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November 27, 2023
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November 13, 2023
Abstract
Growth cones of oligodendrocyte progenitor cells (OPCs) are challenging to investigate with conventional light microscopy due to their small size. Especially substructures such as filopodia, lamellipodia and their underlying cytoskeleton are difficult to resolve with diffraction limited microscopy. Light microscopy techniques, which surpass the diffraction limit such as stimulated emission depletion microscopy, often require expensive setups and specially trained personnel rendering them inaccessible to smaller research groups. Lately, the invention of expansion microscopy (ExM) has enabled super-resolution imaging with any light microscope without the need for additional equipment. Apart from the necessary resolution, investigating OPC growth cones comes with another challenge: Imaging the topography of membranes, especially label- and contact-free, is only possible with very few microscopy techniques one of them being scanning ion conductance microscopy (SICM). We here present a new imaging workflow combining SICM and ExM, which enables the visualization of OPC growth cone nanostructures. We correlated SICM recordings and ExM images of OPC growth cones captured with a conventional widefield microscope. This enabled the visualization of the growth cones’ membrane topography as well as their underlying actin and tubulin cytoskeleton.
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Open Access
November 10, 2023
Abstract
HnRNPs are ubiquitously expressed RNA-binding proteins, tightly controlling posttranscriptional gene regulation. Consequently, hnRNP networks are essential for cellular homeostasis and their dysregulation is associated with cancer and other diseases. However, the physiological function of hnRNPs in non-cancerous cell systems are poorly understood. We analyzed the importance of HNRNPDL in endothelial cell functions. Knockdown of HNRNPDL led to impaired proliferation, migration and sprouting of spheroids. Transcriptome analysis identified cyclin D1 ( CCND1 ) and tropomyosin 4 ( TPM4 ) as targets of HNRNPDL, reflecting the phenotypic changes after knockdown. Our findings underline the importance of HNRNPDL for the homeostasis of physiological processes in endothelial cells.
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November 10, 2023
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The prevention and treatment of gastric cancer has been the focus and difficulty of medical research. We aimed to explore the mechanism of inhibiting migration and invasion of gastric cancer cells by methionine restriction (MR). The human gastric cancer cell lines AGS and MKN45 cultured with complete medium (CM) or medium without methionine were used for in vitro experiments. MKN45 cells were injected tail vein into BALB/c nude mice and then fed with normal diet or methionine diet for in vivo experiments. MR treatment decreased cell migration and invasion, increased E-cadherin expression, decreased N-cadherin and p-p65 expressions, and inhibited nuclear p65 translocation of AGS and MKN45 cells when compared with CM group. MR treatment increased IκBα protein expression and protein stability, and decreased IκBα protein ubiquitination level and TRIM47 expression. TRIM47 interacted with IκBα protein, and overexpression of TRIM47 reversed the regulatory effects of MR. TRIM47 promoted lung metastasis formation and partially attenuated the effect of MR on metastasis formation in vivo compared to normal diet group mice. MR reduces TRIM47 expression, leads to the degradation of IκBα, and then inhibits the translocation of nuclear p65 and the migration and invasion of gastric cancer cells.
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October 31, 2023
Abstract
Platelet-derived growth factor (PDGF)-induced changes in vascular smooth muscle cells (VSMCs) stimulate vascular remodeling, resulting in vascular diseases such as pulmonary arterial hypertension. VSMCs communicate with endothelial cells through extracellular vesicles (EVs) carrying cargos, including microRNAs. To understand the molecular mechanisms through which PDGF-stimulated pulmonary artery smooth muscle cells (PASMCs) interact with pulmonary artery endothelial cells (PAECs) under pathological conditions, we investigated the crosstalk between PASMCs and PAECs via extracellular vesicle miR-409-5p under PDGF stimulation. miR-409-5p expression was upregulated in PASMCs upon PDGF signaling, and it was released into EVs. The elevated expression of miR-409-5p was transported to PAECs and led to their impaired function, including reduced NO release, which consequentially resulted in enhanced PASMC proliferation. We propose that the positive regulatory loop of PASMC-extracellular vesicle miR-409-5p-PAEC is a potential mechanism underlying the proliferation of PASMCs under PDGF stimulation. Therefore, miR-409-5p may be a novel therapeutic target for the treatment of vascular diseases, including pulmonary arterial hypertension.
