Browsing by Subject "PROTECTS"

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  • Pakarinen, Emmi; Lindholm, Paivi; Saarma, Mart; Lindahl, Maria (2022)
    Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) display cytoprotective effects in animal models of neurodegenerative diseases. These endoplasmic reticulum (ER)-resident proteins belong to the same protein family and function as ER stress regulators. The relationship between CDNF and MANF function, as well as their capability for functional compensation, is unknown. We aimed to investigate these questions by generating mice lacking both CDNF and MANF. Results showed that CDNF-deficient Manf(-/-) mice presented the same phenotypes of growth defect and diabetes as Manf(-/-) mice. In the muscle, CDNF deficiency resulted in increased activation of unfolded protein response (UPR), which was aggravated when MANF was ablated. In the brain, the combined loss of CDNF and MANF did not exacerbate UPR activation caused by the loss of MANF alone. Consequently, CDNF and MANF deficiency in the brain did not cause degeneration of dopamine neurons. In conclusion, CDNF and MANF present functional redundancy in the muscle, but not in the other tissues examined here. Thus, they regulate the UPR in a tissue-specific manner.
  • Galli, Emilia; Lindholm, Päivi; Kontturi, Leena-Stiina; Saarma, Mart; Urtti, Arto; Yliperttula, Marjo (2019)
    Cerebral Dopamine Neurotrophic Factor (CDNF) shows beneficial effects in rodent models of Parkinson?s and Alzheimer?s disease. The brain is a challenging target for protein therapy due to its exclusive blood?brain barrier. Hence, the therapeutic protein should be delivered directly to the brain parenchyma. Implantation of encapsulated mammalian cells that constantly secrete CDNF is a potential approach for targeted and long-term protein delivery to the brain. In this study, we generated several CDNF-secreting cell clones derived from human retinal pigment epithelial cell line ARPE-19, and studied CDNF secretion from the clones maintained as monolayers and in polymeric microcapsules. The secretion of wild type (wt) CDNF transgene was low and the majority of the produced protein remained intracellular, locating mainly to the endoplasmic reticulum (ER). The secretion of wtCDNF decreased to even lower levels when the clones were in a non-dividing state, as in the microcapsules. Both codon optimization and deletion of the putative ER-retrieval signal (four last amino acids: KTEL) improved CDNF secretion. More importantly, the secretion of KTEL-deleted CDNF remained constant in the non-dividing clones. Thus, cells expressing KTEL-deleted CDNF, in contrast to wtCDNF, can be considered for cell encapsulation applications if the KTEL-deleted CDNF is proven to be biologically active in vivo.
  • Wang, Liang; Li, Menglu; Bu, Qian; Li, Hongchun; Xu, Wei; Liu, Chunqi; Gu, Hui; Zhang, Jiamei; Wan, Xuemei; Zhao, Yinglan; Cen, Xiaobo (2019)
    Much efforts have been tried to clarify the molecular mechanism of alcohol-induced brain damage from the perspective of genome and protein; however, the effect of chronic alcohol exposure on global lipid profiling of brain is unclear. In the present study, by using Q-TOF/MS-based lipidomics approach, we investigated the comprehensive lipidome profiling of brain from the rats orally administrated with alcohol daily, continuously for one year. Through systematically analysis of all lipids in prefrontal cortex (PFC) and striatum region, we found that long-term alcohol exposure profoundly modified brain lipidome profiling. Notably, three kinds of lipid classes, glycerophospholipid (GP), glycerolipid (GL) and fatty acyls (FA), were significantly increased in these two brain regions. Interestingly, most of the modified lipids were involved in synthetic pathways of endoplasmic reticulum (ER), which may result in ER stress-related metabolic disruption. Moreover, alcohol-modified lipid species displayed long length of carbon chain with high degree of unsaturation. Taken together, our results firstly present that chronic alcohol exposure markedly modifies brain lipidomic profiling, which may activate ER stress and eventually result in neurotoxicity. These findings provide a new insight into the mechanism of alcohol-related brain damage.
