Fructose metabolism is unregulated in cancers and placentae.

Fructose and lactate are present in high concentrations in uterine luminal fluid, fetal fluids and fetal blood of ungulates and cetaceans, but their roles have been ignored and they have been considered waste products of pregnancy. This review provides evidence for key roles of both fructose and lactate in support of key metabolic pathways required for growth and development of fetal-placental tissues, implantation and placentation. The uterus and placenta of ungulates convert glucose to fructose via the polyol pathway.

The history of interferon-stimulated genes in pregnant cattle, sheep, and pigs.

In Brief: The trophectoderm of the elongating conceptuses of cattle, sheep, and pigs secrete high amounts of interferons that increase or induce the expression of interferon-stimulated genes (ISGs) in the endometrium. Research concerning ISGs, performed from 1995 through 2023, is reviewed in this manuscript.

Abstract: Expression of the classical interferon (IFN) stimulated genes (ISGs) increases in the endometrial stroma and glandular epithelium (GE) through activation of signal transducer and activator of transcription (STAT) signaling in response to the secretion of IFN tau (IFNT) and IFN gamma (IFNG) by the conceptuses of ruminants, including cattle and sheep, and pigs, respectively.

Early Embryonic Development in Agriculturally Important Species.

The fertilization of oocytes ovulated by pigs, sheep, cows, and horses is not considered a limiting factor in successful establishment of pregnancy. Pig, sheep, and cow embryos undergo cleavage to the blastocyst stage, hatch from the zona pellucida, and undergo central-type implantation. Hatched blastocysts of pigs, sheep, and cows transition from tubular to long filamentous forms to establish surface area for exchange of nutrients and gases with the uterus.

Progesterone regulates tissue non-specific alkaline phosphatase (TNSALP) expression and activity in ovine utero-placental tissues.

Background: Tissue non-specific alkaline phosphatase (TNSALP; encoded by the ALPL gene) has a critical role in the postnatal regulation of phosphate homeostasis, yet how TNSALP activity and expression are regulated during pregnancy remain largely unknown. This study tested the hypothesis that progesterone (P4) and/or interferon tau (IFNT) regulate TNSALP activity during pregnancy in sheep.

Methods: In Exp.

Metabolism and Nutrition of L-Glutamate and L-Glutamine in Ruminants.

Although both L-glutamate (Glu) and L-glutamine (Gln) have long been considered nutritionally nonessential in ruminants, these two amino acids have enormous nutritional and physiological importance. Results of recent studies revealed that extracellular Gln is extensively degraded by ruminal microbes, but extracellular Glu undergoes little catabolism by these cells due to the near absence of its uptake. Ruminal bacteria hydrolyze Gln to Glu plus ammonia and, intracellularly, use both amino acids for protein synthesis.

Metabolic pathways of glucose and fructose: II Spatiotemporal expression of genes involved in synthesis and transport of lactate in ovine conceptuses†.

Lactate, an abundant molecule in fetal fluids and blood of mammalian species, is often overlooked as a metabolic waste product generated during pregnancy. Most of the glucose and fructose consumed by ovine conceptuses is converted to lactate, but proteins involved in lactate metabolism and transport have not been investigated. This study characterized total lactate produced by ovine conceptuses throughout gestation, as well as expression of mRNAs and proteins involved in lactate metabolism.

Metabolic pathways for glucose and fructose: I synthesis and metabolism of fructose by ovine conceptuses†.

Fructose, the most abundant hexose sugar in fetal fluids and the blood of sheep and other ungulates and cetaceans, is synthesized from glucose via the polyol pathway in trophectoderm and chorion. However, the cell-specific and temporal expression of enzymes for the synthesis and metabolism of fructose in sheep conceptuses (embryo and placental membranes) and placentomes has not been characterized. This study characterized key enzymes involved in fructose synthesis and metabolism by ovine conceptuses throughout pregnancy.

Pig conceptuses utilize extracellular vesicles for interferon-gamma-mediated paracrine communication with the endometrium†.

Interferon-gamma (IFNG) is a pro-inflammatory cytokine secreted by the porcine conceptus (embryo and extra-embryonic membranes) during the peri-implantation period of pregnancy. IFNG modifies the endometrial inflammatory immune response and is required for the implantation and survival of the conceptus. It is not known how IFNG from the conceptus trophectoderm is transported across the endometrial luminal epithelium (LE).

Understanding placentation in ruminants: a review focusing on cows and sheep.

