Publications by authors named "M C Satterfield"

98 Publications

First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of SPR720, a Novel Oral Bacterial DNA Gyrase (GyrB) Inhibitor for Mycobacterial Infections.

Antimicrob Agents Chemother 2021 Sep 7:AAC0120821. Epub 2021 Sep 7.

Spero Therapeutics, Inc., Cambridge, MA, United States.

SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis. SPR719 has demonstrated activity against clinically relevant mycobacteria and in murine and hollow fiber infection models. This Phase 1 randomized, double-blind, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) trial evaluated the safety, tolerability, and pharmacokinetics of SPR720/SPR719. A total of 96 healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 (or placebo) as single oral doses ranging from 100 mg to 2000 mg, or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events (AEs) were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. The median SPR719 T ranged from 2.8 to 8.0 hours across cohorts, and the t ranged from 2.9 to 4.5 hours and was shown to be dose-independent. Dosing with food decreased SPR719 plasma exposure by approximately 20%. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Days 1 and 7, suggesting induction of an elimination pathway. However, plasma AUC was comparable between Days 7 and 14. Results of this first-in-human study suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720.
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http://dx.doi.org/10.1128/AAC.01208-21DOI Listing
September 2021

Effect of maternal overnutrition on predisposition to insulin resistance in the foal: Foal skeletal muscle development and insulin signaling.

Domest Anim Endocrinol 2021 Oct 2;77:106648. Epub 2021 Jul 2.

Department of Animal Science, Texas A&M University, College Station, Texas 77843. Electronic address:

Skeletal muscle plays an integral role in the ability of a horse to perform at high levels. Shifts in skeletal muscle development in response to maternal plane of nutrition may have substantial and lasting impacts on athletic performance and whole-body metabolism. Therefore, sixteen Quarter Horse mares were used in a completely randomized design and maintained at a body condition score (BCS) 6 until start of third trimester. On d 235 of gestation, mares were randomly assigned to receive one of two dietary treatments with a diet formulated to meet requirements during late gestation (CON; n = 8), and an overfed diet (HIGH; n = 8) where mares received an additional 40% above CON. Five h after parturition, foals were euthanized, and gluteus medius, triceps brachii, and semitendinosus were harvested for analyses. Gene expression was determined by qPCR and western immunoblotting was used to quantify total and phosphorylated forms of proteins involved in skeletal muscle metabolism with tubulin as the loading control. All data were analyzed using PROC MIXED of SAS. Foals from HIGH mares exhibited larger skeletal muscle fibers by area (P <0.05), and a shift in muscle fiber development towards type I slow twitch muscle fibers (P <0.05). Relative expression of glucose transporter 4 (GLUT4) was lower in HIGH foals compared to CON in gluteus medius (P = 0.05). Insulin receptor isoform B (INSR-B) and insulin-like growth factor 1 receptor (IGF1R) were greater in triceps brachii of HIGH foals compared to CON (P ≤ 0.03). Insulin receptor isoform A (INSR-A), however, tended to be lower in triceps brachii of HIGH compared to CON (P = 0.10). Ratios of phosphorylated to total extracellular signal-regulated protein kinase 1/2 (ERK1/2) and c-June N-terminal kinase (JNK) were higher in HIGH foals compared to CON (P ≤0.04) in gluteus medius. There were no differences observed for phosphorylated to total protein ratios in semitendinosus and triceps brachii muscles; however, total ERK1/2 tended to be elevated (P <0.10) in semitendinosus from CON foals compared to HIGH. There was no difference in phosphorylated or total protein kinase B (AKT) (P >0.14). These data indicate hypertrophy of skeletal muscle fibers and a shift towards type I slow twitch fibers in HIGH foals. Furthermore, this study identifies muscle specific changes in gene expression and downstream insulin receptor signaling, which may contribute to future metabolic abnormalities in response to maternal overnutrition.
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http://dx.doi.org/10.1016/j.domaniend.2021.106648DOI Listing
October 2021

Placental adaptation to maternal malnutrition.

Reproduction 2021 Sep 9;162(4):R73-R83. Epub 2021 Sep 9.

Department of Animal Science, Texas A&M University, College Station, Texas, USA.

