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Item Open Access Functional Expression of Human α9* Nicotinic Acetylcholine Receptors in X. laevis Oocytes Is Dependent on the α9 Subunit 5′ UTR(Nazarbayev University School of Sciences and Humanities, 2013-05-23) Olena, FilchakovaNicotinic acetylcholine receptors (nAChRs) containing the α9 subunit are expressed in a wide variety of non-neuronal tissues ranging from immune cells to breast carcinomas. The α9 subunit is able to assemble into a functional homomeric nAChR and also co-assemble with the α10 subunit into functional heteromeric nAChRs. Despite the increasing awareness of the important roles of this subunit in vertebrates, the study of human α9-containing nAChRs has been severely limited by difficulties in its expression in heterologous systems. In Xenopus laevis oocytes, functional expression of human α9α10 nAChRs is very low compared to that of rat α9α10 nAChRs. When oocytes were co-injected with cRNA of α9 and α10 subunits of human versus those of rat, oocytes with the rat α9 human α10 combination had an ∼-fold higher level of acetylcholine-gated currents (IACh) than those with the human α9 rat α10 combination, suggesting difficulties with human α9 expression. When the ratio of injected human α9 cRNA to human α10 cRNA was increased from 1∶1 to 5∶1, IACh increased 36-fold (from 142±23 nA to 5171±748 nA). Functional expression of human α9-containing receptors in oocytes was markedly improved by appending the 5′-untranslated region of alfalfa mosaic virus RNA4 to the 5′-leader sequence of the α9 subunit cRNA. This increased the functional expression of homomeric human α9 receptors by 70-fold (from 7±1 nA to 475±158 nA) and of human α9α10 heteromeric receptors by 80-fold (from 113±62 nA to 9192±1137 nA). These findings indicate the importance of the composition of the 5′ untranslated leader sequence for expression of α9-containing nAChRs.Item Open Access Antiviral Resistance of Splenocytes in Aged Mice(Nazarbayev University School of Sciences and Humanities, 2017-03-30) Burster, TimoWe compared the susceptibility to viral infection of splenocytes, isolated from young versus old CBA mice, and evaluated the antiviral actions of lactoferrin in splenocytes infected with Encephalomyocarditis virus (EMCV). Recombinant mouse lactoferrin (rmLF) and bovine lactoferrin (bLF) were used. There were no differences in the susceptibility to EMCV infection in the studied age categories. Both types of lactoferrins were protective in young and old mice. The study confirmed the undisturbed viral resistance in old mice and the protective actions of lactoferrin in viral infection. The antiviral action of the homologous mouse lactoferrin was demonstrated for the first time.Item Open Access Extracellular vesicles in gastrointestinal cancer in conjunction with microbiota: On the border of Kingdoms(Nazarbayev University School of Sciences and Humanities, 2017-12-01) Barteneva, Natasha S.; Baiken, Yeldar; Sautbayeva, Zarina; Kauanova, SholpanExtracellular vesicle (EV) production is a universal feature of metazoan cells as well as prokaryotes (bMVs - bacterial microvesicles). They are small vesicles with phospholipid membrane carrying proteins, DNA and different classes of RNAs and are heavily involved in intercellular communication acting as vectors of information to target cells. For the last decade, the interest in EV research has exponentially increased though thorough studies of their roles in various pathologies that was not previously possible due to technical limitations. This review focuses on research evaluating the role of EV production in gastrointestinal (GI) cancer development in conjunction with GI microbiota and inflammatory diseases. We also discuss recent studies on the promising role of EVs and their content as biomarkers for early diagnosis of GI cancers. The bMVs have also been implicated in the pathogenesis of GI chronic inflammatory diseases, however, possible role of bMVs in tumorigenesis remains underestimated. We propose that EVs from eukaryotic cells as well as from different microbial, fungi, parasitic species and edible plants in GI tract act as mediators of intracellular and inter-species communication, particularly facilitating tumor cell survival and multi-drug resistance. In