and increasing apoptosis. Furthermore, HT inhibited the PI3K signaling pathway and, consequently, the MAPK pathway was activated. Inflammation tests revealed that HT acts as an anti-inflammatory agent, reducing NO levels in Raw264.7 cells previously stimulated by lipopolysaccharide (LPS). These processes were confirmed by the changes in the expression of the main markers of inflammation and cancer. In conclusion, HT has an anticancer and anti-inflammatory effect in the cell lines studied, which were Raw264.7, Jurkat, and HL60, and could be used as a natural drug in the treatment of liquid cancers, leukemias, myelomas and lymphomas.  相似文献   

12.
The composition of IL-23R complex is similar to that of the IL-12 receptor (IL-12R) complex with a shared IL-12R-β1 chain. The IL-12R-β1 heterodimerizes with IL-23R and IL-12R-β2 to form IL-23R and IL-12R complexes, respectively. The IL-12R-β2 has been shown to function as a tumor suppressor gene and apoptotic inducer. However, whether IL-23R also functions in cell apoptosis is currently unknown. In this study, we demonstrate for the first time that overexpression of IL-23R markedly induces cell apoptosis in both 293ET and HeLa cells. The activations of caspase 3 and caspase 9 are induced by IL-23R. Mechanistic study reveals that IL-23R markedly inhibits RAS/MAPK and STAT3 but not STAT1 and PI-3K/Akt signaling pathways in both 293ET and HeLa cells. Overexpression of IL-23R significantly up-regulates IL-12Rβ1 expression but not IL-23α and IL-12β expressions in both cell lines. Therefore, our data strongly indicates that IL-23R is able to induce cell apoptosis by activating the intrinsic mitochondrial pathways associated with the inhibition in RAS/MAPK and STAT3 activations in mammalian cells.  相似文献   

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Iron is essential for multiple bacterial processes and is thus required for host colonization and infection. The antimicrobial activity of multiple iron chelators and gallium-based therapies against different bacterial species has been characterized in preclinical studies. In this review, we provide a synthesis of studies characterizing the antimicrobial activity of the major classes of iron chelators (hydroxamates, aminocarboxylates and hydroxypyridinones) and gallium compounds. Special emphasis is placed on recent in-vitro and in-vivo studies with the novel iron chelator DIBI. Limitations associated with iron chelation and gallium-based therapies are presented, with emphasis on limitations of preclinical models, lack of understanding regarding mechanisms of action, and potential host toxicity. Collectively, these studies demonstrate potential for iron chelators and gallium to be used as antimicrobial agents, particularly in combination with existing antibiotics. Additional studies are needed in order to characterize the activity of these compounds under physiologic conditions and address potential limitations associated with their clinical use as antimicrobial agents.  相似文献   

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Cancer is a horrific disease that, to date, has no cure. It is caused by various factors and takes many lives. Apoptosis is a programmed cell death mechanism and if it does not function correctly in cancer cells, it can lead to severe disease. There are various signaling pathways for regulating apoptosis in cancer cells. Flavonoids are non-artificial natural bioactive compounds that are gaining attention as being capable of for inducing apoptosis in cancer cells. Among these, in this study, we focus on flavones. Flavones are a subclass of the numerous available flavonoids and possess several bioactive functions. Some of the most reported and well-known critical flavones, namely apigenin, acacetin, baicalein, luteolin, tangeretin, and wogonin, are discussed in depth in this review. Our main aim is to investigate the effects of the selected flavones on apoptosis and cell signaling pathways that contribute to death due to various types of cancers.  相似文献   

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Kallmann syndrome is the result of innate genetic defects in the fibroblast growth factor (FGF) regulated signaling network causing diminished signal transduction. One of the rare mutations associated with the syndrome alters the Sprouty (Spry)4 protein by converting the serine at position 241 into a tyrosine. In this study, we characterize the tyrosine Spry4 mutant protein in the primary human embryonic lung fibroblasts WI-38 and osteosarcoma-derived cell line U2OS. As demonstrated in a cell signaling assay, Spry4 gains the capability of inhibiting FGF, but not epithelial growth factor (EGF)-induced signaling as a consequence of the tyrosine substitution. Additionally, migration of normal embryonic lung fibroblasts and osteosarcoma-derived cells is potently inhibited by the tyrosine Spry4 variant, while an effect of the wildtype Spry4 protein is hardly measureable. Concerning cell proliferation, the unaltered Spry4 protein is ineffective to influence the WI-38 cells, while the mutated Spry4 protein decelerates the cell doubling. In summary, these data emphasize that like the other mutations associated with Kallmann syndrome the described Spry4 mutation creates a hyperactive version of a selective inhibitory molecule and can thereby contribute to a weakened FGF signaling. Additionally, the study pinpoints a Spry4 variation expanding the applicability of Spry4 in a potential cancer therapy.  相似文献   

