lidia nierobisz - Academia.edu (original) (raw)

Papers by lidia nierobisz

Current Chemical Genomics, Nov 1, 2013

Myoblast proliferation and differentiation are essential for normal skeletal muscle growth and re... more Myoblast proliferation and differentiation are essential for normal skeletal muscle growth and repair. Muscle recovery is dependent on the quiescent population of muscle stem cells-satellite cells. During muscle injury, satellite cells become mitotically active and begin the repair process by fusing with each other and/or with myofibers. Aging, prolonged inactivity, obesity, cachexia and other muscle wasting diseases are associated with a decreased number of quiescent and proliferating satellite cells, which impedes the repair process. A high-content/high-throughput platform was developed and utilized for robust phenotypic evaluation of human primary satellite cells in vitro for the discovery of chemical probes that may improve muscle recovery. A 1600 compound pilot screen was developed using two highly annotated small molecule libraries. This screen yielded 15 dose responsive compounds that increased proliferation rate in satellite cells derived from a single obese human donor. Two of these compounds remained dose responsive when counter-screened in 3-donor obese superlot. The Alk-5 inhibitor LY364947, was used as a positive control for assessing satellite cell proliferation/delayed differentiation. A multivariate approach was utilized for exploratory data analysis to discover proliferation vs. differentiation-dependent changes in cellular phenotype. Initial screening efforts successfully identified a number of phenotypic outcomes that are associated with desired effect of stimulation of proliferation and delayed differentiation.

Chapter 3 Table Calculated crude protein and amino acid composition of 0.88 NRC, 1.00 NRC, and 1.... more Chapter 3 Table Calculated crude protein and amino acid composition of 0.88 NRC, 1.00 NRC, and 1.12 NRC experimental diets.

Current Chemical Genomics, 2013

NIEROBISZ, LIDIA SYLWIA. The Effect of Early Post-Hatch Dietary Amino Acid Levels on Satellite Ce... more NIEROBISZ, LIDIA SYLWIA. The Effect of Early Post-Hatch Dietary Amino Acid Levels on Satellite Cell Dynamics in Turkeys. (Under the direction of Paul Mozdziak.) Satellite cells are defined as myonuclear myogenic stem cells residing between sarcolemma and basal lamina of the myofiber. Myofiber number is established during embryonic development. Post-hatch and post-natal muscle growth occurs exclusively through an increase in myofiber size. The increase of myofiber size in early post-hatch turkeys is predominantly dependent on the contribution of new myonuclei to pre-existing myofibers by the mitotically active satellite cell population. Preliminary data in broilers has revealed that supplementation with amino acid deficient diet immediately post-hatch results in an increase satellite cell mitotic activity in Pectoralis thoracicus muscle in 3-day-old chicks as compared to birds fed adequate and above requirement amino acid levels. Additionally, chicks denied feed for first three days ...

Comparative Biochemistry and Physiology B, Nov 1, 2007

Understanding the relationship between nutrition and satellite cell activity will be beneficial i... more Understanding the relationship between nutrition and satellite cell activity will be beneficial in obtaining optimal muscle growth and meat production. The objective of this study was to evaluate the effect of early post-hatch levels of dietary amino acids+/-0.88 NRC, 1.00 NRC, and 1.12 NRC), and feed deprivation on the satellite cell mitotic activity, pectoralis thoracicus muscle weight, and body weight of male turkeys (Meleagris gallopavo). Birds from each treatment were injected with 5-bromo-2'-deoxyuridine (BrdU) to label mitotically active cells. The right pectoralis thoracicus was harvested 1 h after BrdU injection for immunohistochemical and myofiber diameter analysis. On the third day post-hatch, satellite cell mitotic activity was the highest (P<0.05) in the 0.88 NRC amino acid treatment group and the lowest (P<0.05) in the feed-deprived group. On the fourth day post-hatch, feed-deprived birds exhibited the lowest (P<0.05) satellite cell mitotic activity and muscle weight. At 140 days of age, there were no significant differences (P>0.05) between treatments in body weight or pectoralis thoracicus muscle weight. Research evaluating species-related differences in apoptotic events and in genes regulating cell proliferation may be necessary to devise feeding strategies aimed at obtaining optimal pectoralis thoracicus muscle yield at market age.

