Vascular Endothelial Growth Factor-B Blockade with CSL346 in Diabetic Kidney Disease: A Phase 2A Randomized Controlled Trial.

Key Points: The vascular endothelial growth factor B inhibitor CSL346 (8 or 16 mg/kg q4w) did not reduce urinary albumin-creatinine ratio at week 16 versus placebo in patients with type 2 diabetes mellitus and diabetic kidney disease. CSL346 was generally well tolerated at both doses; however, CSL346 (16 mg/kg) significantly increased diastolic BP versus placebo.

Background: Increased vascular endothelial growth factor B (VEGF-B) expression in patients with diabetic kidney disease (DKD) is associated with increased lipid deposition in glomerular podocytes.

Privigen® has similar pharmacokinetic properties in primary and secondary immune deficiency.

Purpose: Primary (PID) and secondary immune deficiencies (SID) represent diverse groups of diagnoses, yet both can be effectively treated with intravenous immunoglobulin (IVIG) replacement therapy. Guidelines for the use of IVIG in SID vary due to the paucity of data. The objective was to analyze available IVIG Privigen® (IgPro10, CSL Behring, Bern, Switzerland) data on Efficiency Index (EI) and pharmacokinetic (PK) parameters in patients with PID and SID.

Enhancement of stress resilience through histone deacetylase 6-mediated regulation of glucocorticoid receptor chaperone dynamics.

Background: Acetylation of heat shock protein 90 (Hsp90) regulates downstream hormone signaling via the glucocorticoid receptor (GR), but the role of this molecular mechanism in stress homeostasis is poorly understood. We tested whether acetylation of Hsp90 in the brain predicts and modulates the behavioral sequelae of a mouse model of social stress.

Methods: Mice subjected to chronic social defeat stress were stratified into resilient and vulnerable subpopulations.

Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells.

EA.hy 926 cells grown under low folate conditions adopt a "pro-atherosclerotic" morphology and biochemical phenotype. Pharmacologically relevant doses of the antifolate drug methotrexate (MTX) were applied to EA.

Antidepressant-like properties of novel HDAC6-selective inhibitors with improved brain bioavailability.

HDAC inhibitors have been reported to produce antidepressant and pro-cognitive effects in animal models, however, poor brain bioavailability or lack of isoform selectivity of current probes has limited our understanding of their mode of action. We report the characterization of novel pyrimidine hydroxyl amide small molecule inhibitors of HDAC6, brain bioavailable upon systemic administration. We show that two compounds in this family, ACY-738 and ACY-775, inhibit HDAC6 with low nanomolar potency and a selectivity of 60- to 1500-fold over class I HDACs.

Pemetrexed alters folate phenotype and inflammatory profile in EA.hy 926 cells grown under low-folate conditions.

Elevated homocysteine is a risk marker for several major human pathologies. Emerging evidence suggests that perturbations of folate/homocysteine metabolism can directly modify production of inflammatory mediators. Pemetrexed acts by inhibiting thymidylate synthetase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT).

HDAC6 regulates glucocorticoid receptor signaling in serotonin pathways with critical impact on stress resilience.

Genetic variations in certain components of the glucocorticoid receptor (GR) chaperone complex have been associated with the development of stress-related affective disorders and individual variability in therapeutic responses to antidepressants. Mechanisms that link GR chaperoning and stress susceptibility are not well understood. Here, we show that the effects of glucocorticoid hormones on socioaffective behaviors are critically regulated via reversible acetylation of Hsp90, a key component of the GR chaperone complex.

Intron retention facilitates splice variant diversity in calcium-activated big potassium channel populations.

We report that the stress axis-regulated exon (STREX)-containing calcium-activated big potassium (BKCa) channel splice variant expression and physiology are regulated in part by cytoplasmic splicing and intron retention. NextGen sequencing of the mRNA complement of pooled hippocampal dendrite samples found intron 17a (i17a), the intron immediately preceding STREX, in the BKCa mRNA. Further molecular analyses of i17a revealed that the majority of i17a-containing BKCa channel mRNAs associate with STREX.

Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers.

Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atrium, but the source and mechanism of these beats remains unclear. The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium and reactive species regulation in melanocytes.

Insulin causes hyperthermia by direct inhibition of warm-sensitive neurons.

Objective: Temperature and nutrient homeostasis are two interdependent components of energy balance regulated by distinct sets of hypothalamic neurons. The objective is to examine the role of the metabolic signal insulin in the control of core body temperature (CBT).

Research Design And Methods: The effect of preoptic area administration of insulin on CBT in mice was measured by radiotelemetry and respiratory exchange ratio.

Transcriptome transfer produces a predictable cellular phenotype.

Cellular phenotype is the conglomerate of multiple cellular processes involving gene and protein expression that result in the elaboration of a cell's particular morphology and function. It has been thought that differentiated postmitotic cells have their genomes hard wired, with little ability for phenotypic plasticity. Here we show that transfer of the transcriptome from differentiated rat astrocytes into a nondividing differentiated rat neuron resulted in the conversion of the neuron into a functional astrocyte-like cell in a time-dependent manner.

Cytoplasmic BK(Ca) channel intron-containing mRNAs contribute to the intrinsic excitability of hippocampal neurons.

High single-channel conductance K+ channels, which respond jointly to membrane depolarization and micromolar concentrations of intracellular Ca2+ ions, arise from extensive cell-specific alternative splicing of pore-forming alpha-subunit mRNAs. Here, we report the discovery of an endogenous BK(Ca) channel alpha-subunit intron-containing mRNA in the cytoplasm of hippocampal neurons. This partially processed mRNA, which comprises approximately 10% of the total BK(Ca) channel alpha-subunit mRNAs, is distributed in a gradient throughout the somatodendritic space.

In vivo identification of ribonucleoprotein-RNA interactions.

To understand the role of RNA-binding proteins (RBPs) in the regulation of gene expression, methods are needed for the in vivo identification of RNA-protein interactions. We have developed the peptide nucleic acid (PNA)-assisted identification of RBP technology to enable the identification of proteins that complex with a target RNA in vivo. Specific regions of the 3' and 5' UTRs of ankylosis mRNA were targeted by antisense PNAs transported into cortical neurons by the cell-penetrating peptide transportan 10.