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October 30, 2023
Abstract
Proteolytic activity in the tumour microenvironment is an important factor in cancer development since it can also affect intracellular signalling pathways via positive feedback loops that result in either increased tumour growth or resistance to anticancer mechanisms. In this study, we demonstrated extracellular cathepsin L-mediated cleavage of epidermal growth factor receptor (EGFR) and identified the cleavage site in the extracellular domain after R224. To further evaluate the relevance of this cleavage, we cloned and expressed a truncated version of EGFR, starting at G225, in HeLa cells. We confirmed the constitutive activation of the truncated protein in the absence of ligand binding and determined possible changes in intracellular signalling. Furthermore, we determined the effect of truncated EGFR protein expression on HeLa cell viability and response to the EGFR inhibitors, tyrosine kinase inhibitor (TKI) erlotinib and monoclonal antibody (mAb) cetuximab. Our data reveal the nuclear localization and phosphorylation of EGFR and signal trancducer and activator of transcription 3 (STAT3) in cells that express the truncated EGFR protein and suggest that these phenomena cause resistance to EGFR inhibitors.
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Open Access
October 12, 2023
Abstract
Retracing human cognitive origins started out at the systems level with the top-down interpretation of archaeological records spanning from man-made artifacts to endocasts of ancient skulls. With emerging evolutionary genetics and organoid technologies, it is now possible to deconstruct evolutionary processes on a molecular/cellular level from the bottom-up by functionally testing archaic alleles in experimental models. The current challenge is to complement these approaches with novel strategies that allow a holistic reconstruction of evolutionary patterns across human cognitive domains. We argue that computational neuroarcheology can provide such a critical mesoscale framework at the brain network-level, linking molecular/cellular (bottom-up) to systems (top-down) level data for the correlative archeology of the human mind.
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October 3, 2023
Abstract
Infections remain the most common cause of death after traumatic spinal cord injury, likely due to a developing immune deficiency syndrome. This, together with a somewhat contradictory development of autoimmunity in many patients, are two major components of the maladaptive systemic immune response. Although the local non-resolving inflammation in the lesioned spinal cord may lead to an antibody formation against autoantigens of the injured spinal cord tissue, there are also natural (pre-existing) autoantibodies independent of the injury. The way in which these autoantibodies with different origins affect the neuronal and functional outcome of spinal cord-injured patients is still controversial.
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September 28, 2023
Abstract
Patients with acute myocardial infarction complicated with diabetes are more likely to develop myocardial ischemia/reperfusion (I/R) injury (MI/RI) during reperfusion therapy. Both HMGB1 and RAGE play important roles in MI/RI. However, the specific mechanisms of HMGB1 associated with RAGE are not fully clarified in diabetic MI/RI. This study aimed to investigate whether the HMGB1-RAGE axis induces diabetic MI/RI via regulating autophagy and apoptosis. A db/db mouse model of MI/RI was established, where anti-HMGB1 antibody and RAGE inhibitor (FPS-ZM1) were respectively injected after 10 min of reperfusion. The results showed that treatment with anti-HMGB1 significantly reduced the infarct size, serum LDH, and CK-MB level. Similar situations also occurred in mice administrated with FPS-ZM1, though the HMGB1 level was unchanged. Then, we found that treatment with anti-HMGB1 or FPS-ZM1 performed the same effects in suppressing the autophagy and apoptosis, as reflected by the results of lower LAMP2 and LC3B levels, increased Bcl-2 level, reduced BAX and caspase-3 levels. Moreover, the Pink1/Parkin levels were also inhibited at the same time. Collectively, this study indicates that the HMGB1-RAGE axis aggravated diabetic MI/RI via apoptosis and Pink1/Parkin mediated autophagy pathways, and inhibition of HMGB1 or RAGE contributes to alleviating those adverse situations.
