Browsing by Subject "SENESCENCE"

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  • Jantti, Maria H.; Talman, Virpi; Räsänen, Kati; Tarvainen, Ilari; Koistinen, Hannu; Tuominen, Raimo K. (2018)
    Prostate cancer is one of the most common cancers in men. Although it has a relatively high 5-year survival rate, development of resistance to standard androgen-deprivation therapy is a significant clinical problem. Therefore, novel therapeutic strategies are urgently needed. The protein kinase C (PKC) family is a putative prostate cancer drug target, but so far no PKC-targeting drugs are available for clinical use. By contrast to the standard approach of developing PKC inhibitors, we have developed isophthalate derivatives as PKC agonists. In this study, we have characterized the effects of the most potent isophthalate, 5-(hydroxymethyl) isophthalate 1a3 (HMI-1a3), on three prostate cancer cell lines (LNCaP, DU145, and PC3) using both 2D and 3D cell culture models. In 2D cell culture, HMI-1a3 reduced cell viability or proliferation in all cell lines as determined by the metabolic activity of the cells (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay) and thymidine incorporation. However, the mechanism of action in LNCaP cells was different to that in DU145 or PC3 cells. In LNCaP cells, HMI-1a3 induced a PKC-dependent activation of caspase 3/7, indicating an apoptotic response, whereas in DU145 and PC3 cells, it induced senescence, which was independent of PKC. This was observed as typical senescent morphology, increased beta-galactosidase activity, and upregulation of the senescence marker p21 and downregulation of E2F transcription factor 1. Using a multicellular spheroid model, we further showed that HMI-1a3 affects the growth of LNCaP and DU145 cells in a 3D culture, emphasizing its potential as a lead compound for cancer drug development.
  • Lengefeld, Jette; Cheng, Chia-Wei; Maretich, Pema; Blair, Marguerite; Hagen, Hannah; McReynolds, Melanie R.; Sullivan, Emily; Majors, Kyra; Roberts, Christina; Kang, Joon Ho; Steiner, Joachim D.; Miettinen, Teemu P.; Manalis, Scott R.; Antebi, Adam; Morrison, Sean J.; Lees, Jacqueline A.; Boyer, Laurie A.; Yilmaz, Ömer H.; Amon, Angelika (2021)
    Stem cells are remarkably small. Whether small size is important for stem cell function is unknown. We find that hematopoietic stem cells (HSCs) enlarge under conditions known to decrease stem cell function. This decreased fitness of large HSCs is due to reduced proliferation and was accompanied by altered metabolism. Preventing HSC enlargement or reducing large HSCs in size averts the loss of stem cell potential under conditions causing stem cell exhaustion. Last, we show that murine and human HSCs enlarge during aging. Preventing this age-dependent enlargement improves HSC function. We conclude that small cell size is important for stem cell function in vivo and propose that stem cell enlargement contributes to their functional decline during aging.
