Hypoxia (i.e. oxygen deprivation) activates the hypoxia-signalling pathway, primarily via hypoxia-inducible transcription factors (HIF) for numerous target genes, which mediate angiogenesis, metabolism and coagulation, among other processes to try to replenish tissues with blood and oxygen. Hypoxia signalling dysregulation also commonly occurs during chronic inflammation. We sampled gingival tissues from rhesus monkeys (Macaca mulatta; 3-25 years old) and total RNA was isolated for microarray analysis. HIF1A, HIF1B and HIF2A were significantly different in healthy aged tissues, and both HIF1A and HIF3A were positively correlated with aging. Beyond these transcription factor alterations, analysis of patterns of gene expression involved in hypoxic changes in tissues showed specific increases in metabolic pathway hypoxia-inducible genes, whereas angiogenesis pathway gene changes were more variable in healthy aging tissues across the animals. With periodontitis, aging tissues showed decreases in metabolic gene expression related to carbohydrate/lipid utilization (GBE1, PGAP1, TPI1), energy metabolism and cell cycle regulation (IER3, CCNG2, PER1), with up-regulation of transcription genes and cellular proliferation genes (FOS, EGR1, MET, JMJD6) that are hypoxia-inducible. The potential clinical implications of these results are related to the epidemiological findings of increased susceptibility and expression of periodontitis with aging. More specifically the findings describe that hypoxic stress may exist in aging gingival tissues before documentation of clinical changes of periodontitis and, so, may provide an explanatory molecular risk factor for an elevated capacity of the tissues to express destructive processes in response to changes in the microbial biofilms characteristic of a more pathogenic microbial challenge.

Some metabolic pathways are nearly ubiquitous among organisms: the genes encoding the enzymes for such pathways must therefore be ancient and essential. De novo pyrimidine biosynthesis is an example of one such metabolic pathway. In animals a single protein called CAD carries the first three steps of this pathway. The same three enzymes in prokaryotes are associated with separate proteins. The CAD gene appears to have evolved through a process of gene duplication and DNA rearrangement, leading to an in-frame gene fusion encoding a chimeric protein. A driving force for the creation of eukaryotic genes encoding multienzymatic proteins such as CAD may be the advantage of coordinate expression of enzymes catalyzing steps in a biosynthetic pathway. The analogous structure in bacteria is the operon. Differences in the translational mechanisms of eukaryotes and prokaryotes may have dictated the different strategies used by organisms to evolve coordinately regulated genes.

Impairment of vascular pathways of cerebral β-amyloid (Aβ) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aβ clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aβ co-deposits. LRP1-mediated Aβ transport across the blood-brain barrier and Aβ clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aβ deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aβ pathology.

Background Mitochondrial dysfunction contributes to the cardiac remodeling triggered by type 2 diabetes (T2D). Mitochondrial Ca 2+ concentration ([Ca 2+ ] m ) modulates the oxidative state and cytosolic Ca 2+ regulation. Thus, we investigated how T2D affects mitochondrial Ca 2+ fluxes, the downstream consequences on myocyte function, and the effects of normalizing mitochondrial Ca 2+ transport. Methods and Results We compared myocytes/hearts from transgenic rats with late‐onset T2D (rats that develop late‐onset T2D due to heterozygous expression of human amylin in the pancreatic β‐cells [HIP] model) and their nondiabetic wild‐type (WT) littermates. [Ca 2+ ] m was significantly lower in myocytes from diabetic HIP rats compared with WT cells. Ca 2+ extrusion through the mitochondrial Na + /Ca 2+ exchanger (mitoNCX) was elevated in HIP versus WT myocytes, particularly at moderate and high [Ca 2+ ] m , while mitochondrial Ca 2+ uptake was diminished. Mitochondrial Na + concentration was comparable in WT and HIP rat myocytes and remained remarkably stable while manipulating mitoNCX activity. Lower [Ca 2+ ] m was associated with oxidative stress, increased sarcoplasmic reticulum Ca 2+ leak in the form of Ca 2+ sparks, and mitochondrial dysfunction in T2D hearts. MitoNCX inhibition with CGP‐37157 reduced oxidative stress, Ca 2+ spark frequency, and stress‐induced arrhythmias in HIP rat hearts while having no significant effect in WT rats. In contrast, activation of the mitochondrial Ca 2+ uniporter with SB‐202190 enhanced spontaneous sarcoplasmic reticulum Ca 2+ release and had no significant effect on arrhythmias in both WT and HIP rat hearts. Conclusions [Ca 2+ ] m is reduced in myocytes from rats with T2D due to a combination of exacerbated mitochondrial Ca 2+ extrusion through mitoNCX and impaired mitochondrial Ca 2+ uptake. Partial mitoNCX inhibition limits sarcoplasmic reticulum Ca 2+ leak and arrhythmias in T2D hearts, whereas mitochondrial Ca 2+ uniporter activation does not.

Many supplemental Se-dependent metabolic effects are mediated through the function of selenoproteins. The full complement and relative abundance of selenoproteins expressed by highly metabolic cattle tissues have not been characterized in cattle. The complement and number of selenoprotein mRNA transcripts expressed by the pituitary and liver of healthy growing beef steers (n = 7 to 8) was characterized using NanoString methodology (Study 1). Of the 25 known bovine selenoproteins, 24 (all but SELENOH) were expressed by the pituitary and 23 (all but SELENOH and SELENOV) by the liver. Transcript abundance ranged (P ≤ 0.05) over 5 orders of magnitude in the pituitary (> 10,000 for GPX3, < 10 for DIO1 and GPX2) and liver (> 35,000 for SELENOP, < 10 for DIO2). Also unknown is the sensitivity of the selenoprotein transcriptome to the form of supplemental Se. The effect of form of supplemental Se on the relative content of selenoprotein mRNA species in the pituitary and liver of steers grazing a Se-deficient (0.07 ppm Se) tall fescue pasture and consuming 85 g/d of a basal vitamin-mineral mix that contained 35 ppm Se as either ISe (n = 6), organically-bound Se (SELPLEX; OSe, n = 7 to 8), or a 1:1 blend of ISe and OSe (MIX, n = 7 to 8) was determined by RT-PCR after sequence-validating the 25 bovine selenoprotein cDNA products (Study 2). In the pituitary, Se form affected (P < 0.05) the relative content of 9 selenoprotein mRNAs and 2 selenoprotein P receptor mRNAs in a manner consistent with a greater capacity to manage against oxidative damage, maintain cellular redox balance, and have a better control of protein-folding in the pituitaries of OSe and MIX versus ISe steers. In the liver, expression of 5 selenoprotein mRNA was affected (P ≤ 0.05) in a manner consistent with MIX steers having greater redox signaling capacity and capacity to manage oxidative damage than ISe steers. We conclude that inclusion of 3 mg Se/d as OSe or MIX versus ISe, forms of supplemental Se in vitamin-mineral mixes alters the selenoprotein transcriptome in a beneficial manner in both the pituitary and liver of growing steers consuming toxic endophyte-infected tall fescue.