conclusion, we suggest that matching sequences from EV proteomes (available from public databases) with known protein sequences of microbiome gut bacteria will be useful in identification of antigen mimicry between evolutionary conservative protein sequences. Using this approach we identified Bacteroides spp. pseudokinase with activation loop and homology to PDGFRα, providing a proof-of-concept strategy. We speculate that existence of microbial pseudokinase that ‘mimics’ PDGFRα may be related to PDGFRα and Bacteroides spp. roles in colorectal carcinogenesis that require further investigation.Item Open Access Antimicrobial susceptibility of Brucella melitensis in Kazakhstan(Nazarbayev University School of Sciences and Humanities, 2017-12-28) Ramankulov, Yerlan; Shevtsov, Alexandr; Syzdykov, Marat; Kuznetsov, Andrey; Shevtsova, Elena; Berdimuratova, Kalysh; Kasim, MukanovBackground: Kazakhstan belongs to countries with a high level of brucellosis among humans and farm animals. Although antibiotic therapy is the main way to treat acute brucellosis in humans there is still little information on a circulation of the antibiotic-resistant Brucella strains in the Central Eurasia. In this article we describe an occurrence of the drug resistance of Brucella melitensis isolates in Kazakhstan which is among the largest countries of the region. Methods: Susceptibilities to tetracyclin, gentamycin, doxycyclin, streptomycin and rifampicin were investigated in 329 clinical isolates of Brucella melitensis using E-test method. Results: All isolates were susceptible to streptomycin, tetracycline and doxycycline. 97.3% of the Brucella isolates were susceptible to gentamycin, although only 37.4% of isolates were susceptible to rifampicin. 21.9% of isolates had intermediate resistance, and 26.4% of isolates were resistant to this antibacterial drug. Conclusion: Isolates of Brucella melitensis circulating in Kazakhstan are susceptible to streptomycin, doxicyclin, tetracyclin and gentamycin. At the same time the resistance to rifampicin is widespread, almost half of the isolates were rifampicin-resistant (including the intermediate resistance).Item Open Access Non-centrosomal MTs play a crucial role in organization of MT array in interphase fibroblasts(AIMS Press, 2018) Zvorykina, Yekaterina; Tvorogova, Anna; Gladkikh, Aleena; Vorobyev, IvanMicrotubules in interphase fibroblast-like cells are thought to be organized in a radial array growing from a centrosome-based microtubule-organizing center (MTOC) to the cell edges. However, many morphogenetic processes require the asymmetry of the microtubules (MT) array. One of the possible mechanisms of this asymmetry could be the presence of non-centrosomal microtubules in different intracellular areas. To evaluate the role of centrosome-born and non-centrosomal microtubules in the organization of microtubule array in motile 3T3 fibroblasts, we have performed the high-throughput analysis of microtubule growth in different functional zones of the cell and distinguished three subpopulations of growing microtubules (centrosome-born, marginal and inner cytoplasmic). Centrosome as an active microtubule-organizing center was absent in half of the cell population. However, these cells do not show any difference in microtubule growth pattern. In cells with active centrosome, it was constantly forming short (ephemeral) MTs, and ~15–20 MT per minute grow outwards for a distance >1 µm. Almost no persistent growth of microtubules was observed in these cells with the average growth length of 5–6 µm and duration of growth periods within 30 s. However, the number of growing ends increased towards cell margin, especially towards the active edges. We found the peripheral cytoplasmic foci of microtubule growth there. During recovery from nocodazole treatment microtubules started to grow around the centrosome in a normal way and independently in all the cell areas. Within 5 minutes microtubules continued to grow mainly near the cell edge. Thus, our data confirm the negligible role of centrosome as MTOC in 3T3 fibroblasts and propose a model of non-centrosomal microtubules as major players that create the cell asymmetry in the cells with a mesenchymal type of motility. We suggest that increased density of dynamic microtubules near