  • Peivastegan, Bahram; Hadizadeh, Iman; Nykyri, Johanna; Nielsen, Kare Lehmann; Somervuo, Panu; Sipari, Nina; Tran, Cuong; Pirhonen, Minna (2019)
    BackgroundStored potato (Solanum tuberosum L.) tubers are sensitive to wet conditions that can cause rotting in long-term storage. To study the effect of water on the tuber surface during storage, microarray analysis, RNA-Seq profiling, qRT-PCR and phytohormone measurements were performed to study gene expression and hormone content in wet tubers incubated at two temperatures: 4 degrees C and 15 degrees C. The growth of the plants was also observed in a greenhouse after the incubation of tubers in wet conditions.ResultsWet conditions induced a low-oxygen response, suggesting reduced oxygen availability in wet tubers at both temperatures when compared to that in the corresponding dry samples. Wet conditions induced genes coding for heat shock proteins, as well as proteins involved in fermentative energy production and defense against reactive oxygen species (ROS), which are transcripts that have been previously associated with low-oxygen stress in hypoxic or anoxic conditions. Wet treatment also induced senescence-related gene expression and genes involved in cell wall loosening, but downregulated genes encoding protease inhibitors and proteins involved in chloroplast functions and in the biosynthesis of secondary metabolites. Many genes involved in the production of phytohormones and signaling were also affected by wet conditions, suggesting altered regulation of growth by wet conditions. Hormone measurements after incubation showed increased salicylic acid (SA), abscisic acid (ABA) and auxin (IAA) concentrations as well as reduced production of jasmonate 12-oxo-phytodienoic acid (OPDA) in wet tubers. After incubation in wet conditions, the tubers produced fewer stems and more roots compared to controls incubated in dry conditions.ConclusionsIn wet conditions, tubers invest in ROS protection and defense against the abiotic stress caused by reduced oxygen due to excessive water. Changes in ABA, SA and IAA that are antagonistic to jasmonates affect growth and defenses, causing induction of root growth and rendering tubers susceptible to necrotrophic pathogens. Water on the tuber surface may function as a signal for growth, similar to germination of seeds.
  • Huang, Yue; Zou, Jie; Kang, Zongjing; Zhang, Xiaoping; Penttinen, Petri; Zhang, Xiaoping; Li, Xiaolin (2021)
    We inoculated Tuber aestivum and Tuber sinoaestivum on Carya illinoinensis to explore the effects of inoculation on host plant growth, enzyme activities, the physicochemical properties of rhizosphere soil, the denitrifying bacterial community in the rhizosphere, and the distribution of mating type genes in the rhizosphere. We found that the Tuber spp. inoculation increased the height of the host plant and that the stem circumference of the host was greater two months after inoculation. Six months after inoculation, the peroxidase activity of the seedlings inoculated with T. sinoaestivum was higher than that of the control. At four and six months after inoculation, the superoxidase dismutase activities of the seedlings inoculated with T. aestivum were higher than those of the seedlings inoculated with T. sinoaestivum. Six months after inoculation, nitrate nitrogen content was lowest in the control and highest in the T. sinoaestivum treatment. Among the nirS-type denitrifying bacteria community, the relative abundances of Proteobacteria were high. T. aestivum and T. sinoaestivum inoculation did not affect the diversity of denitrifying bacteria. The mating type genes MAT1-1-1 and MAT1-2-1 were detected in the rhizosphere of C. illinoinensis inoculated with T. sinoaestivum and T. aestivum, and MAT1-1-1 dominated over MAT1-21. (c) 2021 British Mycological Society. Published by Elsevier Ltd. All rights reserved.
  • Kilpinen, Lotta; Parmar, Amarjit; Greco, Dario; Korhonen, Matti; Lehenkari, Petri; Saavalainen, Paivi; Laitinen, Saara (2016)
    Mesenchymal stromal cells (MSC) are currently used in many cell based therapies. Prior to use in therapy, extensive expansion is required. We used microarray profiling to investigate expansion induced miRNA and mRNA expression changes of bone marrow MSCs (BM-MSCs) derived from old and young donors. The expression levels of 36 miRNAs were altered in cells derived from the old and respectively 39 miRNAs were altered in cells derived from young donors. Of these, only 12 were differentially expressed in both young and old donor BM-MSCs, and their predicted target mRNAs, were mainly linked to cell proliferation and senescence. Further qPCR verification showed that the expression of miR-1915-3p, miR-1207, miR-3665, and miR-762 correlated with the expansion time at passage 8. Previously described BM-MSC-specific miRNA fingerprints were also detected but these remained unchanged during expansion. Interestingly, members of well-studied miR-17/92 cluster, involved in cell cycle regulation, aging and also development of immune system, were down regulated specifically in cells from old donors. The role of this cluster in MSC functionality is worth future studies since it links expansion, aging and immune system together.