Mammals differ regarding their placentae, but in all species placental trophoblasts interact intimately with the uterine endometrium to mediate the transfer of nutrients from the mother to the embryo/fetus through the closely juxtaposed microcirculatory systems of the uterus and placenta. Placentation in ruminants is intermediate between the non-invasive type, as observed in the epitheliochorial placenta of pigs, and the invasive type, as observed in the haemochorial placentae of mice and humans. In ruminants, placental trophoblast cells invade uterine endometrial tissue, but invasion is believed to be limited to the endometrial luminal epithelium (LE).

Early Syncytialization of the Ovine Placenta Revisited.

Placentation is the development of a temporary arrangement between the maternal uterus and blastocyst-derived placental tissues designed to transport nutrients, gases, and other products from the mother to the embryo and fetus. Placentation differs histologically among species, but all types of placentation share the common trait of utilizing highly complex cell-to-cell and tissue-to-tissue morphological and biochemical interactions to remodel the uterine-placental interface. An elegant series of electron microscopy (EM) images supports the classification of ovine placentation as synepitheliochorial, because uterine luminal epithelial (LE) cells are maintained at the uterine-placental interface through incorporation into trophoblast syncytial plaques.

Synthesis of glycine from 4-hydroxyproline in tissues of neonatal pigs with intrauterine growth restriction.

This study tested the hypothesis that the synthesis of glycine from 4-hydroxyproline (an abundant amino acid in milk and neonatal blood) was impaired in tissues of piglets with intrauterine growth restriction (IUGR), thereby contributing to a severe glycine deficiency in these compromised neonates. At 0, 7, 14, and 21 days of age, IUGR piglets were euthanized, and tissues (liver, small intestine, kidney, pancreas, stomach, skeletal muscle, and heart) were obtained for metabolic studies, as well as the determination of enzymatic activities, cell-specific localization, and expression of mRNAs for glycine-synthetic enzymes. The results indicated relatively low enzymatic activities for 4-hydroxyproline oxidase (OH-POX), proline oxidase, serine hydroxymethyltransferase, threonine dehydrogenase (TDH), alanine: glyoxylate transaminase, and 4-hydroxy-2-oxoglutarate aldolase in the kidneys and liver from 0- to 21-day-old IUGR pigs, in the pancreas of 7- to 21-day-old IUGR pigs, and in the small intestine and skeletal muscle (except TDH) of 21-day-old IUGR pigs.

Integrins and their potential roles in mammalian pregnancy.

Integrins are a highly complex family of receptors that, when expressed on the surface of cells, can mediate reciprocal cell-to-cell and cell-to-extracellular matrix (ECM) interactions leading to assembly of integrin adhesion complexes (IACs) that initiate many signaling functions both at the membrane and deeper within the cytoplasm to coordinate processes including cell adhesion, migration, proliferation, survival, differentiation, and metabolism. All metazoan organisms possess integrins, and it is generally agreed that integrins were associated with the evolution of multicellularity, being essential for the association of cells with their neighbors and surroundings, during embryonic development and many aspects of cellular and molecular biology. Integrins have important roles in many aspects of embryonic development, normal physiology, and disease processes with a multitude of functions discovered and elucidated for integrins that directly influence many areas of biology and medicine, including mammalian pregnancy, in particular implantation of the blastocyst to the uterine wall, subsequent placentation and conceptus (embryo/fetus and associated placental membranes) development.

Synthesis of glycine from 4-hydroxyproline in tissues of neonatal pigs.

Glycine from sow's milk only meets 20% of the requirement of suckling piglets. However, how glycine is synthesized endogenously in neonates is not known. This study determined glycine synthesis from 4-hydroxyproline (an abundant amino acid in milk and neonatal blood) in tissues of sow-reared piglets with normal birth weights.

Bruton's tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination.

Bruton's tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE).

Creatine metabolism at the uterine-placental interface throughout gestation in sheep†.

The placenta requires high levels of adenosine triphosphate to maintain a metabolically active state throughout gestation. The creatine-creatine kinase-phosphocreatine system is known to buffer adenosine triphosphate levels; however, the role(s) creatine-creatine kinase-phosphocreatine system plays in uterine and placental metabolism throughout gestation is poorly understood. In this study, Suffolk ewes were ovariohysterectomized on Days 30, 50, 70, 90, 110 and 125 of gestation (n = 3-5 ewes/per day, except n = 2 on Day 50) and uterine and placental tissues subjected to analyses to measure metabolites, mRNAs, and proteins related to the creatine-creatine kinase-phosphocreatine system.