the active lamellum could be supported by microtubule-based microtubule nucleation.Item Open Access A bioinformatics potpourri(Nazarbayev University School of Sciences and Humanities, 2018-01-19) Schönbach, Christian; Li, Jinyan; Ma, Lan; Horton, Paul; Sjaugi, Muhammad FarhanThe 16th International Conference on Bioinformatics (InCoB) was held at Tsinghua University, Shenzhen from September 20 to 22, 2017. The annual conference of the Asia-Pacific Bioinformatics Network featured six keynotes, two invited talks, a panel discussion on big data driven bioinformatics and precision medicine, and 66 oral presentations of accepted research articles or posters. Fifty-seven articles comprising a topic assortment of algorithms, biomolecular networks, cancer and disease informatics, drug-target interactions and drug efficacy, gene regulation and expression, imaging, immunoinformatics, metagenomics, next generation sequencing for genomics and transcriptomics, ontologies, post-translational modification, and structural bioinformatics are the subject of this editorial for the InCoB2017 supplement issues in BMC Genomics, BMC Bioinformatics, BMC Systems Biology and BMC Medical Genomics. New Delhi will be the location of InCoB2018, scheduled for September 26–28, 2018.Item Open Access Cyclic AMP pathway suppress autoimmune neuroinflammation by inhibiting functions of encephalitogenic CD4 T cells and enhancing M2 macrophage polarization at the site of inflammation(Nazarbayev University School of Sciences and Humanities, 2018-01-28) Barteneva, Natasha S.Although it has been demonstrated that cAMP pathway affect both adaptive and innate cell functions, the role of this pathway in the regulation of T-cell-mediated central nervous system (CNS) autoimmune inflammation, such as in experimental autoimmune encephalomyelitis (EAE), remains unclear. It is also unclear how cAMP pathway affects the function of CD4 T cells in vivo at the site of inflammation. We found that adenylyl cyclase activator Forskolin besides inhibition of functions autoimmune CD4 T cells also upregulated microRNA (miR)-124 in the CNS during EAE, which is associated with M2 phenotype of microglia/macrophages. Our study further established that in addition to direct influence of cAMP pathway on CD4 T cells, stimulation of this pathway promoted macrophage polarization toward M2 leading to indirect inhibition of function of T cells in the CNS. We demonstrated that Forskolin together with IL-4 or with Forskolin together with IL-4 and IFNγ effectively stimulated M2 phenotype of macrophages indicating high potency of this pathway in reprogramming of macrophage polarization in Th2-and even in Th1/Th2-mixed inflammatory conditions such as EAE. Mechanistically, Forskolin and/or IL-4 activated ERK pathway in macrophages resulting in the upregulation of M2-associated molecules miR-124, arginase (Arg)1, and Mannose receptor C-type 1 (Mrc1), which was reversed by ERK inhibitors. Administration of Forskolin after the onset of EAE substantially upregulated M2 markers Arg1, Mrc1, Fizz1, and Ym1 and inhibited M1 markers nitric oxide synthetase 2 and CD86 in the CNS during EAE resulting in decrease in macrophage/microglia activation, lymphocyte and CD4 T cell infiltration, and the recovery from the disease. Forskolin inhibited proliferation and IFNγ production by CD4 T cells in the CNS but had rather weak direct effect on proliferation of autoimmune T cells in the periphery and in vitro, suggesting prevalence of indirect effect of Forskolin on differentiation and functions of autoimmune CD4 T cells in vivo. Thus, our data indicate that Forskolin has potency to skew balance toward M2 affecting ERK pathway in macrophages and indirectly inhibit pathogenic CD4 T cells in the CNS leading to the suppression of autoimmune inflammation. These data may have also implications for future therapeutic approaches to inhibit autoimmune Th1 cells at the site of tissue inflammation.Item Open Access Therapeutic potential of a scorpion venom-derived antimicrobial peptide and its homologs against antibiotic-resistant Gram-positive bacteria(Nazarbayev University School of Sciences and Humanities, 2018-05-28) Xie, Yingqiu; Liu, Gaomin; Yang, Fan; Li, Fangfang; Li, Zhongjie; Lang, Yange; Shen, Bingzheng; Wu, Yingliang; Li, Wenxin; Harrison, Patrick