PLOS ONE, Oct 25, 2018

Obesity and insulin resistance are primary risk factors for Non-Alcoholic Fatty Liver Disease (NA... more Obesity and insulin resistance are primary risk factors for Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is generally exhibited by non-progressive simple steatosis. However, a significant subset of patient's progress to nonalcoholic steatohepatitis (NASH) that is defined by the presence of steatosis, inflammation and hepatocyte injury with fibrosis. Unfortunately, there are no approved therapies for NAFLD or NASH and therefore therapeutic approaches are urgently needed. Niclosamide is an U.S. Food and Drug Administration (FDA)-approved anthelmintic drug that mediates its effect by uncoupling oxidative phosphorylation. Niclosamide and its salt forms, Niclosamide Ethanolamine (NEN), and Niclosamide Piperazine (NPP) have shown efficacy in murine models of diet induced obesity characterized by attenuation of the prominent fatty liver disease phenotype and improved glucose metabolism. While the exact mechanism(s) underlying these changes remains unclear, the ability to uncouple oxidative phosphorylation leading to increased energy expenditure and lipid metabolism or attenuation of PKA mediated glucagon signaling in the liver have been proposed. Unfortunately, niclosamide has very poor water solubility, leading to low oral bioavailability. This, in addition to mitochondrial uncoupling activity and potential genotoxicity have reduced enthusiasm for its clinical use. More recently, salt forms of niclosamide, NEN and NPP, have demonstrated improved oral bioavailability while retaining activity. This suggests that development of safer more effective niclosamide derivatives for the treatment of NAFLD and Type 2 Diabetes may be possible. Herein we explored the ability of a series of N-substituted phenylbenzamide derivatives of the niclosamide salicylanilide chemotype to attenuate hepatic steatosis using a novel phenotypic in vitro model of fatty liver and the high fat diet-fed mouse model of diet induced obesity. These studies identified novel compounds with improved pre-clinical properties that attenuate hepatic steatosis in vitro and in vivo. These compounds with improved drug properties may be useful in a1111111111 a1111111111 a1111111111 a1111111111 a1111111111

Comparative Biochemistry and Physiology B, Feb 1, 2011

Coenzyme Q(10) (CoQ(10)) plays an essential role in determination of mitochondrial membrane poten... more Coenzyme Q(10) (CoQ(10)) plays an essential role in determination of mitochondrial membrane potential and substrate utilization in all metabolically important tissues. The objective of the present study was to investigate the effect of Coenzyme Q analog (MitoQ(10)) on oxidative phenotype and adipogenesis in myotubes derived from fast-glycolytic Pectoralis major (PM) and slow-oxidative Anterior latissimus dorsi (ALD) muscles of the turkey (Meleagris gallopavo). The myotubes were subjected to the following treatments: fusion media alone, fusion media+125 nM MitoQ(10), and 500 nM MitoQ(10). Lipid accumulation was visualized by Oil Red O staining and quantified by measuring optical density of extracted lipid at 500 nm. Quantitative Real-Time PCR was utilized to quantify the expression levels of peroxisome proliferator-activated receptor (PPARγ) and PPARγ co-activator-1α (PGC-1α). MitoQ(10) treatment resulted in the highest (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) lipid accumulation in PM myotubes. MitoQ(10) up-regulated genes controlling oxidative mitochondrial biogenesis and adipogenesis in PM myotube cultures. In contrast, MitoQ(10) had a limited effect on adipogenesis and down-regulated oxidative metabolism in ALD myotube cultures. Differential response to MitoQ(10) treatment may be dependent on the cellular redox state. MitoQ(10) likely controls a range of metabolic pathways through its differential regulation of gene expression levels in myotubes derived from fast-glycolytic and slow-oxidative muscles.

Asian-australasian Journal of Animal Sciences, Mar 4, 2008

Avian and mammalian skeletal muscles exhibit a remarkable ability to adjust to physiological stre... more Avian and mammalian skeletal muscles exhibit a remarkable ability to adjust to physiological stressors induced by growth, exercise, injury and disease. The process of muscle recovery following injury and myonuclear accretion during growth is attributed to a small population of satellite cells located beneath the basal lamina of the myofiber. Several metabolic factors contribute to the activation of satellite cells in response to stress mediated by illness, injury or aging. This review will describe the regenerative properties of satellite cells, the processes of satellite cell activation and highlight the potential role of satellite cells in skeletal muscle growth, tissue engineering and meat production.

Glucose tolerance test in DIO mice. 2g/kg of glucose was injected IP and at 15, 30 and 6... more Glucose tolerance test in DIO mice. 2g/kg of glucose was injected IP and at 15, 30 and 60 min, blood glucose levels were measured. (A) Averaged glucose tolerance for 7-day sham cohort and 5 mg/Kg Niclosamide treatment group (n = 3 each, P = 0.05). (B) Comparison of pre and post-7 day treatment with 5 mg/kg Niclosamide (n = 3, P = 0.034). C) Western blot analyses of phosphorylated AMPKα T172, Fatty acid synthase (FAS) and carbonic anhydrase III (CAIII) protein expression in liver tissue samples from male C57BL/6J mice fed HFD treated with 10mg/kg Niclosamide or D) 500200, 500199 or 600453 for 12 days relative to Sham HFD alone (control).</p