  • Yegutkin, Gennady G.; Auvinen, Kaisa; Karikoski, Marika; Rantakari, Pia; Gerke, Heidi; Elima, Kati; Maksimow, Mikael; Quintero, Ileana B.; Vihko, Pirkko; Salmi, Marko; Jalkanen, Sirpa (2014)
  • Witjes, Julia J.; Smits, Loek P.; Pekmez, Ceyda T.; Prodan, Andrei; Meijnikman, Abraham S.; Troelstra, Marian A.; Bouter, Kristien E. C.; Herrema, Hilde; Levin, Evgeni; Holleboom, Adriaan G.; Winkelmeijer, Maaike; Beuers, Ulrich H.; van Lienden, Krijn; Aron-Wisnewky, Judith; Mannisto, Ville; Bergman, Jacques J.; Runge, Jurgen H.; Nederveen, Aart J.; Dragsted, Lars O.; Konstanti, Prokopis; Zoetendal, Erwin G.; de Vos, Willem; Verheij, Joanne; Groen, Albert K.; Nieuwdorp, Max (2020)
    The intestinal microbiota has been linked to the development and prevalence of steatohepatitis in humans. Interestingly, steatohepatitis is significantly lower in individuals taking a plant-based, low-animal-protein diet, which is thought to be mediated by gut microbiota. However, data on causality between these observations in humans is scarce. In this regard, fecal microbiota transplantation (FMT) using healthy donors is safe and is capable of changing microbial composition in human disease. We therefore performed a double-blind randomized controlled proof-of-principle study in which individuals with hepatic steatosis on ultrasound were randomized to two study arms: lean vegan donor (allogenic n = 10) or own (autologous n = 11) FMT. Both were performed three times at 8-week intervals. A liver biopsy was performed at baseline and after 24 weeks in every subject to determine histopathology (Nonalcoholic Steatohepatitis Clinical Research Network) classification and changes in hepatic gene expression based on RNA sequencing. Secondary outcome parameters were changes in intestinal microbiota composition and fasting plasma metabolomics. We observed a trend toward improved necro-inflammatory histology, and found significant changes in expression of hepatic genes involved in inflammation and lipid metabolism following allogenic FMT. Intestinal microbial community structure changed following allogenic FMT, which was associated with changes in plasma metabolites as well as markers of .Conclusion:Allogenic FMT using lean vegan donors in individuals with hepatic steatosis shows an effect on intestinal microbiota composition, which is associated with beneficial changes in plasma metabolites and markers of steatohepatitis.
  • Ebrahimi, Nashmin; Hartikainen, Helina; Simojoki, Asko; Hajiboland, Roghieh; Seppanen, Mervi (2015)
    The uptake by and subsequent translocation of selenium (Se) within the plant is dependent on its chemical form and soil properties that dictate this trace element's bioavailability. Plant species differ in their tendency to accumulate Se. Se taken-up by plants is returned to soil in plant residues, but the bioavailability of organic Se in those residues is poorly known. We investigated the impact of inorganic (Na2SeO4), organic (Se-enriched stem and leaf residues) Se applications and also soil microbial respiration on the growth and Se concentrations of various plant organs of oilseed rape (Brassica napus L.) during its development from the rosette to the seed filling stage. Both inorganic and organic Se slightly improved plant growth and enhanced plant development. Inorganic Se was more bioavailable than the organic forms and resulted in 3-fold to 6-fold higher Se concentrations in the siliques. Inorganic Se in autoclaved soil tended to elevate the Se concentration in all plant parts and at all growth stages. The organic Se raised Se concentrations in plants much less effectively than the inorganic selenate. Therefore, the use of inorganic Se is still recommended for biofortification.