L.; Strong, Peter N.; Miller, Keith; Cao, ZhijianThe alarming rise in the prevalence of antibiotic resistance among pathogenic bacteria poses a unique challenge for the development of effective therapeutic agents. Antimicrobial peptides (AMPs) have attracted a great deal of attention as a possible solution to the increasing problem of antibiotic-resistant bacteria. Marcin-18 was identified from the scorpion Mesobuthus martensii at both DNA and protein levels. The genomic sequence revealed that the marcin-18 coding gene contains a phase-I intron with a GT-AG splice junction located in the DNA region encoding the N-terminal part of signal peptide. The peptide marcin-18 was also isolated from scorpion venom. A protein sequence homology search revealed that marcin-18 shares extremely high sequence identity to the AMPs meucin-18 and megicin-18. In vitro, chemically synthetic marcin-18 and its homologs (meucin-18 and megicin-18) showed highly potent inhibitory activity against Gram-positive bacteria, including some clinical antibiotic-resistant strains. Importantly, in a mouse acute peritonitis model, these peptides significantly decreased the bacterial load in ascites and rescued nearly all mice heavily infected with clinical methicillin-resistant Staphylococcus aureus from lethal bacteremia. Peptides exerted antimicrobial activity via a bactericidal mechanism and killed bacteria through membrane disruption. Taken together, marcin-18 and its homologs have potential for development as therapeutic agents for treating antibiotic-resistant, Gram-positive bacterial infections.Item Open Access Diagnostic Potential of Imaging Flow Cytometry(Nazarbayev University School of Sciences and Humanities, 2018-07-01) Vorobyev, Ivan; Barteneva, Natasha S.Imaging flow cytometry (IFC) captures multichannel images of hundreds of thousands of single cells within minutes. IFC is seeing a paradigm shift from low- to high-information-content analysis, driven partly by deep learning algorithms. We predict a wealth of applications with potential translation into clinical practice.Item Open Access Surface modification of stainless steel for biomedical applications: Revisitinga century-old material(ELSEVIER, 2018-08-24) Kanayeva, Damira; Bekmurzayeva, Aliya; Duncanson, Wynter J.; Azevedo, Helena S.Stainless steel (SS) is widely used in many biomedical applications including bone implants and cardiovascular stents due to its good mechanical properties, biocompatibility and low price. Surface modification allows improving its characteristics without compromising its important bulk properties. SS with improved blood compatibility (blood contacting implants), enhanced ability to resist bacterial infection (long-term devices), better integration with a tissue (bone implants) are examples of successful SS surface modifications. Existing literature on this topic is extensive and has not been covered in an integrated way in previous reviews. This review paper aims to fill this gap, by surveying the literature on SS surface modification methods, as well as to provide guidance for selecting appropriate modification routes tailored for specific biomedical applicationsItem Open Access Specific and reliable detection of Myosin 1C isoform A by RTqPCR in prostate cancer cells(PeerJ Chemistry Journals, 2018-11-20) Saidova, Aleena A.; Potashnikova, Daria M.; Tvorogova, Anna V.; Maly, Ivan V.; Hofmann, Wilma A.; Vorobjev, Ivan A.Prostate cancer (PC) diagnostics and treatment often present a challenging task due to cancer subtype heterogeneity and differential disease progression in patient subgroups. Hence, the critical issue is finding a reliable and sensitive diagnostic and prognostic PC marker, especially for cases of biopsies with low percentages of cancer cells. Isoform A of myosin 1C was shown to be expressed in PC cells and responsible for their invasive properties, however, its feasibility for diagnostic purposes remains to be elucidated.....Item Open Access Myeloid cells in intact human cervical explants capture HIV and can transmit it to CD4 T cells(Nazarbayev University School of Sciences and Humanities, 2018-11-28) Barteneva, Natasha S.The importance of myeloid cells in HIV transmission in the female genital tract is uncertain. Because it is difficult to