The predicted aqueous solubility* at pH 7.4, cLogP, and cLogD (pH 7.4) were calculated u... more The predicted aqueous solubility* at pH 7.4, cLogP, and cLogD (pH 7.4) were calculated using Instant Jchem or MarvinSketch. Inhibition of steatotic phenotype was quantified in PH5CH8 liver cells using the DNL assay. Lipid synthesis was stimulated in triplicate, in the presence of compounds in 10-point dose response between 1μM and 1.9nM. Cells were fixed, labeled and analyzed by high content image analysis. Partial least squares (PLS) regression analysis was used to determine % effect relative to DMSO controls. IC50 values were calculated for each compound.</p

Negative control cells stimulated for de novo lipid synthesis showing... more Negative control cells stimulated for de novo lipid synthesis showing nuclei (gray) and lipids (green) (A) and lipid quantitation of negative control using high-content image analysis resulting in a high lipid score, normalized to 0% effect (C) Positive control—unstimulated cells representing the normal (basal) lipid content with a low lipid score and normalized to 100% effect (B). Representative images from high throughput screening showing negative (D) and positive (E) control wells and stimulated cells treated with 1 μM niclosamide (F). Dose response analysis of test compounds Triacsin C (G) and niclosamide (H) shown in blue. Green and red lines represent the mean and standard error of stimulated and unstimulated cells.</p

Pharmacokinetic parameters for phenylbenzamides after 1 mg/kg intravenous injection or 5... more Pharmacokinetic parameters for phenylbenzamides after 1 mg/kg intravenous injection or 5mg/kg oral dose in Sprague Dawley rats.</p

20-week old HFD-fed mice were delivered vehicle or compound daily at 10mg/kg by I.P for ... more 20-week old HFD-fed mice were delivered vehicle or compound daily at 10mg/kg by I.P for 12 days. Body weight measurements and scoring of greasy coat phenotype were performed prior to and following treatment. Histological analysis of H&E stained liver sections were analyzed and the % of steatosis and steatosis score are reported.</p

The values shown represent the mean number of revertant colonies in the presence and abs... more The values shown represent the mean number of revertant colonies in the presence and absence of exogenous metabolic activation (Aroclor 1254 induced rat liver S9) from 3 replicate wells. The positive control chemicals were 2-Aminoanthracene (2-AA) for all S9 activation experiments, 2-nitrofluorene (2-NF 2) for TA98, SA for TA100 and TA1535, ICR-191 for TA-1537 and MNNG for WP2 uvrA. * indicates compounds that exhibit statistically significant increases in mean revertant colonies (p<0.05) as indicated by the Ames assay.</p

20-week old HFD-fed mice were delivered vehicle or compound daily via intraperitoneal in... more 20-week old HFD-fed mice were delivered vehicle or compound daily via intraperitoneal injection for 12 days and compared to sham mice fed 10% fat diet. Representative images of H&E stained liver sections from 10% fat diet mice (A) 60% HFD-fed mice (B) or 60% HFD-fed mice treated with niclosamide (C) or 500199 (D) at 10mg/kg.</p

Metabolic stability of phenylbenzamides in human and male mouse liver microsomes.</p

Cellular respiration rate was measured in HEK293 cells expressing human OCT1 using the M... more Cellular respiration rate was measured in HEK293 cells expressing human OCT1 using the Mitoexpress-Xtra kit. The lifetime slope was plotted against concentration of compound. Oxygen consumption measurements were obtained immediately after treatment and for a period of 2 hours. The slope was calculated from the linear portion of the 2-hour kinetic run. Basal respiration (no treatment, green), stimulated respiration (1uM FCCP, blue) and no cell control (black) are shown. Changes with * indicate statistically significant (p<0.05) OCR values compared to basal OCR values.</p

A) Cells were seeded at 10,000 cells per well 24 hours prior to treating cells with indi... more A) Cells were seeded at 10,000 cells per well 24 hours prior to treating cells with indicated concentration of compound or DMSO (CTL) for 4 hours. 16μL of cell lysate was incubated with HTRF phospho-AMPK detection reagents and fluorescence emission read at 665nm and 620nm using a PHERAstar platereader. The mean and standard deviation of the HTRF Ratio from three replicate wells is shown. The unstimulated (DMSO) and positive controls lysates are shown in green and red respectively.</p

Current Chemical Genomics, Nov 1, 2013

Current Chemical Genomics, 2013

Comparative Biochemistry and Physiology B, Nov 1, 2007

PLOS ONE, Oct 25, 2018

Comparative Biochemistry and Physiology B, Feb 1, 2011

Asian-australasian Journal of Animal Sciences, Mar 4, 2008

Metabolic stability of phenylbenzamides in human and male mouse liver microsomes.</p