Browsing by Subject "glutathione"

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  • Hentila, Jaakko; Nissinen, Tuuli A.; Korkmaz, Ayhan; Lensu, Sanna; Silvennoinen, Mika; Pasternack, Arja; Ritvos, Olli; Atalay, Mustafa; Hulmi, Juha J. (2019)
    Muscle wasting in cancer cachexia can be alleviated by blocking activin receptor type 2 (ACVR2) ligands through changes in protein synthesis/degradation. These changes in cellular and protein metabolism may alter protein homeostasis. First, we elucidated the acute (1-2 days) and 2-week effects of blocking ACVR2 ligands by soluble activin receptor 2B (sACVR2B-Fc) on unfolded protein response (UPR), heat shock proteins (HSPs) and redox balance in a healthy mouse skeletal muscle. Second, we examined UPR, autophagy and redox balance with or without sACVR2B-Fc administration in muscle and liver of C26 tumor-bearing mice. The indicators of UPR and HSPs were not altered 1-2 days after a single sACVR2B-Fc administration in healthy muscles, but protein carbonyls increased (p <0.05). Two weeks of sACVR2B-Fc administration increased muscle size, which was accompanied by increased UPR markers: GRP78 <0.05), phosphorylated elF2 alpha <0.01) and HSP47 (p <0.01). Additionally, protein carbonyls and reduced form of glutathione increased (GSH) (p <0.05). On the other hand, C26 cancer cachexia manifested decreased UPR markers (p-elF2 alpha, HSP47, p-JNK; p <0.05) and antioxidant GSH (p <0.001) in muscle, whereas the ratio of oxidized to reduced glutathione increased (GSSG/GSH; p <0.001). Administration of sACVR2B-Fc prevented the decline in GSH and increased some of the UPR indicators in tumor-bearing mice. Additionally, autophagy markers LC3II/I (p <0.05), Beclin-1 (p <0.01), and P62 (p <0.05) increased in the skeletal muscle of tumor-bearing mice. Finally, indicators of UPR, PERK, p-elF2 alpha and GRP78, increased (p <0.05), whereas ATF4 was strongly decreased (p <0.01) in the liver of tumor-bearing mice while sACVR2B-Fc had no effect. Muscle GSH and many of the altered UPR indicators correlated with tumor mass, fat mass and body mass loss. In conclusion, experimental cancer cachexia is accompanied by distinct and tissue-specific changes in proteostasis. Muscle hypertrophy induced by blocking ACVR2B ligands may be accompanied by the induction of UPR and increased protein carbonyls but blocking ACVR2B ligands may upregulate antioxidant protection.
  • Taavitsainen, Eveliina; Kortesoja, Maarit; Bruun, Tanja; Johansson, Niklas G; Hanski, Leena (2020)
    Antibiotic-tolerant persister bacteria involve frequent treatment failures, relapsing infections and the need for extended antibiotic treatment. The virulence of an intracellular human pathogen C. pneumoniae is tightly linked to its propensity for persistence and means for its chemosensitization are urgently needed. In the current work, persistence of C. pneumoniae clinical isolate CV6 was studied in THP-1 macrophages using quantitative PCR and quantitative culture. A dibenzocyclooctadiene lignan schisandrin reverted C. pneumoniae persistence and promoted productive infection. The concomitant administration of schisandrin and azithromycin resulted in significantly improved bacterial eradication compared to sole azithromycin treatment. In addition, the closely related lignan schisandrin C was superior to azithromycin in eradicating the C. pneumoniae infection from the macrophages. The observed chemosensitization of C. pneumoniae was associated with the suppression of cellular glutathione pools by the lignans, implying to a previously unknown aspect of chlamydia-host interactions. These data indicate that schisandrin lignans induce a phenotypic switch in C. pneumoniae, promoting the productive and antibiotic-susceptible phenotype instead of persistence. By this means, these medicinal plant -derived compounds show potential as adjuvant therapies for intracellular bacteria resuscitation.
  • De, Swarnalok; Chavez-Calvillo, Gabriela; Wahlsten, Matti; Mäkinen, Kristiina (2018)
    Infection caused by the synergistic interaction of two plant viruses is typically manifested by severe symptoms and increased accumulation of either virus. In potex-potyviral synergism, the potyviral RNA silencing suppressor helper component proteinase (HCPro) is known to enhance the pathogenicity of the potexvirus counterpart. In line with this, Potato virus X (PVX; genus Potexvirus) genomic RNA (gRNA) accumulation and gene expression from subgenomic RNA (sgRNA) are increased in Nicotiana benthamiana by Potato virus A (PVA; genus Potyvirus) HCPro expression. Recently, we have demonstrated that PVA HCPro interferes with the host cell methionine cycle by interacting with its key enzymes S-adenosyl-l-methionine synthetase (SAMS) and S-adenosyl-l-homocysteine hydrolase (SAHH). To study the involvement of methionine cycle enzymes in PVX infection, we knocked down SAMS and SAHH. Increased PVX sgRNA expression between 3 and 9 days post-infiltration (dpi) and upregulation of (-)-strand gRNA accumulation at 9 dpi were observed in the SAHH-silenced background. We found that SAMS and SAHH silencing also caused a significant reduction in glutathione (GSH) concentration, specifically in PVX-infected plants between 2 and 9 dpi. Interestingly, HCPro expression in PVX-infected plants caused an even stronger reduction in GSH levels than did SAMS+SAHH silencing and a similar level of reduction was also achieved by knocking down GSH synthetase. PVX sgRNA expression was increased in the GSH synthetase-silenced background. GSH is a major antioxidant of plant cells and therefore GSH shortage may explain the strong oxidative stress and severe symptoms observed during potex-potyvirus mixed infection.
  • Hovinen, Topi (Helsingfors universitet, 2016)
    Folate deficiency (FD) has been found to cause number of medical conditions varying from megaloblastic anemia to fetal neural tube defects but the molecular basis behind these has remained poorly understood. We studied the metabolic consequences of FD in mouse liver and brain, concentrating on transsulfuration pathway and cysteine-dependent pathways. Data was acquired with mass spectrometry based metabolomics and western blotting. We found that FD induces lack of cysteine in liver and brain, causing further imbalances in cysteine-derived metabolites such as glutathione and taurine. Changes in enzyme expression show that hepatic cells prioritize glutathione synthesis over taurine synthesis, while the brain does vice versa. We then supplemented FD mice with N-acetylcysteine (NAC), precursor of cysteine. NAC supplementation restored hepatic bile acid and blood glutathione levels of FD tissues. These results improved our understanding of FD induced metabolic imbalances and proved that NAC significantly rescues some of these changes.
  • Mardinoglu, Adil; Bjornson, Elias; Zhang, Cheng; Klevstig, Martina; Söderlund, Sanni; Ståhlman, Marcus; Adiels, Martin; Hakkarainen, Antti; Lundbom, Nina; Kilicarslan, Murat; Hallström, Björn M.; Lundbom, Jesper; Verges, Bruno; Barrett, Peter Hugh R.; Watts, Gerald F.; Serlie, Mireille J.; Nielsen, Jens; Uhlen, Mathias; Smith, Ulf; Marschall, Hanns-Ulrich; Taskinen, Marja-Riitta; Boren, Jan (2017)
    To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD(+) and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD(+) repletion on the development of NAFLD, we added precursors for GSH and NAD(+) biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.