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September 15, 2023
Abstract
Nitro-fatty acids (NFAs) are endogenous lipid mediators capable of post-translational modifications of selected regulatory proteins. Here, we investigated the anti-cancerous effects of nitro-oleic acid (NO 2 OA) and its combination with gamma irradiation on different cancer cell lines. The effects of NO 2 OA on cell death, cell cycle distribution, or expression of p21 and cyclin D1 proteins were analyzed in cancer (A-549, HT-29 and FaDu) or normal cell lines (HGF, HFF-1). Dose enhancement ratio at 50 % survival fraction (DER IC50 ) was calculated for samples pre-treated with NO 2 OA followed by gamma irradiation. NO 2 OA suppressed viability and induced apoptotic cell death. These effects were cell line specific but not in general selective for cancer cells. HT-29 cell line exerted higher sensitivity toward NO 2 OA treatment among cancer cell lines tested: induction of cell cycle arrest in the G2/M phase was associated with an increase in p21 and a decrease in cyclin D1 expression. Pre-treatment of HT-29 cells with NO 2 OA prior irradiation showed a significantly increased DER IC50 , demonstrating radiosensitizing effects. In conclusion, NO 2 OA exhibited potential for combined chemoradiotherapy. Our results encourage the development of new NFAs with improved features for cancer chemoradiation.
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September 12, 2023
Abstract
N6-methyladenosine (m6A) and N7-methylguanosine (m7G) modification of RNA represent two major intracellular post-transcriptional regulation modes of gene expression. However, the crosstalk of these two epigenetic modifications in tumorigenesis remain poorly understood. Here, we show that m6A methyltransferase METTL3-mediated METTL1 promotes cell proliferation of head and neck squamous cell carcinoma (HNSC) through m7G modification of the cell-cycle regulator CDK4. By mining the database GEPIA, METTL1 was shown to be up-regulated in a broad spectrum of human cancers and correlated with patient clinical outcomes, particularly in HNSC. Mechanistically, METTL3 methylates METTL1 mRNA and mediates its elevation in HNSC via m6A. Functionally, over-expression of METTL1 enhances HNSC cell growth and facilitates cell-cycle progress, while METTL1 knockdown represses these biological behaviors. Moreover, METTL1 physically binds to CDK4 transcript and regulates its m7G modification level to stabilize CDK4. Importantly, the inhibitory effects of METTL1 knockdown on the proliferation of HNSC, esophageal cancer (ESCA), stomach adenocarcinoma (STAD), and colon adenocarcinoma (COAD) were significantly mitigated by over-expression of CDK4. Taken together, this study expands the understanding of epigenetic mechanisms involved in tumorigenesis and identifies the METTL1/CDK4 axis as a potential therapeutic target for digestive system tumors.
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Open Access
September 12, 2023
Abstract
Advances of in vitro culture models have allowed unprecedented insights into human neurobiology. At the same time genetic screening has matured into a robust and accessible experimental strategy allowing for the simultaneous study of many genes in parallel. The combination of both technologies is a newly emerging tool for neuroscientists, opening the door to identifying causal cell- and tissue-specific developmental and disease mechanisms. However, with complex experimental genetic screening set-ups new challenges in data interpretation and experimental scope arise that require a deep understanding of the benefits and challenges of individual approaches. In this review, we summarize the literature that applies genetic screening to in vitro brain models, compare experimental strengths and weaknesses and point towards future directions of these promising approaches.
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September 8, 2023
Abstract
Microtubules are highly polar structures and are characterized by high anisotropy and stiffness. In neurons, they play a key role in the directional transport of vesicles and organelles. In the neuronal projections called axons, they form parallel bundles, mostly oriented with the plus-end towards the axonal termination. Their physico-chemical properties have recently attracted attention as a potential candidate in sensing, processing and transducing physical signals generated by mechanical forces. Here, we discuss the main evidence supporting the role of microtubules as a signal hub for axon growth in response to a traction force. Applying a tension to the axon appears to stabilize the microtubules, which, in turn, coordinate a modulation of axonal transport, local translation and their cross-talk. We speculate on the possible mechanisms modulating microtubule dynamics under tension, based on evidence collected in neuronal and non-neuronal cell types. However, the fundamental question of the causal relationship between these mechanisms is still elusive because the mechano-sensitive element in this chain has not yet been identified.
