| 2. |
- Cruz, Raquel, et al.
(författare)
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Novel genes and sex differences in COVID-19 severity
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
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Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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| 3. |
- Liu, Zhigang, et al.
(författare)
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Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1, s. 855-
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.
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| 4. |
- Olejnicka, Beata Teresa
(författare)
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Insulin-Producing Cells, Iron, Oxidative Stress, and Lysosomal Pathology
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Accumulating evidence suggests that injnries caused by oxygen-derived radicals contribute to the destruction of pancreatic islet ß-cells in autoinnnune diabetes mellitus (diabetes type I, or IDDM). Oxidative stress may be caused by an enhanced production of oxygen-derived radicals, or by a decreased scavenging of such molecules. It was recently suggested that iron-mediated intralysosomal oxidative reactions result in the destabilization of lysosomal membranes, leakage of lysosomal contents to the cytosol, cellular destruction and, moreover, that such mechanisms may operate in IDDM.In the present study, we have investigated the mechanisms by which hydrogen peroxide induces cell damage, and its possible relationship to intralysosomal iron. The work was done on three insulin-producing insulinoma cell lines: HIT-TI5, NIT-1, and RINmF cells, on mouse pancreatic islets ß-cells, and the macrophage-like J-774 cells. In particular, we studied the influence of induced autophagocytosis (by glucose- and amino acid starvation) on the sensitivity to oxidative stress; the influence of high-glucose growth media on hydrogen peroxide cytotoxicity; the protective effects by starvation-stimulated intracellular fertitin synthesis against oxidative stress; the possible relationship between oxidative stress, lysosomal destabilization and apoptotic/necrotic cell death; and the impact of iron chelation on lysosomal stability, and insulinoma- and ß-cell survival.A higb susceptibility to oxidative stress was demonstrated for all the insulin-producing cells. Starvation-induced autophagocytosis increased the concentration of desfertioxarnine-available lowmolecular- weight iron in HIT-T15 cells, as assayed by HPLC. Tbe iron was mainly found in secondary lysosomes, as shown by the autometallography technique when applied at electron nticroscopical level. Starvation enhanced oxidative stress-induced damage of the IDT-T15, RINm5F and J-774 cells, as assayed by the trypan blue dye exclusion test and tests for lysosomal stability (the actidine orange relocation/uptake tests). In contrast, the pronounced starvationinduced autophagocytosis that was shown by the most vulnerable insulinoma cell line (NIT -1) was paralleled by enhanced resistance to oxidative stress, and by increased lysosomal stability as well. A rapid NIT -1 fertitin synthesis was demonstrated by inununocytochentistry under conditions of starvation. It is believed that autophagocytotic lysosomal uptake of non-iron-saturated fertitin will allow such fertitin to act as an iron chelator and stabilize lysosomes against oxidative stress. NIT -1 and B-cells which were subjected to a low level of oxidative stress (30 J.LM H20 2 for 15 min) were still largely intact at the light nticroscopical level ,but 10-20% of the cells exhibited nuclear chromatin condensation as an early sign of apoptosis when examined by the Ho334/PI staining technique, or by TEM, 0.5-1 h after the insult. At the same point of time, a decrease in the number of intact lysosomes was also observed. The rate of oxidative stress-induced lysosomal destabilization progressed with time, and a widespread apoptotic/necrotic-type degeneration/fragmentation ensued, as demonstrated by SEM, TEM, and the TUNEL-reaction. The ntitochondria revealed a mixture of lamelliform and swollen cristae, indicating altered properties of the mitochondrial membranes. Pre-treatment with the iron chelator desfenioxamine attenuated the lysosomal destabilization, and increased cell viability, following exposure to oxidative stress.At high-glucose conditions, the ~02-sensitivity of HIT-T15, NIT-I, and B-cells was reduced which, was consistent with a moderately enhanced stability of their lysosomes, as measured by the acridine orange-relocation test, and with reduced amounts of desfenioxamine-available iron.We conclude that the decisive role of free lysosomal iron in oxidative stress is strongly supported by the following lines of evidence, provided by the present study (a) glucose- and amino acid-starvation promotes autophagic/crinophagic activity of the cells, resulting in enrichment of intracellular (intralysosomal) desfenioxamine-available iron; (b) high-glucose conditions depress autophagic/crinophagic activity and, consequently, the occurrence of intralysosomal iron; (c) starvation-stimulated fenitin synthesis enhances lysosomal stability during oxidative stress by limiting lysosomal redox-active iron; (d) lysosomal destabilization and related apoptotic cell death are associated with the amounts of intralysosomal iron in redox -active form,
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