Dietary supplementation with L-citrulline improves placental angiogenesis and embryonic survival in gilts.

This study was conducted with gilts as an animal model to test the hypothesis that dietary supplementation with L-citrulline (Cit) improves placental angiogenesis and embryonic survival. Between Days 14 and 25 of gestation, each gilt was fed a corn- and soybean-meal-based diet (2 kg/day) supplemented with 0.4% Cit or an isonitrogenous amount of L-alanine (Control).

Dietary supplementation with 0.4% L-arginine between days 14 and 30 of gestation enhances NO and polyamine syntheses and water transport in porcine placentae.

Background: Most embryonic loss in pigs occurs before d 30 of gestation. Dietary supplementation with L-arginine (Arg) during early gestation can enhance the survival and development of conceptuses (embryo/fetus and its extra-embryonic membranes) in gilts. However, the underlying mechanisms remain largely unknown.

The ovine conceptus utilizes extracellular serine, glucose, and fructose to generate formate via the one carbon metabolism pathway.

Highly proliferative cells rely on one carbon (1C) metabolism for production of formate required for synthesis of purines and thymidine for nucleic acid synthesis. This study was to determine if extracellular serine and/or glucose and fructose contribute the production of formate in ovine conceptuses. Suffolk ewes (n = 8) were synchronized to estrus, bred to fertile rams, and conceptuses were collected on Day 17 of gestation.

Creatine metabolism at the uterine-conceptus interface during early gestation in sheep†.

Ruminant conceptuses that elongate and attach to the uterine luminal epithelium (LE) to establish pregnancy require a large amount of adenosine triphosphate (ATP). The creatine (Cr)-creatine kinase (CK)-phosphocreatine (PCr) system re-generates ATP in dividing and migrating cells such as the conceptus trophectoderm cells. However, little is known about metabolism of Cr within uterine and conceptus tissues in livestock species during early gestation.

Inhibition of SHMT2 mRNA translation increases embryonic mortality in sheep†.

The one-carbon metabolism (OCM) pathway provides purines and thymidine for synthesis of nucleic acids required for cell division, and S-adenosyl methionine for polyamine and creatine syntheses and the epigenetic regulation of gene expression. This study aimed to determine if serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in the OCM pathway, is critical for ovine trophectoderm (oTr) cell function and conceptus development by inhibiting translation of SHMT2 mRNA using a morpholino antisense oligonucleotide (MAO). In vitro treatment of oTr cells with MAO-SHMT2 decreased expression of SHMT2 protein, which was accompanied by reduced proliferation (P = 0.

Ovine conceptus tissue metabolizes fructose for metabolic support during the peri-implantation period of pregnancy†.

Roles of fructose in elongating ovine conceptuses are poorly understood, despite it being the major hexose sugar in fetal fluids and plasma throughout gestation. Therefore, we determined if elongating ovine conceptuses utilize fructose via metabolic pathways for survival and development. Immunohistochemical analyses revealed that trophectoderm and extra-embryonic endoderm express ketohexokinase and aldolase B during the peri-implantation period of pregnancy for conversion of fructose into fructose-1-phosphate for entry into glycolysis and related metabolic pathways.

Temporal and spatial expression of aquaporins 1, 5, 8, and 9: Potential transport of water across the endometrium and chorioallantois of pigs.

Introduction: The uterus and placenta transport water during pregnancy recognition signaling, conceptus implantation, and placental development/placentation. This is likely influenced by aquaporins (AQPs) in the reproductive tract. This study determined mRNA and cell-type specific expression of AQP 1, 5, 8, and 9 proteins in the porcine uterus and placenta.

Osteopontin (OPN)/Secreted Phosphoprotein 1 (SPP1) Binds Integrins to Activate Transport of Ions Across the Porcine Placenta.

Background: Fetal-placental development depends on a continuous and efficient supply of nutrients from maternal blood that are acquired by exchange through the placenta. However, the placenta is a low permeability barrier, and effective transport of substances depends on specific transport mechanisms. Active transport requires that ions or nutrients be moved against an electrical and/or concentration gradient.

Metabolic pathways utilized by the porcine conceptus, uterus, and placenta.

Conceptus elongation and early placentation involve growth and remodeling that requires proliferation and migration of cells. This demands conceptuses expend energy before establishment of a placenta connection and when they are dependent upon components of histotroph secreted or transported into the uterine lumen from the uterus. Glucose and fructose, as well as many amino acids (including arginine, aspartate, glutamine, glutamate, glycine, methionine, and serine), increase in the uterine lumen during the peri-implantation period.