study the early events in HIV transmission in humans, most of our knowledge is based on animal models of SIV infection in Rhesus macaques and more recently HIV infection in humanized mice. However, these models may not accurately recapitulate transmission in the human genital tract. CD14+ myeloid cells are the most abundant hematopoietic cells in the human cervical mucosa, comprising 40–50% of CD45+ mononuclear cells. Most CD14+ cells are CD14+CD11c– macrophages and about a third are CD14+CD11c+ tissue dendritic cells, which express the HIV-binding receptors, DC-SIGN and CX3CR1. To examine the role of mucosal myeloid cells in HIV transmission, we infected intact healthy human cervical explants with CCR5–tropic HIV-1 ex vivo and then sorted populations of cervical immune cells 20 h later to determine whether they took up virus and could transmit it to activated CD4 T cells. Viral RNA was detected in CD14+ myeloid cells in all but one of 10 donor tissue samples, even when HIV RNA was not detected in CD4+ T cells. HIV RNA was detected predominantly in CD14+CD11c+ dendritic cells rather than in CD14+CD11c– macrophages. The reverse transcriptase inhibitor, nevirapine, reduced HIV RNA in CD4+ T cells, but not in CD14+ cells. Moreover, integrated HIV DNA were not detected above background in myeloid cells but was detected in T cells. These data suggest that although HIV replicates in T cells, myeloid cells in the female genital mucosa capture viral particles, but do not replicate the virus at early timepoints. However, sorted CD14+ myeloid cells isolated 20 h post-infection from 5 HIV-infected cervical explants tested all transmitted HIV to activated CD4+ T cells, while only 1 sample of sorted CD4+ T cells did. Thus, myeloid cells in human cervical tissue capture HIV and are an important early cellular storage site of infectious virus.Item Open Access Dynamic microtubules drive fibroblast spreading(Biology Open, 2018-12-13) Tvorogova, Anna; Saidova, Aleena; Smirnova, Tatiana; Vorobjev, IvanWhen cells with a mesenchymal type of motility come into contact with an adhesive substrate they adhere and start spreading by the formation of lamellipodia. Using a label-free approach and virtual synchronization approach we analyzed spreading in fibroblasts and cancer cells. In all cell lines spreading is a non-linear process undergoing isotropic or anisotropic modes with first fast (5–20 min) and then slow (30–120 min) phases. In the first 10 min cell area increases 2–4 times, while the absolute rate of initial spreading decreases 2–8 times....Item Open Access Systematic analysis of NLMP suggests nuclear localization of RTK/MET kinases resemble cancer cell clearance(Nazarbayev University School of Sciences and Humanities, 2019-01-30) Xie, Yingqiu; Nurkesh, Ayan; Ibragimova, Nazgul; Zhanzak, Zhuldyz; Meyerbekova, Aizhan; Alexeyeva, Zhanna; Yesbolatova, Aiya; Satayeva, Madina; Mustafa, Aidana; Manarbek, L.; Maipas, Aisulu; Altaikyzy, Akerke; Keneskhanova, Zhibek; Akbay, Burkitkan; Chen, ZhenbangBackgroundSome membrane proteins can translocate into the nucleus, defined as nuclear localized membrane proteins (NLMPs), including receptor tyrosine kinases (RTKs). We previously showed that nuclear MET (nMET), a member of RTKs, mediates cancer stem-like cells self-renewal to promote cancer recurrence. However, it is unknown that nMET or mMET, which is the ancestor in the evolution of cancer cell survival and clearance. Here, we aim to study the NLMP functions in cell death, differentiation and survival.MethodWe applied the systematic reanalysis of functional NLMP and clinical investigations of nMET from databases. In addition, we used soft agar assay, immunoblotting, flow cytometry, and immunofluorescence confocal microscopy for examinations of nMET functions including stem-like cell formation, cell signaling, cell cycle regulation, and co-localization with regulators of cell signaling. ShRNA, antibody of recognizing surface membrane MET based treatment were used to downregulate endogenous nMET to uncover its function.ResultsWe predicted and demonstrated that nMET and nEGFR are most likely not ancestors. nMET overexpression induces both cell death and survival with drug resistance and stem cell-like characters. Moreover, the paradoxical function of nMET in both cell