Maternal malnutrition gives rise to both short- and long-term consequences for the survival and health of the offspring. As the intermediary between mother and fetus, the placenta has the potential to interpret environmental signals, such as nutrient availability, and adapt to support fetal growth and development. While this potential is present, it is clear that at times placental adaptation fails to occur resulting in poor pregnancy outcomes. This review will focus on placental responses to maternal undernutrition related to changes in placental vascularization and hemodynamics and placental nutrient transport systems across species. While much of the available literature describes placental responses that result in poor fetal outcomes, novel models have been developed to utilize the inherent variation in fetal weight when dams are nutrient restricted to identify placental adaptations that result in normal-weight offspring. Detailed analyses of the spectrum of placental responses to maternal malnutrition point to alternations in placental histoarchitectural and vascular development, amino acid and lipid transport mechanisms, and modulation of immune-related factors. Dietary supplementation with selected nutrients, such as arginine, has the potential to improve placental growth and function through a variety of mechanisms including stimulating cell proliferation, protein synthesis, angiogenesis, vasodilation, and gene regulation. Improved understanding of placental responses to environmental cues is necessary to develop diagnostic and intervention strategies to improve pregnancy outcomes.
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http://dx.doi.org/10.1530/REP-21-0179DOI Listing
September 2021

Placental Transcriptome Adaptations to Maternal Nutrient Restriction in Sheep.

Int J Mol Sci 2021 Jul 17;22(14). Epub 2021 Jul 17.

Department of Animal Science, Texas A & M University, College Station, TX 77843, USA.

Placental development is modified in response to maternal nutrient restriction (NR), resulting in a spectrum of fetal growth rates. Pregnant sheep carrying singleton fetuses and fed either 100% ( = 8) or 50% (NR; = 28) of their National Research Council (NRC) recommended intake from days 35-135 of pregnancy were used to elucidate placentome transcriptome alterations at both day 70 and day 135. NR fetuses were further designated into upper (NR NonSGA; = 7) and lower quartiles (NR SGA; = 7) based on day 135 fetal weight. At day 70 of pregnancy, there were 22 genes dysregulated between NR SGA and 100% NRC placentomes, 27 genes between NR NonSGA and 100% NRC placentomes, and 22 genes between NR SGA and NR NonSGA placentomes. These genes mediated molecular functions such as MHC class II protein binding, signaling receptor binding, and cytokine activity. Gene set enrichment analysis (GSEA) revealed significant overrepresentation of genes for natural-killer-cell-mediated cytotoxicity in NR SGA compared to 100% NRC placentomes, and alterations in nutrient utilization pathways between NR SGA and NR NonSGA placentomes at day 70. Results identify novel factors associated with impaired function in SGA placentomes and potential for placentomes from NR NonSGA pregnancies to adapt to nutritional hardship.
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http://dx.doi.org/10.3390/ijms22147654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306922PMC
July 2021

Maternal nutrient restriction alters thyroid hormone dynamics in placentae of sheep having small for gestational age fetuses.

Domest Anim Endocrinol 2021 Oct 2;77:106632. Epub 2021 May 2.

Department of Animal Science, Texas A&M University, 2471 TAMU, College Station, Texas 77843. Electronic address:

Thyroid hormones regulate a multitude of metabolic and cellular processes involved in placental and fetal growth, while maternal nutrient restriction (NR) has the potential to influence these processes. Those fetuses most impacted by NR, as categorized by weight, are termed small for gestational age (SGA), but the role of thyroid hormones in these pregnancies is not fully understood. Therefore, the aims of the present study were to determine effects of NR during pregnancy on maternal and fetal thyroid hormone concentrations, as well as temporal and cell-specific expression of mRNAs and proteins for placental thyroid hormone transporters, thyroid hormone receptors, and deiodinases in ewes having either SGA or normal weight fetuses. Ewes with singleton pregnancies were fed either a 100% NRC (n = 8) or 50% NRC (NR; n = 28) diet from Days 35 to 135 of pregnancy with a single placentome surgically collected on Day 70. Fetal weight at necropsy on Day 135 was used to designate the fetuses as NR NonSGA (n = 7; heaviest NR fetuses) or NR SGA (n = 7; lightest NR fetuses). Thyroid hormone levels were lower in NR SGA compared to NR NonSGA ewes, while all NR fetuses had lower concentrations of thyroxine at Day 135. Expression of mRNAs for thyroid hormone transporters SLC16A2, SLC16A10, SLCO1C1, and SLCO4A1 were altered by day, but not nutrient restriction. Expression of THRA mRNA and protein was dysregulated in NR SGA fetuses with protein localized to syncytial and stromal cells in placentomes in all groups. The ratio of deiodinases DIO2 and DIO3 was greater for NR SGA placentae at Day 70, while DIO3 protein was less abundant in placentae from NR SGA than 100% NRC ewes. These results identify mid-gestational modifications in thyroid hormone-associated proteins in placentomes of ewes having SGA fetuses, as well as a potential for placentomes from NonSGA pregnancies to adapt to, and overcome, nutritional restrictions during pregnancy.
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http://dx.doi.org/10.1016/j.domaniend.2021.106632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380679PMC
October 2021
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