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Major depressive disorder is a common and devastating psychiatric disease, and the prevalence and burden are substantially increasing worldwide. Multiple studies of depression patients have implicated glucose metabolic dysfunction in the pathophysiology of depression. However, the molecular mechanisms by which glucose and related metabolic pathways modulate depressive-like behaviors are largely uncharacterized. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is a glucose metabolite with pivotal functions as a donor molecule for O-GlcNAcylation. O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, catalyzes protein posttranslational modification by O-GlcNAc and acts as a stress sensor. Here, we show that Ogt mRNA was increased in depression patients and that astroglial OGT expression was specifically upregulated in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social-defeat stress. The selective deletion of astrocytic OGT resulted in antidepressant-like effects, and moreover, astrocytic OGT in the mPFC bidirectionally regulated vulnerability to social stress. Furthermore, OGT modulated glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1) in astrocytes. OGT astrocyte-specific knockout preserved the neuronal morphology atrophy and [Ca.sup.2+] activity deficits caused by chronic stress and resulted in antidepressant effects. Our study reveals that astrocytic OGT in the mPFC regulates depressive-like behaviors through the O-GlcNAcylation of GLT-1 and could be a potential target for antidepressants., Introduction The lifetime prevalence (~17%), disability (as a leading cause), and socioeconomic burden associated with major depressive disorder (MDD) render it one of the most common and devastating psychiatric illnesses [...]

Background Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q.sub.10 (CoQ.sub.10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ.sub.10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. Case-Diagnosis/Treatment We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ.sub.10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ.sub.10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. Conclusions COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ.sub.10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition., Author(s): Michelle C. Starr [sup.1] , Irene J. Chang [sup.2] , Laura S. Finn [sup.3] , Angela Sun [sup.4] , Austin A. Larson [sup.5] , Jens Goebel [sup.6] , Coral [...]

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine whether gain of function in FAO (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) in TECs. Cpt1a- knockin (CPT1A-KI) mice subjected to 3 models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy [FAN], and adenine-induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted proinflammatory response, and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restored oxidative metabolism and mitochondrial number and enhanced bioenergetics, increasing palmitate oxidation and ATP levels, changes that were also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients showed decreased CPT1 levels and increased accumulation of short- and middlechain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD., Introduction Organ fibrosis constitutes a significantly prevalent pathological entity associated with high morbidity and mortality and presents a major biomedical challenge. Although fibrosis may affect any tissue of the human [...]

Abstract: Acetyl amantadine (AcAm) is produced from amantadine (Am) in vivo upon catalysis by spermidine/spermine [N.sup.1]-acetyl transferase (SSAT). SSAT is a biomarker for multiple aggressive cancers, and the analysis of [...]

Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 'A' allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Natl decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Natl overexpression produced opposite effects. Nat7-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Natl heterozygote mice. Our results support a role for NAT2 in insulin sensitivity., Introduction Insulin resistance (IR) is present in the vast majority of patients who eventually develop type 2 diabetes and seems to be a necessary, but not sufficient, abnormality leading to [...]