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Pesticide resistance in insects is an example of adaptive evolution occurring in pest species and is driven by the artificial introduction of pesticides. The diamondback moth (DBM), Plutella xylostella (Lepidoptera: Plutellidae), has evolved resistance to various insecticides. Understanding the genetic changes underpinning the resistance to pesticides is necessary for the implementation of pest control measures. We sequenced the genome of six resistant and six susceptible DBM individuals separately and inferred the genomic regions of greatest divergence between strains using FST and θπ. Among several genomic regions potentially related to insecticide resistance, CYP6B6-like was observed with significant divergence between the resistant and susceptible strains, with a missense mutation located near the substrate recognition site (SRS) and four SNPs in the promoter. To characterize the relative effects of directional selection via insecticide tolerance (‘strain’) as compared to acute exposure to insecticide (‘treatment’), four pairwise comparisons were carried out between libraries to determine the differentially expressed genes. Most resistance-related differentially expressed genes were identified from the comparison of the strains and enriched in pathways for exogenous detoxification including cytochrome P450 and the ABC transporter. Further confirmation came from the weighted gene co-expression network analysis, which indicated that genes in the significant module associated with chlorantraniliprole resistance were enriched in pathways for exogenous detoxification, and that CYP6B6-like represented a hub gene in the “darkred” module. Furthermore, RNAi knock-down of CYP6B6-like increases P. xylostella sensitivity to chlorantraniliprole. Our study thus provides a genetic foundation underlying selection for pesticide resistance and plausible mechanisms to explain fast evolved adaptation through genomic divergence and altered gene expression in insects.  相似文献   

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Nasopharyngeal carcinoma (NPC) has a higher incidence in Taiwan than worldwide. Although it is a radiosensitive malignancy, cancer recurrence is still high in the advanced stages because of its ability to induce lymph node metastasis. Picrasidine I from Picrasma quassioides has been reported as a potential drug for targeting multiple signaling pathways. The present study aimed to explore the role of picrasidine I in the apoptosis of NPC cells. Our results show that picrasidine I induced cytotoxic effects in NPC cells and caused cell cycle arrest in the sub-G1, S, and G2/M phases. Western blot analysis further demonstrated that the modulation of apoptosis through the extrinsic and intrinsic pathways was involved in picrasidine I-induced cell death. Downregulation of the ERK1/2 and Akt signaling pathways was also found in picrasidine I-induced apoptosis. Additionally, the apoptosis array showed that picrasidine I significantly increased heme oxygenase-1 (HO-1) expression, which could act as a critical molecule in picrasidine I-induced apoptosis in NPC cells. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets also revealed that the HMOX1 mRNA level (HO-1) is lower in patients with head and neck squamous carcinoma (HNSCC) and NPC than in patients without cancer. Our study indicated that picrasidine I exerts anticancer effects in NPC by modulating HO-1 via the ERK and Akt signaling pathways.  相似文献   

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The expression of Hemoglobin (Hb) is not restricted to erythrocytes but is also present in neurons. Hb is selectively enriched in vulnerable mesencephalic dopaminergic neurons of Parkinson’s disease (PD) instead of resistant neurons. Controversial results of neuronal Hb levels have been reported in postmortem brains of PD patients: although neuronal Hb levels may decline in PD patients, elderly men with higher Hb levels have an increased risk of developing PD. α-synuclein, a key protein involved in PD pathology, interacts directly with Hb protein and forms complexes in erythrocytes and brains of monkeys and humans. These complexes increase in erythrocytes and striatal cytoplasm, while they decrease in striatal mitochondria with aging. Besides, the colocalization of serine 129-phosphorylated (Pser129) α-synuclein and Hb β chains have been found in the brains of PD patients. Several underlying molecular mechanisms involving mitochondrial homeostasis, α-synuclein accumulation, iron metabolism, and hormone-regulated signaling pathways have been investigated to assess the relationship between neuronal Hb and PD development. The formation of fibrils with neuronal Hb in various neurodegenerative diseases may indicate a common fibrillization pathway and a widespread target that could be applied in neurodegeneration therapy.  相似文献   

20.
Genetic and epigenetic changes in the mitogen activated protein kinase (MAPK) signaling render urothelial cancer a potential target for tyrosine kinase inhibitor (TKI) treatment. However, clinical trials of several TKIs failed to prove efficacy. In this context, we investigated changes in MAPK signaling activity, downstream apoptotic regulators and changes in cell cycle distribution in different urothelial cancer cell lines (UCCs) upon treatment with the multikinase inhibitor sorafenib. None of the classical sorafenib targets (vascular endothelial growth factor receptor 1/-receptor 2, VEGFR1/-R2; platelet-derived growth factor receptor α/-receptor β, PDGFR-α/-β; c-KIT) was expressed at significant levels leaving RAF proteins as its likely molecular target. Low sorafenib concentrations paradoxically increased cell viability, whereas higher concentrations induced G1 arrest and eventually apoptosis. MAPK signaling remained partly active after sorafenib treatment, especially in T24 cells with an oncogenic HRAS mutation. AKT phosphorylation was increased, suggesting compensatory activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Sorafenib regularly down regulated the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) protein, but combinatorial treatment with ABT-737 targeting other B-cell lymphoma 2 (Bcl-2) family proteins did not result in synergistic effects. In summary, efficacy of sorafenib in urothelial cancer cell lines appears hampered by limited effects on MAPK signaling, crosstalk with further cancer pathways and an anti-apoptotic state of UCCs. These observations may account for the lack of efficacy of sorafenib in clinical trials and should be considered more broadly in the development of signaling pathway inhibitors for drug therapy in urothelial carcinoma.  相似文献   

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