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September 8, 2023
Abstract
The exact mechanisms involved in flaviviruses virions’ release and the specific secretion of viral proteins, such as the Non Structural protein-1 (NS1), are still unclear. While these processes might involve vesicular transport to the cell membrane, NS1 from some flaviviruses was shown to participate in viral assembly and release. Here, we assessed the effect of the Zika virus (ZIKV) NS1 expression on the cellular proteome to identify trafficking-related targets that may be altered in the presence of the viral protein. We detected an increase in the synaptotagmin-9 (SYT9) secretory protein, which participates in the intracellular transport of protein-laden vesicles. We confirmed the effect of NS1 on SYT9 levels by transfection models while also detecting a significant subcellular redistribution of SYT9. We found that ZIKV prM-Env proteins, required for the viral particle release, also increased SYT9 levels and changed its localization. Finally, we demonstrated that ZIKV cellular infection raises SYT9 levels and promotes changes in its subcellular localization, together with a co-distribution with both Env and NS1. Altogether, the data suggest SYT9’s implication in the vesicular transport of viral proteins or virions during ZIKV infection, showing for the first time the association of synaptotagmins with the flavivirus’ life cycle.
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August 31, 2023
Abstract
To exploit the full potential of optogenetics, we need to titrate and tailor optogenetic methods to emulate naturalistic circuit function. For that, the following prerequisites need to be met: first, we need to target opsin expression not only to genetically defined neurons per se, but to specifically target a functional node. Second, we need to assess the scope of optogenetic modulation, i.e. the fraction of optogenetically modulated neurons. Third, we need to integrate optogenetic control in a closed loop setting. Fourth, we need to further safe and stable gene expression and light delivery to bring optogenetics to the clinics. Here, we review these concepts for the human and rodent brain.
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August 17, 2023
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Glucosinolates are plant thioglucosides, which act as chemical defenses. Upon tissue damage, their myrosinase-catalyzed hydrolysis yields aglucones that rearrange to toxic isothiocyanates. Specifier proteins such as thiocyanate-forming protein from Thlaspi arvense (TaTFP) are non-heme iron proteins, which capture the aglucone to form alternative products, e.g. nitriles or thiocyanates. To resolve the electronic state of the bound iron cofactor in TaTFP, we applied continuous wave electron paramagnetic resonance (CW EPR) spectroscopy at X -and Q -band frequencies (∼9.4 and ∼34 GHz). We found characteristic features of high spin and low spin states of a d 5 electronic configuration and local rhombic symmetry during catalysis. We monitored the oxidation states of bound iron during conversion of allylglucosinolate by myrosinase and TaTFP in presence and absence of supplemented Fe 2+ . Without added Fe 2+ , most high spin features of bound Fe 3+ were preserved, while different g ’-values of the low spin part indicated slight rearrangements in the coordination sphere and/or structural geometry. We also examined involvement of the redox pair Fe 3+ /Fe 2 in samples with supplemented Fe 2+ . The absence of any EPR signal related to Fe 3+ or Fe 2+ using an iron-binding deficient TaTFP variant allowed us to conclude that recorded EPR signals originated from the bound iron cofactor.
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August 8, 2023
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The activity of neuronal Kv7.2/Kv7.3 channels is critically dependent on PIP 2 and finely modulated by cholesterol. Here, we report the crosstalk between cholesterol and PIP 2 in the regulation of Kv7.2/Kv7.3 channels. Our results show that currents passing through Kv7.2/Kv7.3 channels in cholesterol-depleted cells, by acute application of methyl-β-cyclodextrin (MβCD), were less sensitive to PIP 2 dephosphorylation strategies than those of control cells, suggesting that cholesterol depletion enhances the Kv7.2/Kv7.3–PIP 2 interaction. In contrast, the sensitivity of Kv7.2/Kv7.3 channels to acute membrane cholesterol depletion by MβCD was not altered in mutant channels with different apparent affinities for PIP 2 .
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June 27, 2023
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Neuromuscular cell culture models are used to investigate synapse formation and function, as well as mechanisms of de-and regeneration in neuromuscular diseases. Recent developments including 3D culture technique and hiPSC technology have propelled their ability to complement insights from in vivo models. However, most cultures have not considered Schwann cells, the glial part of NMJs. In the following, a brief overview of different types of neuromuscular cocultures is provided alongside examples for studies that included Schwann cells. From these, findings concerning the effects of Schwann cells on those cultures are summarized and future lines of research are proposed.
