Biology subjects

Nowak, W. N.

Publications and source records attributed to Nowak, W. N..

4 recordsLinked to original sources

bioRxiv2024

Effect of Western diet on body composition, locomotor performance and blood biochemical profile in the bank vole

ObjectiveThe adverse effects of diets high in both fat and simple sugars ("Western diets", WD), which are one of the causes of the epidemics of obesity and related disorders, have been extensively studied in laboratory rodents, but not in non-laboratory animals, which limits the scope of conclusions. For example, a few studies have shown that, unlike the laboratory mice or rats, non-laboratory rodents that reduce body mass for winter do not develop obesity when fed a high-fat diet. However, it is not known whether these rodents are also resistant to the adverse effects of WD. Here, we investigated the effects of WD on body composition, locomotor performance and blood biochemical profile in such a rodent, the bank vole (Clethrionomys = Myodes glareolus). MethodsYoung voles were fed either a standard diet or one of six versions of WD (varying in fat, sucrose, and cholesterol content) from the age of 21 days until adulthood (16 individuals per group), and then several morpho-physiological and biochemical traits were analyzed. ResultsNeither body mass, fat content nor blood glucose were elevated by WD (p[≥]0.11). Basal metabolic rate, sprint speed, endurance distance, and aerobic exercise capacity were also not significantly affected by the diet (p[≥]0.2). However, altered respiratory exchange rates indicated altered metabolic pathways, and the liver and spleen were enlarged in the groups fed WD with added cholesterol (p[≤]0.002). Similarly, concentrations of cholesterol, high-density lipoprotein (HDL), non-HDL, glutamic pyruvic transaminase, glutamic oxaloacetate transaminase (GOT), and lactate dehydrogenase (LDH) were elevated in the WD groups, especially the cholesterol-supplemented WD (p[≤]0.0001), indicating altered liver function. ConclusionsBank voles appeared to be resistant to diet-induced obesity and diabetes, but not to other adverse effects of WD, especially cholesterol-supplemented WD. Therefore, the bank vole is a promising model species to study diet-induced liver disease in lean individuals.

physiology↗

bioRxiv2024

Effect of heme oxygenase-1 on the expression of interferon-stimulated genes

Heme oxygenase-1 (HO1, Hmox1) degrades excess heme and is considered an anti-oxidative and anti-inflammatory enzyme. Our previous studies in Hmox1 knockout mice revealed induction of interferon-stimulated genes (ISGs) in all cell types analyzed, despite unchanged interferon production. Here, we sought to identify the pathway underlying HO1-dependent ISG regulation and determine how ISG expression changes in cultured cells in response to stressors typical of Hmox1-deficient mice. Using murine wild-type and Hmox1-deficient (KO-Hmox1) fibroblasts, we showed that in cells cultured under control conditions, the expression of most of the tested ISGs was independent of cellular HO1 status. We then analyzed the effect of extrinsic stressors: hemolytic, oxidative, genotoxic, and replication stress, proinflammatory TNF, and endogenous heme overload. TNF (upregulated in Hmox1 knockout mice) was the sole and universal ISG inducer in both wild-type and KO-Hmox1 fibroblasts. Unexpectedly, the response of KO-Hmox1 cells to exogenous TNF was weakened, probably due to impaired NF-{kappa}B activity and reduced p65 nuclear retention. A similar decrease we observed for STAT1. Additionally, the presence of TREX1 exonuclease in the nucleus indicated impaired nuclear envelope integrity. Noteworthy, HO1 colocalizes with PARP1, a protein regulating cytoplasmic-nuclear transport. Olaparib-mediated PARP1 inhibition abolished TNA-induced nuclear accumulation of p65 and STAT1 in wild-type cells, but not in KO-Hmox1 counterparts. In summary, the inflammation typical of Hmox1-deficient mice appears to be a major inducer of ISGs in vivo. Despite this, the inflammatory response to exogenous TNF is attenuated in KO-Hmox1 cells, likely due to decreased nuclear retention of NF-{kappa}B and STAT1.

immunology↗

bioRxiv2024

Treatment with 2-phospho-L-ascorbic acid mitigates biochemical phenotypes of heme oxygenase 1 deficiency

Heme oxygenase 1 (HO-1) deficiency is a fatal genetic disorder characterized by impaired heme catabolism, leading to excessive oxidative damage and cell death. Despite evidence from non-human models suggesting mitochondrial dysfunction, the precise pathomechanisms in humans remain unclear, resulting in a lack of effective treatments. Using patient-derived lymphoblastoid cells and HO-1 knockout HEK293T cell models, we demonstrate that HO-1 deficiency is associated with altered mitochondrial morphology and impaired mitochondrial function. Furthermore, it is linked to significant ascorbic acid depletion, accompanied by compensatory upregulation of SVCT2, a key ascorbic acid transporter. Treatment with 2-phospho-L-ascorbic acid, a stable vitamin C analog, restores intracellular ascorbic acid levels and protects cells from hemin-induced cytotoxicity, highlighting its potential as a novel therapeutic strategy for HO-1 deficiency. Our study underscores the critical role of oxidative stress and mitochondrial dysfunction in HO-1 deficiency, paving the way for targeted interventions in this devastating disorder.

molecular biology↗

bioRxiv2018

Heme oxygenase-1 deficiency affects bone marrow niche and triggers premature exhaustion of hematopoietic stem cells.

While intrinsic changes in aging hematopoietic stem cells (HSCs) are well-characterized, it remains unclear how hematopoietic niche affects HSC aging. Here, we demonstrate that cells in the niche -- endothelial cells (ECs) and CXCL12-abundant reticular cells (CARs) -- highly express the heme-degrading enzyme, heme oxygenase 1 (HO-1), but then decrease its expression with age. RNA-sequencing shows that ECs and CARs from HO-1-deficient animals (HO-1-/-) produce less hematopoietic factors. Consequently, HSCs from young HO-1-/- animals lose quiescence and regenerative potential. Young HO-1-/- HSCs exhibit features of premature aging on the transcriptional and functional level. HO-1+/+ HSCs transplanted into HO-1-/- recipients exhaust their regenerative potential early and do not reconstitute secondary recipients. In turn, transplantation of HO-1-/- HSCs to the HO-1+/+ recipients recovers the regenerative potential of HO-1-/- HSCs and reverses their transcriptional alterations. Thus, HSC-extrinsic activity of HO-1 prevents HSCs from premature aging and may restore the function of aged HSCs.

cell biology↗