death and cell survival is explained by the fact that nMET induces stem cell-like cell growth, DNA damage repair, to evade the drug sensitization for survival of single cells while non-stem cell-like nMET expressing single cells may undergo clearance by cell death through cell cycle arrest induced by p21.ConclusionTaken together, our data suggest a link between nuclear RTK and cancer cell evolutionary clearance via cell death, and drug resistance for survival through stemness selection. Targeting evolved nuclear RTKs in cancer stem cells would be a novel avenue for precision cancer therapy.Item Open Access Lessons from the Discovery of Mitochondrial Fragmentation (Fission): A Review and Update(Nazarbayev University School of Sciences and Humanities, 2019-02-20) Vorobyev, Ivan; Zorov, Dmitry; Popkov, Vasily; Babenko, Valentina; Zorova, Ljubava; Pevzner, Irina; Silachev, Denis; Zorov, Savva; Andrianova, Nadezda; Plotnikov, EgorThirty-five years ago, we described fragmentation of the mitochondrial population in a living cell into small vesicles (mitochondrial fission). Subsequently, this phenomenon has become an object of general interest due to its involvement in the process of oxidative stress-related cell death and having high relevance to the incidence of a pathological phenotype. Tentatively, the key component of mitochondrial fission process is segregation and further asymmetric separation of a mitochondrial body yielding healthy (normally functioning) and impaired (incapable to function in a normal way) organelles with subsequent decomposition and removal of impaired elements through autophagy (mitophagy). We speculate that mitochondria contain cytoskeletal elements, which maintain the mitochondrial shape, and also are involved in the process of intramitochondrial segregation of waste products. We suggest that perturbation of the mitochondrial fission/fusion machinery and slowdown of the removal process of nonfunctional mitochondrial structures led to the increase of the proportion of impaired mitochondrial elements. When the concentration of malfunctioning mitochondria reaches a certain threshold, this can lead to various pathologies, including aging. Overall, we suggest a process of mitochondrial fission to be an essential component of a complex system controlling a healthy cell phenotype. The role of reactive oxygen species in mitochondrial fission is discussed.Item Open Access Vitamin D and Its Synthetic Analogs(Journal of Medicinal Chemistry, 2019-03-27) Miguel A., Maestro; Ferdinand, Molnar; Carsten, CarlbergFor many individuals, in particular during winter, supplementation with the secosteroid vitamin D3 is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of 1,25(OH)2D3 at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR’s ligand-binding domain with various vitamin D compounds allow a detailed molecular understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and molecular insight derived from new structural information on the VDR protein.Item Open Access Cell surface cathepsin G can be used as an additional marker to distinguish T cell subsets(SPANDIDOS, 2019-04) Penczek, Adriane; Burster, TimoThe serine protease cathepsin G (CatG) is involved in numerous processes associated with the innate and adaptive immune system. During an immune response, neutrophils secrete CatG, which can bind to the cell surface of immune cells to provoke the proteolytic processing of cytokines and chemokines in order to stimulate lymphocytes. The present study analyzed peripheral blood mononuclear cells to characterize T cell populations in terms of their CatG content by flow cytometry. It was identified that CatG was exclusively present on the cell surface of a subset of T regulatory cells (Tregs), cluster of differentiation (CD) 39(+) Tregs, which expressed CatG in contrast to CD39(-) Tregs. Additionally, CatG was expressed on double positive CD4(+)CD8(+) T cells, T helper (Th) 9 cells and Th22 cells, implicating CatG as a novel marker to distinguish certain T cell subsets.Item Open Access APBioNet's annual International Conference on Bioinformatics (InCoB) returns to India in 2018(Nazarbayev University School of Sciences and Humanities, 2019-04-18) Schönbach, Christian; Ahmad, Shandar; Gromiha, Michael M.; Raghava, Gajendra