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May 30, 2023
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Understanding how neuronal networks generate complex behavior is one of the major goals of Neuroscience. Neurotransmitter and Neuromodulators are crucial for information flow between neurons and understanding their dynamics is the key to unravel their role in behavior. To understand how the brain transmits information and how brain states arise, it is essential to visualize the dynamics of neurotransmitters, neuromodulators and neurochemicals. In the last five years, an increasing number of single-wavelength biosensors either based on periplasmic binding proteins (PBPs) or on G-protein-coupled receptors (GPCR) have been published that are able to detect neurotransmitter release in vitro and in vivo with high spatial and temporal resolution. Here we review and discuss recent progress in the development of these sensors, their limitations and future directions.
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May 11, 2023
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This study attempted to investigate the effect of circ_0051799 on the immune microenvironment of lung adenocarcinoma (LUAD) and the relationship between circ_0051799 and exosomes. The number and morphology of exosomes were verified by nanoparticle tracking, transmission electron microscopy and western blotting. CCK8, EdU, Transwell and flow cytometry were used to verify the regulatory role of exosomes and circ_0051799 on tumor progression. Dual luciferase reporting and RNA immunoprecipitation were used to verify the targeted regulatory relationship between circ_0051799, miR-214-3p and IGF2BP3. WB was used to verify the role of the JAK/STAT pathway in circ_0051799 regulation. Ectopic tumor grafts and in situ models were used to validate in vivo their role in regulating LUAD progression. Hypoxic environment could alter but does not alter its shape. Exosomes can participate in the regulation of macrophage polarization by circ_0051799. In vitro and in vivo assays had shown that circ_0051799 could affect the proliferation and metastasis of LUAD through targeting miR-214-3p mediated IGF2BP3 regulated JAK/STAT pathway. This study found that hypoxia can affect LUAD process by promoting the regulation of macrophage polarization by exosome circ_0051799.
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March 22, 2023
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Glycoprotein (GP) Ib-IX-V is the second most abundant platelet receptor for thrombin and other ligands crucial for hemostasis and thrombosis. Its activity is involved in platelet adhesion to vascular injury sites and thrombin-induced platelet aggregation. GPIb-IX-V is a heteromeric complex composed of four subunits, GPIbα, GPIbβ, GPV and GPIX, in a stoichiometric ratio that has been wildly debated. Despite its important physiological roles, the overall structure and molecular arrangement of GPIb-IX-V are not yet fully understood. Here, we purify stable and functional human GPIb-IX-V complex from reconstituted EXPi293F cells in high homogeneity, and perform biochemical and structural characterization of this complex. Single-particle cryo-electron microscopy structure of GPIb-IX-V is determined at ∼11 Å resolution, which unveils the architecture of GPIb-IX-V and its subunit organization. Size-exclusion chromatography-multi-angle static light scattering analysis reveals that GPIb-IX-V contains GPIb-IX and GPV at a 1:1 stoichiometric ratio and surface plasmon resonance assays show that association of GPV leads to slow kinetics of thrombin binding to GPIb-IX-V. Taken together, our results provide the first three-dimensional architecture of the intact GPIb-IX-V complex, which extends our understanding of the structure and functional mechanism of this complex in hemostasis and thrombosis.
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March 6, 2023
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Salvia miltiorrhiza ( Salvia miltiorrhiza ) root , as a traditional herb , is widely applied to pharmacotherapy for vascular system disease. In this study, we elucidate the therapy mechanism of Salvia miltiorrhiza by using a model of hindlimb ischemia. Blood perfusion measurement showed that intravenous administration of the Water Extract of Salvia miltiorrhiza (WES) could facilitate damaged hindlimb blood flow recovery and blood vessel regeneration. In vitro mRNA screen assay in cultured human umbilical vein endothelial cells (HUVECs) show that WES induced increased NOS3 , VEGFA, and PLAU mRNA levels. Endothelial NOS (eNOS) promotor reporter analysis revealed that WES and the major ingredients danshensu (DSS) could enhance eNOS promoter activity. Additionally, we found that WES and its ingredients, including DSS, protocatechuic aldehyde (PAI), and salvianolic acid A (SaA), promoted HUVECs growth by the endothelial cell viability assays. A mechanistic approach confirmed that WES augments HUVECs proliferation through the activation of extracellular signal-regulated kinase (ERK) signal pathway. This study reveals that WES promotes ischemic remodeling and angiogenesis through its multiple principal ingredients, which target and regulate multiple sites of the network of the blood vessel endothelial cell regenerating process.
