ATN blood biomarkers are related to digital cognitive assessment in type 1 diabetes.

Introduction: Associations between amyloid-tau-neurodegeneration (ATN) plasma biomarkers and cognition have not been characterized in adults with type 1 diabetes (T1D).

Methods: Using data from participants in the Glycemic Variability and Fluctuations in Cognitive Status in Adults with T1D (GluCog) study ( = 114), we evaluated associations between phosphorylated tau (pTau)181, pTau217, β-amyloid 42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) and self-administered digital cognitive tests, adjusting for age, sex, education, comorbidities (e.g.

Role for CCN1 in lysophosphatidic acid response in PC-3 human prostate cancer cells.

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are bioactive phospholipids that act as mitogens in various cancers. Both LPA and S1P activate G-protein coupled receptors (GPCRs). We examined the role of CCN1/CYR61, an inducible matricellular protein, in LPA-induced signal transduction in PC-3 human prostate cancer cells.

The (in)visible Brazilians: A perspective review on the need for brain health and dementia research with Brazilian immigrants in the United States.

Introduction: The Brazilian population in the United States (U.S.), a Latinx subgroup, is rapidly growing and aging but remains underrepresented in U.

Loss of Rbl2 (Retinoblastoma-Like 2) Exacerbates Myocardial Ischemia/Reperfusion Injury.

Background The postmitotic state of adult cardiomyocytes, maintained by the cell cycle repressor Rbl2 (retinoblastoma-like 2), is associated with considerable resistance to apoptosis. However, whether Rbl2 regulates cardiomyocyte apoptosis remains unknown. Methods and Results Here, we show that ablation of Rbl2 increased cardiomyocyte apoptosis following acute myocardial ischemia/reperfusion injury, leading to diminished cardiac function and exaggerated ventricular remodeling in the long term.

Acute and early developmental outcomes of children with Duarte galactosemia.

A recent study demonstrated that children with Duarte galactosemia (DG) do not show increased prevalence of detectable developmental complications when 6-12 years old. However, that study left unanswered whether infants with DG might be at increased risk for acute problems when drinking milk or whether children with DG younger than 6 years might show increased prevalence of perhaps transient developmental challenges. Here, we have addressed both of these questions by analyzing parent/guardian-reported data collected retrospectively for 350 children, 206 with DG and 144 unaffected siblings from the same families.

Cellular and molecular outcomes of glutamine supplementation in the brain of succinic semialdehyde dehydrogenase-deficient mice.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with low levels of glutamine in the brain, suggesting that central glutamine deficiency contributes to pathogenesis. Recently, we attempted to rescue the disease phenotype of mice, a murine model of SSADHD with dietary glutamine supplementation. No clinical rescue and no central glutamine improvement were observed.

Longitudinal metabolomics in dried bloodspots yields profiles informing newborn screening for succinic semialdehyde dehydrogenase deficiency.

Analyses of 19 amino acids, 38 acylcarnitines, and 3 creatine analogues (https://clir.mayo.edu) were implemented to test the hypothesis that succinic semialdehyde dehydrogenase deficiency (SSADHD) could be identified in dried bloodspots (DBS) using currently available newborn screening methodology.

Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use-limiting visual field defects.

Vigabatrin (VGB; 4-aminohex-5-enoic acid), an antiepileptic irreversibly inactivating GABA transaminase (GABA-T), manifests use-limiting ocular toxicity. Hypothesizing that the active enantiomer of VGB would preferentially accumulate in eye and visual cortex (VC) as one potential mechanism for ocular toxicity, we infused racemic VGB into mice via subcutaneous minipump at 35, 70, and 140 mg/kg/d (n = 6-8 animals/dose) for 12 days. VGB enantiomers, total GABA and β-alanine (BALA), 4-guanidinobutyrate (4-GBA), and creatine were quantified by mass spectrometry in eye, brain, liver, prefrontal cortex (PFC), and VC.

Chronic alcohol consumption exacerbates murine cytomegalovirus infection via impairing nonspecific and specific NK activation in mice.

Chronic alcohol consumption increases the susceptibility to infectious diseases by compromising the immune system. Cytomegalovirus infection is common in humans and usually is asymptomatic in immunocompetent people. However, it can induce life-threatening medical complications in immunocompromised individuals such as alcoholics.

In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17-dihydroexemestane.

Exemestane (EXE) is an endocrine therapy commonly used by postmenopausal women with hormone-responsive breast cancer due to its potency in inhibiting aromatase-catalyzed estrogen synthesis. Preliminary in vitro studies sought to identify phase I EXE metabolites and hepatic cytochrome P450s (CYP450s) that participate in EXE biotransformation. Phase I metabolites were identified by incubating EXE with HEK293-overexpressed CYP450s.

Exemestane potency is unchanged by common nonsynonymous polymorphisms in CYP19A1: results of a novel anti-aromatase activity assay examining exemestane and its derivatives.

Exemestane (EXE) treats estrogen receptor positive (ER+) breast cancer in postmenopausal women by inhibiting the estrogen-synthesizing cytochrome P450 CYP19A1. Variability in the severity and incidence of side effects as well as overall drug efficacy may be partially explained by genetic factors, including nonsynonymous variation in CYP19A1, also known as aromatase. The present study identified phase I EXE metabolites in human liver microsomes (HLM) and investigated mechanisms that may alter the extent of systemic estrogen deprivation in EXE-treated women with breast cancer, including whether functional polymorphisms in aromatase cause differential inhibition by EXE and whether EXE metabolites possess anti-aromatase activity.

A pharmacokinetic evaluation and metabolite identification of the GHB receptor antagonist NCS-382 in mouse informs novel therapeutic strategies for the treatment of GHB intoxication.

Gamma-aminobutyric acid (GABA) is an endogenous inhibitory neurotransmitter and precursor of gamma-hydroxybutyric acid (GHB). NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzo-cyclohept-6-ylideneacetic acid), a known GHB receptor antagonist, has shown significant efficacy in a murine model of succinic semialdehyde dehydrogenase deficiency (SSADHD), a heritable neurological disorder featuring chronic elevation of GHB that blocks the final step of GABA degradation. NCS-382 exposures and elimination pathways remain unknown; therefore, the goal of the present work was to obtain in vivo pharmacokinetic data in a murine model and to identify the NCS-382 metabolites formed by mouse and human.