  • ARISE Investigators; Luethi, Nora; Bailey, Michael; Harjola, V-P; Okkonen, M.; Pettilä, V.; Sutinen, E.; Wilkman, E. (2020)
    Purpose: To assess the impact of gender and pre-menopausal state on short- and long-term outcomes in patients with septic shock. Material and methods: Cohort study of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial, an international randomized controlled trial comparing early goal-directed therapy (EGDT) to usual care in patients with early septic shock, conducted between October 2008 and April 2014. The primary exposure in this analysis was legal gender and the secondary exposure was pre-menopausal state defined by chronological age ( Results: 641 (40.3%) of all 1591 ARISE trial participants in the intention-to-treat population were females and overall, 337 (21.2%) (146 females) patients were 50 years of age or younger. After risk-adjustment, we could not identify any survival benefit for female patients at day 90 in the younger (50 years) age-group (aOR: 1.10 (0.81-1.49), p = .56). Similarly, there was no gender-difference in ICU, hospital, 1-year mortality nor quality of life measures. Conclusions: This post-hoc analysis of a large multi-center trial in early septic shock has shown no short- or long-term survival effect for women overall as well as in the pre-menopausal age-group. (C) 2019 Elsevier Inc. All rights reserved.
  • Chen, Yan; Ma, Yuan; Feng, Jin Jin; Wang, Yi He; Li, Tian Fang; Nurmi, Katariina; Eklund, Kari K.; Wen, Jian Guo (2021)
    NLRP3 inflammasome has been implicated in impaired post-injury muscle healing and in muscle atrophy. Histamine receptors play an important role in inflammation, but the role of histamine H-3 receptor (H3R) in myocyte regeneration and in the regulation of NLRP3 inflammasome is not known. We studied the effects of H3R signaling on C2C12 myocyte viability, apoptosis, and tumor necrosis factor alpha (TNF alpha)-induced NLRP3 inflammasome activation during striated myogenic differentiation at three time points (days 0, 3, and 6). Expression of Nlrp3, interleukin-1 beta (IL-1 beta), and myogenesis markers were determined. TNF alpha reduced overall viability of C2C12 cells, and exposure to TNF alpha induced apoptosis of cells at D6. Activation of H3R had no effect on viability or apoptosis, whereas inhibition of H3R increased TNF alpha-induced apoptosis. Stimulation of C2C12 cells with TNF alpha increased Nlrp3 mRNA expression at D3 and D6. Moreover, TNF alpha reduced the expression of myogenesis markers MyoD1, Myogenin, and Myosin-2 at D3 and D6. H3R attenuated TNF alpha-induced expression of Nlrp3 and further inhibited the myogenesis marker expression; while H3R -blockage enhanced the proinflammatory effects of TNF alpha and increased the myogenesis marker expression. TNF alpha-induced secretion of mature IL-1 beta was dependent on the activation of the NLRP3 inflammasome, as shown by the reduced secretion of mature IL-1 beta upon treatment of the cells with the small molecule inhibitor of the NLRP3 inflammasome (MCC950). The activation of H3R reduced TNF alpha-induced IL-1 beta secretion, while the H3R blockage had an opposite effect. In conclusion, the modulation of H3R activity regulates the effects of TNF alpha on C2C12 myocyte differentiation and TNF alpha-induced activation of NLRP3 inflammasome. Thus, H3R signaling may represent a novel target for limiting postinjury muscle inflammation and muscle atrophy.
  • Syed, Mansoor; Das, Pragnya; Pawar, Aishwarya; Aghai, Zubair H.; Kaskinen, Anu; Zhuang, Zhen W.; Ambalavanan, Namasivayam; Pryhuber, Gloria; Andersson, Sture; Bhandari, Vineet (2017)
    Hyperoxia-induced acute lung injury (HALI) is a key contributor to the pathogenesis of bronchopulmonary dysplasia (BPD) in neonates, for which no specific preventive or therapeutic agent is available. Here we show that lung micro-RNA (miR)-34a levels are significantly increased in lungs of neonatal mice exposed to hyperoxia. Deletion or inhibition of miR-34a improves the pulmonary phenotype and BPD-associated pulmonary arterial hypertension (PAH) in BPD mouse models, which, conversely, is worsened by miR-34a overexpression. Administration of angiopoietin-1, which is one of the downstream targets of miR34a, is able to ameliorate the BPD pulmonary and PAH phenotypes. Using three independent cohorts of human samples, we show that miR-34a expression is increased in type 2 alveolar epithelial cells in neonates with respiratory distress syndrome and BPD. Our data suggest that pharmacologic miR-34a inhibition may be a therapeutic option to prevent or ameliorate HALI/BPD in neonates.