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March 2, 2023
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Hepatic metastasis is a major cause of colorectal cancer (CRC)-related deaths. Presently, the role of long non-coding RNAs (lncRNAs) in hepatic metastases from CRC is elusive. We dissected possible interplay between LINC00858/miR-132-3p/IGF2BP1 via bioinformatics approaches. Subsequently we analyzed mRNA expression of LINC00858, miR-132-3p and IGF2BP1 through qRT-PCR. Western blot was used to detect protein expression of IGF2BP1. RNA immunoprecipitation chip and dual-luciferase assay validated interaction between LINC00858 and miR-132-3p, as well as miR-132-3p and IGF2BP1. Cell viability, invasion, and migration were examined via CCK-8, colony formation, transwell and wound healing assays. Effect of LINC00858 on CRC hepatic metastases was validated via in vivo assay. Upregulated LINC00858 and IGF2BP1, and downregulated miR-132-3p were predicted in tumor tissues of patients with hepatic metastases from CRC. There were targeting relationships between LINC00858 and miR-132-3p, as well as miR-132-3p and IGF2BP1. Besides, LINC00858 facilitated progression of CRC cells. Rescue assay suggested that silencing LINC00858 suppressed CRC cell progression, while further silencing miR-132-3p or overexpressing IGF2BP1 reversed such effects. LINC00858 could facilitate CRC tumor growth and hepatic metastases. LINC00858 induced CRC hepatic metastases via regulating miR-132-3p/ IGF2BP1, and this study may deliver a new diagnostic marker for the disease.
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April 28, 2020
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α-Synuclein fibrillation is now regarded as a major pathogenic process in Parkinson’s disease and its proteinaceous deposits are also detected in other neurological disorders including Alzheimer's disease. Therefore anti-amyloidegenic compounds may delay or prevent the progression of synucleinopathies disease. Molecular chaperones are group of proteins which mediate correct folding of proteins by preventing unsuitable interactions which may lead to aggregation. The objective of this study was to investigate the anti-amyloidogenic effect of molecular chaperone artemin on α-synuclein. As the concentration of artemin was increased up to 4 μg/ml, a decrease in fibril formation of α-synuclein was observed using ThT fluorescence and congo red assay. TEM images also demonstrated a reduction in fibrils in the presence of artemin. The secondary structure of α-synuclein was similar to its native form prior to fibrillation when incubated with artemin. A cell-based assay has shown that artemin inhibits α-synuclein aggregation and reduce cytoxicity, apotosis and ROS production. Our results revealed that artemin has efficient chaperon activity for preventing α-synuclein fibril formation and toxicity.
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February 22, 2020
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Ants (Hymenoptera, Apocrita, Aculeata, Formicoidea) comprise a well-succeeded group of animals. Like bees and wasps, ants are mostly venomous, having a sting system to deliver a mixture of bioactive organic compounds and peptides. The predatory giant ant Dinoponera quadriceps belongs to the subfamily Ponerinae that include one of the largest known ant species in the world. In the present study, low molecular weight compounds and peptides were identified by on-line peptide mass fingerprint. These include neuroactive biogenic amines (histamine, tyramine, and dopamine), monoamine alkaloid (phenethylamine), free amino acids (e.g., glutamic acid and proline), free thymidine and cytosine. To the best of our knowledge most of these components are described for the first time in an ant venom. Multifunctional dinoponeratoxin peptides variants (pilosulin- and ponericin-like peptides) were characterized that possess antimicrobial, hemolytic, and histamine-releasing properties. These venom components, particularly peptides, might synergistically contribute to the overall venom activity and toxicity, for immobilizing live prey, and defending D. quadriceps against aggressors, predators and potential microbial infection.