  • Salmenperä, Pertteli; Karhemo, Piia-Riitta; Rasanen, Kati; Laakkonen, Pirjo; Vaheri, Antti (2016)
    Stromal fibroblasts have an important role in regulating tumor progression. Normal and quiescent fibroblasts have been shown to restrict and control cancer cell growth, while cancer-associated, i.e. activated fibroblasts have been shown to enhance proliferation and metastasis of cancer cells. In this study we describe generation of quiescent fibroblasts in multicellular spheroids and their effects on squamous cell carcinoma (SCC) growth in soft-agarose and xenograft models. Quiescent phenotype of fibroblasts was determined by global down-regulation of expression of genes related to cell cycle and increased expression of p27. Interestingly, microarray analysis showed that fibroblast quiescence was associated with similar secretory phenotype as seen in senescence and they expressed senescence-associated-beta-galactosidase. Quiescent fibroblasts spheroids also restricted the growth of RT3 SCC cells both in softagarose and xenograft models unlike proliferating fibroblasts. Restricted tumor growth was associated with marginally increased tumor cell senescence and cellular differentiation, showed with senescenceassociated-beta-galactosidase and cytokeratin 7 staining. Our results show that the fibroblasts spheroids can be used as a model to study cellular quiescence and their effects on cancer cell progression. (C) 2016 Elsevier Inc. All rights reserved.
  • Katayama, Shintaro; Skoog, Tiina; Jouhilahti, Eeva-Mari; Siitonen, H. Annika; Nuutila, Kristo; Tervaniemi, Mari H.; Vuola, Jyrki; Johnsson, Anna; Lonnerberg, Peter; Linnarsson, Sten; Elomaa, Outi; Kankuri, Esko; Kere, Juha (2015)
    Background: Keratinocytes (KCs) are the most frequent cells in the epidermis, and they are often isolated and cultured in vitro to study the molecular biology of the skin. Cultured primary cells and various immortalized cells have been frequently used as skin models but their comparability to intact skin has been questioned. Moreover, when analyzing KC transcriptomes, fluctuation of polyA+ RNA content during the KCs' lifecycle has been omitted. Results: We performed STRT RNA sequencing on 10 ng samples of total RNA from three different sample types: i) epidermal tissue (split-thickness skin grafts), ii) cultured primary KCs, and iii) HaCaT cell line. We observed significant variation in cellular polyA+ RNA content between tissue and cell culture samples of KCs. The use of synthetic RNAs and SAMstrt in normalization enabled comparison of gene expression levels in the highly heterogenous samples and facilitated discovery of differences between the tissue samples and cultured cells. The transcriptome analysis sensitively revealed genes involved in KC differentiation in skin grafts and cell cycle regulation related genes in cultured KCs and emphasized the fluctuation of transcription factors and non-coding RNAs associated to sample types. Conclusions: The epidermal keratinocytes derived from tissue and cell culture samples showed highly different polyA+ RNA contents. The use of SAMstrt and synthetic RNA based normalization allowed the comparison between tissue and cell culture samples and thus proved to be valuable tools for RNA-seq analysis with translational approach. Transciptomics revealed clear difference both between tissue and cell culture samples and between primary KCs and immortalized HaCaT cells.
  • Ronnegard, Lars; McFarlane, S. Eryn; Husby, Arild; Kawakami, Takeshi; Ellegren, Hans; Qvarnstrom, Anna (2016)
    1. Genomewide association studies (GWAS) enable detailed dissections of the genetic basis for organisms' ability to adapt to a changing environment. In long-term studies of natural populations, individuals are often marked at one point in their life and then repeatedly recaptured. It is therefore essential that a method for GWAS includes the process of repeated sampling. In a GWAS, the effects of thousands of single-nucleotide polymorphisms (SNPs) need to be fitted and any model development is constrained by the computational requirements. A method is therefore required that can fit a highly hierarchical model and at the same time is computationally fast enough to be useful. 2. Our method fits fixed SNP effects in a linear mixed model that can include both random polygenic effects and permanent environmental effects. In this way, the model can correct for population structure and model repeated measures. The covariance structure of the linear mixed model is first estimated and subsequently used in a generalized least squares setting to fit the SNP effects. The method was evaluated in a simulation study based on observed genotypes from a long-term study of collared flycatchers in Sweden. 3. The method we present here was successful in estimating permanent environmental effects from simulated repeated measures data. Additionally, we found that especially for variable phenotypes having large variation between years, the repeated measurements model has a substantial increase in power compared to a model using average phenotypes as a response. 4. The method is available in the R package RepeatABEL. It increases the power in GWAS having repeated measures, especially for long-term studies of natural populations, and the R implementation is expected to facilitate modelling of longitudinal data for studies of both animal and human populations.