  • Depommier, Clara; Van Hul, Matthias; Everard, Amandine; Delzenne, Nathalie M.; De Vos, Willem M.; Cani, Patrice D. (2020)
    Accumulating evidence points to Akkermansia muciniphila as a novel candidate to prevent or treat obesity-related metabolic disorders. We recently observed, in mice and in humans, that pasteurization of A. muciniphila increases its beneficial effects on metabolism. However, it is currently unknown if the observed beneficial effects on body weight and fat mass gain are due to specific changes in energy expenditure. Therefore, we investigated the effects of pasteurized A. muciniphila on whole-body energy metabolism during high-fat diet feeding by using metabolic chambers. We confirmed that daily oral administration of pasteurized A. muciniphila alleviated diet-induced obesity and decreased food energy efficiency. We found that this effect was associated with an increase in energy expenditure and spontaneous physical activity. Strikingly, we discovered that energy expenditure was enhanced independently from changes in markers of thermogenesis or beiging of the white adipose tissue. However, we found in brown and white adipose tissues that perilipin2, a factor associated with lipid droplet and known to be altered in obesity, was decreased in expression by pasteurized A. muciniphila. Finally, we observed that treatment with pasteurized A. muciniphila increased energy excretion in the feces. Interestingly, we demonstrated that this effect was not due to the modulation of intestinal lipid absorption or chylomicron synthesis but likely involved a reduction of carbohydrates absorption and enhanced intestinal epithelial turnover. In conclusion, this study further dissects the mechanisms by which pasteurized A. muciniphila reduces body weight and fat mass gain. These data also further support the impact of targeting the gut microbiota by using specific bacteria to control whole-body energy metabolism.
  • Kolosowska, Natalia; Keuters, Meike H.; Wojciechowski, Sara; Keksa-Goldsteine, Velta; Laine, Mika; Malm, Tarja; Goldsteins, Gundars; Koistinaho, Jari; Dhungana, Hiramani (2019)
    Neuroinflammation is strongly induced by cerebral ischemia. The early phase after the onset of ischemic stroke is characterized by acute neuronal injury, microglial activation, and subsequent infiltration of blood-derived inflammatory cells, including macrophages. Therefore, modulation of the microglial/macrophage responses has increasingly gained interest as a potential therapeutic approach for the ischemic stroke. In our study, we investigated the effects of peripherally administered interleukin 13 (IL-13) in a mouse model of permanent middle cerebral artery occlusion (pMCAo). Systemic administration of IL-13 immediately after the ischemic insult significantly reduced the lesion volume, alleviated the infiltration of CD45(+) leukocytes, and promoted the microglia/macrophage alternative activation within the ischemic region, as determined by arginase 1 (Arg1) immunoreactivity at 3 days post-ischemia (dpi). Moreover, IL-13 enhanced the expression of M2a alternative activation markers Arg1 and Ym1 in the peri-ischemic (PI) area, as well as increased plasma IL-6 and IL-10 levels at 3 dpi. Furthermore, IL-13 treatment ameliorated gait disturbances at day 7 and 14 and sensorimotor deficits at day 14 post-ischemia, as analyzed by the CatWalk gait analysis system and adhesive removal test, respectively. Finally, IL-13 treatment decreased neuronal cell death in a coculture model of neuroinflammation with RAW 264.7 macrophages. Taken together, delivery of IL-13 enhances microglial/macrophage anti-inflammatory responses in vivo and in vitro, decreases ischemia-induced brain cell death, and improves sensory and motor functions in the pMCAo mouse model of cerebral ischemia.
  • Jarvela, Sally; Rantala, Immo; Rodriguez, Alejandra; Kallio, Heini; Parkkila, Seppo; Kinnula, Vuokko L.; Soini, Ylermi; Haapasalo, Hannu (2010)