P.S.; Ranganathan, ShobaInCoB, one of the largest annual bioinformatics conferences in the Asia-Pacific region since its launch in 2002, returned to New Delhi, India after 12 years, with a conference attendance of 314 delegates. The 2018 conference had sessions on Big Data and Algorithms, Next Generation Sequencing and Omics Science, Structure, Function and Interactions, Disease and Drug Discovery and Plant and Agricultural Bioinformatics. The conference also featured an industry track as well as panel discussions on Women in Bioinformatics and Democratization vs. Quality control in academic publishing. Asia Pacific Bioinformatics Interaction & Networking Society (APbians) was launched as an APBionet Special Interest Group. Of the 52 oral presentations made, 22 were accepted in supplemental issues of BMC Bioinformatics, BMC Genomics or BMC Medical Genomics and are briefly reviewed here. Next year's InCoB will be held in Jakarta, Indonesia from September 10-12, 2019.Item Open Access Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer(Nazarbayev University School of Sciences and Humanities, 2019-04-18) Xie, Yingqiu; Fan, Haiyan; Wenfu, Lu; Yang, Qing; Nurkesh, Ayan; Yeleussizov, Tleubek; Maipas, Aisulu; Lu, Jiang; Manarbek, L.; Chen, Zh.; Benassi, E.Nuclear receptor tyrosine kinases (nRTKs) are aberrantly upregulated in many types of cancers, but the regulation of nRTK remains unclear. We previously showed androgen deprivation therapy (ADT) induces nMET in castration-resistant prostate cancer (CRPC) specimens. Through gene expression microarray profiles reanalysis, we identified that nMET signaling requires ARF for CRPC growth in Pten/Trp53 conditional knockout mouse model. Accordingly, aberrant MET/nMET elevation correlates with ARF in human prostate cancer (PCa) specimens. Mechanistically, ARF elevates nMET through binding to MET cytoplasmic domain to stabilize MET. Furthermore, carbon nanodots resensitize cancer cells to MET inhibitors through DNA damage response. The inhibition of phosphorylation by carbon nanodots was identified through binding to phosphate group of phospho-tyrosine via computational calculation and experimental assay. Thus, nMET is essential to precision therapy of MET inhibitor. Our findings reveal for the first time that targeting nMET axis by carbon nanodots can be a novel avenue for overcoming drug resistance in cancers especially prostate cancer.Item Open Access Non-linear Dose Response of Lymphocyte Cell Lines to Microtubule Inhibitors(FRONTIERS MEDIA, 2019-04-24) Potashnikova, Daria; Saidova, Aleena; Tvorogova, Anna; Sheval, Eugene; Vorobjev, IvanMicrotubule (MT) inhibitors show anti-cancer activity in a wide range of tumors in vitro and demonstrate high clinical efficacy. To date they are routinely included into many chemotherapeutic regimens. While the mechanisms of MT inhibitors' interactions with tubulin have been well-established, the relationship between their concentration and effect on neoplastic cells is not completely understood. The common notion is that tumor cells are most vulnerable during division and all MT inhibitors block them in mitosis and induce mitotic checkpoint-associated cell death. At the same time multiple evidence of more subtle effects of lower doses of MT inhibitors on cell physiology exist. The extent of efficacy of the low-dose MT inhibitor treatment and the mechanisms of resulting cell death currently present a critical issue in oncology. The prospect of MT inhibitor dose reduction is promising as protocols at higher concentration have multiple side effects. We assessed cell cycle changes and cell death induced by MT inhibitors (paclitaxel, nocodazole, and vinorelbine) on human lymphoid B-cell lines in a broad concentration range. All inhibitors had similar accumulation effects and demonstrated "trigger" concentrations that induce cell accumulation in G2/M phase. Concentrations slightly below the "trigger" promoted cell accumulation in sub-G1 phase. Multi-label analysis of live cells showed that the sub-G1 population is heterogeneous and may include cells that are still viable after 24 h of treatment. Effects observed were similar for cells expressing Tat-protein. Thus cell cycle progression and cell death are differentially affected by high and low MT inhibitor concentrations.