  • Gerards, Mike; Cannino, Giuseppe; de Cozar, Jose M. Gonzalez; Jacobs, Howard T. (2018)
    The Drosophila gene products Bet1, Slh, and CG10144, predicted to function in intracellular vesicle trafficking, were previously found to be essential for mitochondrial nucleoid maintenance. Here we show that Slh and Bet1 cooperate to maintain mitochondrial functions. In their absence, mitochondrial content, membrane potential, and respiration became abnormal, accompanied by mitochondrial proteotoxic stress, but without direct effects on mtDNA. Immunocytochemistry showed that both Slh and Bet1 are localized at the Golgi, together with a proportion of Rab5-positive vesicles. Some Bet1, as well as a tiny amount of Slh, cofractionated with highly purified mitochondria, while live-cell imaging showed coincidence of fluorescently tagged Bet1 with most Lysotracker-positive and a small proportion of Mitotracker-positive structures. This three-way association was disrupted in cells knocked down for Slh, although colocalized lysosomal and mitochondrial signals were still seen. Neither Slh nor Bet1 was required for global mitophagy or endocytosis, but prolonged Slh knockdown resulted in G2 growth arrest, with increased cell diameter. These effects were shared with knockdown of betaCOP but not of CG1044, Snap24, or Syntaxin6. Our findings implicate vesicle sorting at the cis-Golgi in mitochondrial quality control.
  • Friedmann, Andrea; Goehre , Felix; Ludtka, Christopher; Mendel, Thomas; Meisel, Hans-Joerg; Heilmann, Andreas; Schwan, Stefan (2017)
    Degeneration of intervertebral disc (IVD) tissue is characterized by several structural changes that result in variations in disc physiology and loss of biomechanical function. The complex process of degeneration exhibits highly intercorrelated biomechanical, biochemical, and cellular interactions. There is currently some understanding of the cellular changes in degenerated intervertebral disc tissue, but microstructural changes and deterioration of the tissue matrix has previously been rarely explored. In this work, sequestered IVD tissue was successfully characterized using histology, light microscopy, and scanning electron microscopy (SEM) to quantitatively evaluate parameters of interest for intervertebral disc degeneration (IDD) such as delamination of the collagenous matrix, cell density, cell size, and extra cellular matrix (ECM) thickness. Additional qualitative parameters investigated included matrix fibration and irregularity, neovascularization of the IVD, granular inclusions in the matrix, and cell cluster formation. The results of this study corroborated several previously published findings, including those positively correlating female gender and IVD cell density, age and cell size, and female gender and ECM thickness. Additionally, an array of quantitative and qualitative investigations of IVD degeneration could be successfully evaluated using the given methodology, resin-embedded SEM in particular. SEM is especially practical for studying micromorphological changes in tissue, as other microscopy methods can cause artificial tissue damage due to the preparation method. Investigation of the microstructural changes occurring in degenerated tissue provides a greater understanding of the complex process of disc degeneration as a whole. Developing a more complete picture of the degenerative changes taking place in the intervertebral disc is crucial for the advancement and application of regenerative therapies based on the pathology of intervertebral disc degeneration. (C) 2016 Elsevier Ltd. All rights reserved.