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September 1, 2016
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May 14, 2016
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Meprin β is a dimeric type I transmembrane protein and acts as an ectodomain sheddase at the cell surface. It was shown that meprin β cleaves the amyloid precursor protein (APP), thereby releasing neurotoxic amyloid β peptides and implicating a role of meprin β in Alzheimer’s disease. In order to identify non-proteolytic regulators of meprin β, we performed a split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library. In this screen we identified tetraspanin 8 (TSPAN8) as interaction partner for meprin β. Since several members of the tetraspanin family were described to interact with metalloproteases thereby affecting their localization and/or activity, we hypothesized similar functions of TSPAN8 in the regulation of meprin β. We employed cell biological methods to confirm direct binding of TSPAN8 to meprin β. Surprisingly, we did not observe an effect of TSPAN8 on the catalytic activity of meprin β nor on the specific cleavage of its substrate APP. However, both proteins were identified being present in tetraspanin-enriched microdomains. Therefore we hypothesize that TSPAN8 might be important for the orchestration of meprin β at the cell surface with impact on certain proteolytic processes that have to be further identified.
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April 28, 2016
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Gastric cancer is the most common digestive malignant tumor worldwild. EDD1 was reported to be frequently amplified in several tumors and played an important role in the tumorigenesis process. However, the biological role and potential mechanism of EDD1 in gastric cancer remains poorly understood. In this study, we are aim to investigate the effect of EDD1 on gastric cancer progression and to explore the underlying mechanism. The results showed the significant up-regulation of EDD1 in -gastric cancer cell tissues and lines. The expression level of EDD1 was also positively associated with advanced clinical stages and predicted poor overall patient survival and poor disease-free patient survival. Besides, EDD1 knockdown markedly inhibited cell viability, colony formation, and suppressed tumor growth. Opposite results were obtained in gastric cancer cells with EDD1 overexpression. EDD1 knockdown was also found to induce gastric cancer cells apoptosis. Further investigation indicated that the oncogenic role of EDD1 in regulating gastric cancer cells growth and apoptosis was related to its PABC domain and directly through targeting miR-22, which was significantly down-regulated in gastric cancer tissues. Totally, our study suggests that EDD1 plays an oncogenic role in gastric cancer and may be a potential therapeutic target for gastric cancer.
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November 17, 2015
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August 20, 2015
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Recent studies have demonstrated that acquisition of epithelial-mesenchymal transition (EMT) is associated with drug resistance in lung cancer cells. However, the underlying mechanisms are not fully elucidated. Emerging evidence suggests that microRNAs play a crucial role in controlling EMT. The aim of this study was to explore the potential role of miR-125b in governing EMT in paclitaxel-resistant (PR) lung cancer cells. To achieve this goal, we explored the role of miR-125b in regulation of EMT in stable PR lung cancer cells, namely A549-PR and H460-PR. We found that miR-125b was significantly downregulated in A549-PR and H460-PR cells. Notably, ectopic expression of miR-125b led to the reversal of EMT phenotype. Moreover, we found that miR-125b governed PR-induced EMT partly due to down-regulation of its target Sema4C. More importantly, overexpression of miR-125b or depletion of Sema4C sensitized PR cells to paclitaxel. Furthermore, stable overexpression miR-125b in A549-PR cells inhibited tumor xenograft growth in immunodeficient mice. Our study implied that up-regulation of miR-125b could be a novel approach to reverse chemotherapy resistance in lung cancers.
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February 24, 2015
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Many bacteria can take up vitamins from the environment via specific transport machineries. Uptake is essential for organisms that lack complete vitamin biosynthesis pathways, but even in the presence of biosynthesis routes uptake is likely preferred, because it is energetically less costly. Pnu transporters represent a class of membrane transporters for a diverse set of B-type vitamins. They were identified 30 years ago and catalyze transport by the mechanism of facilitated diffusion, without direct coupling to ATP hydrolysis or transport of coupling ions. Instead, directionality is achieved by metabolic trapping, in which the vitamin substrate is converted into a derivative that cannot be transported, for instance by phosphorylation. The recent crystal structure of the nicotinamide riboside transporter PnuC has provided the first insights in substrate recognition and selectivity. Here, we will summarize the current knowledge about the function, structure and evolution of Pnu transporters. Additionally, we will highlight their role for potential biotechnological and pharmaceutical applications.