  • Duan, Baoli; Paquette, Alain; Juneau, Philippe; Brisson, Jacques; Fontaine, Bastien; Berninger, Frank Alexander (2014)
    We investigated the effects of leaf color change in the fall on photosynthetic production and nitrogen resorption. Seedlings of Acer platanoides L. and A. saccharum Marsh. were grown in a shade house for 5 months in either 21 % (intermediate light, M) or 4.9 % (low light, L) of incident irradiance. After this period, a subset of the intermediate-light grown seedlings was transferred to a high-light stress treatment (H). Gas exchange, chlorophyll fluorescence, pigments, antioxidant activity, and nitrogen (N) resorption were examined at three leaf senescence stages during September and October. Our results show that plants of both species produce more anthocyanins in the H treatment. In comparison with plants grown in the L and M treatments, plants of both species in the H treatments had lower chlorophyll, carotenoid and chlorophyll fluorescence parameters (F (v)/F (m), I broken vertical bar (PSII), NPQ and ETR) at the third sampling date (October 12-18), and indicating higher levels of photoinhibition in the seedlings exposed to high light. Our results imply that autumn leaf redness is inducible and closely linked to photo-oxidative stress. However, anthocyanins did not enhance antioxidant capacity in red leaves in either species, when exposed to high light. For both species, our results showed a higher N-resorption for high-light stressed plants. We also observed that the number of abscised leaves at the second sampling dates (September 10) was higher than at the third sampling dates. The intra-leaf distribution of anthocyanin, the association between anthocyanin production and the high-light environments, the retention of red leaves, the substantial physiological gain of photosynthetic activity, as well as the links between anthocyanins and increased N resorption led us to assume that one primary role of autumn anthocyanin could be to protect the photosynthetic apparatus from photo-oxidative damage as light filters rather than as antioxidant. Another major role is to extend carbon capture and help supply the energy needed for N resorption from senescing leaves in both A. saccharum and A. Platanoides during high-light stress. Nevertheless, photoprotective capacity of anthocyanins was not able to fully compensate for photoinhibitory stress as the anthocyanins are not optimally located to efficiently reduce light within the leaves.
  • Das, Sudeep; Imlimthan, Surachet; Airaksinen, Anu; Sarparanta, Mirkka (Springer Nature Switzerland AG, 2021)
    Advances in Experimental Medicine and Biology
    In the recent years, progress in nanotechnology has significantly contributed to the development of novel pharmaceutical formulations to overcome the drawbacks of conventional treatments and improve the therapeutic outcome in many diseases, especially cancer. Nanoparticle vectors have demonstrated the potential to concomitantly deliver diagnostic and therapeutic payloads to diseased tissue. Due to their special physical and chemical properties, the characteristics and function of nanoparticles are tunable based on biological molecular targets and specific desired features (e.g., surface chemistry and diagnostic radioisotope labeling). Within the past decade, several theranostic nanoparticles have been developed as a multifunctional nanosystems which combine the diagnostic and therapeutic functionalities into a single drug delivery platform. Theranostic nanosystems can provide useful information on a real-time systemic distribution of the developed nanosystem and simultaneously transport the therapeutic payload. In general, the diagnostic functionality of theranostic nanoparticles can be achieved through labeling gamma-emitted radioactive isotopes on the surface of nanoparticles which facilitates noninvasive detection using nuclear molecular imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), meanwhile, the therapeutic effect arises from the potent drug released from the nanoparticle. Moreover, some radioisotopes can concurrently emit both gamma radiation and high-energy particles (e.g., alpha, beta, and Auger electrons), prompting the use either alone for radiotheranostics or synergistically with chemotherapy. This chapter provides an overview of the fundamentals of radiochemistry and relevant radiolabeling strategies for theranostic nanosystem development as well as the methods for the preclinical evaluation of radiolabeled nanoparticles. Furthermore, preclinical case studies of recently developed theranostic nanosystems will be highlighted.
  • Cayuela, Hugo; Lemaitre, Jean-Francois; Lena, Jean-Paul; Ronget, Victor; Martinez-Solano, Inigo; Muths, Erin; Pilliod, David S.; Schmidt, Benedikt R.; Sanchez-Montes, Gregorio; Gutierrez-Rodriguez, Jorge; Pyke, Graham; Grossenbacher, Kurt; Lenzi, Omar; Bosch, Jaime; Beard, Karen H.; Woolbright, Lawrence L.; Lambert, Brad A.; Green, David M.; Jreidini, Nathalie; Garwood, Justin M.; Fisher, Robert N.; Matthews, Kathleen; Dudgeon, David; Lau, Anthony; Speybroeck, Jeroen; Homan, Rebecca; Jehle, Robert; Baskale, Eyup; Mori, Emiliano; Arntzen, Jan W.; Joly, Pierre; Stiles, Rochelle M.; Lannoo, Michael J.; Maerz, John C.; Lowe, Winsor H.; Valenzuela-Sanchez, Andres; Christiansen, Ditte G.; Angelini, Claudio; Thirion, Jean-Marc; Merilä, Juha; Colli, Guarino R.; Vasconcellos, Mariana M.; Boas, Taissa C. V.; Arantes, isis da C.; Levionnois, Pauline; Reinke, Beth A.; Vieira, Cristina; Marais, Gabriel A. B.; Gaillard, Jean-Michel; Miller, David A. W. (2022)
    Sex-related differences in mortality are widespread in the animal kingdom. Although studies have shown that sex determination systems might drive lifespan evolution, sex chromosome influence on aging rates have not been investigated so far, likely due to an apparent lack of demographic data from clades including both XY (with heterogametic males) and ZW (heterogametic females) systems. Taking advantage of a unique collection of capture-recapture datasets in amphibians, a vertebrate group where XY and ZW systems have repeatedly evolved over the past 200 million years, we examined whether sex heterogamy can predict sex differences in aging rates and lifespans. We showed that the strength and direction of sex differences in aging rates (and not lifespan) differ between XY and ZW systems. Sex-specific variation in aging rates was moderate within each system, but aging rates tended to be consistently higher in the heterogametic sex. This led to small but detectable effects of sex chromosome system on sex differences in aging rates in our models. Although preliminary, our results suggest that exposed recessive deleterious mutations on the X/Z chromosome (the "unguarded X/Z effect") or repeat-rich Y/W chromosome (the "toxic Y/W effect") could accelerate aging in the heterogametic sex in some vertebrate clades.
  • Brelsford, Craig C.; Trasser, Marieke; Paris, Tom; Hartikainen, Saara M.; Robson, T. Matthew (2022)
    Forest understorey plants receive most sunlight in springtime before canopy closure, and in autumn following leaf-fall. We hypothesized that plant species must adjust their phenological and photoprotective strategies in response to large changes in the spectral composition of the sunlight they receive. Here, we identified how plant species growing in northern deciduous and evergreen forest understoreys differ in their response to blue light and ultraviolet (UV) radiation according to their functional strategy. We installed filters in a forest understorey in southern Finland, to create the following treatments attenuating: UV radiation < 350 nm, all UV radiation (< 400 nm), all blue light and UV radiation (< 500 nm), and a transparent control. In eight species, representing different functional strategies, we assessed leaf optical properties, phenology, and epidermal flavonoid contents over two years. Blue light accelerated leaf senescence in all species measured in the understorey, apart from Quercus robur seedlings, whereas UV radiation only accelerated leaf senescence in Acer platanoides seedlings. More light-demanding species accumulated flavonols in response to seasonal changes in light quality compared to shade-tolerant and wintergreen species and were particularly responsive to blue light. Reduction of blue and UV radiation under shade reveals an important role for microclimatic effects on autumn phenology and leaf photoprotection. An extension of canopy cover under climate change, and its associated suppression of understorey blue light and UV radiation, may delay leaf senescence for understorey species with an autumn niche.