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Diabetic kidney disease (DKD) is the leading cause of end‐stage kidney disease. DKD is a heterogeneous disease with complex pathophysiology where early endothelial dysfunction is associated with disease progression. The Tie2 receptor and Angiopoietin 1 and 2 ligands are critical for maintaining endothelial cell permeability and integrity. Tie2 signaling is negatively regulated by the endothelial specific transmembrane receptor Vascular Endothelial Protein Tyrosine Phosphatase (VEPTP). Genetic deletion of VEPTP protects from hypertension and diabetes induced renal injury in a mouse model of DKD. Here, we show that VEPTP inhibition with an extracellular domain targeting VEPTP antibody induced Tie2 phosphorylation and improved VEGF‐A induced vascular permeability both in vitro and in vivo. Treatment with the VEPTP blocking antibody decreased the renal expression of endothelial activation markers (Angpt2, Edn1, and Icam1) but failed to improve kidney function in db/db uninephrectomized ReninAAV DKD mice. [ABSTRACT FROM AUTHOR]

Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2[sup.Brdm1] mutant mice, which have a deletion in the PAS domain of the Per2 protein, show alterations in the glutamatergic system. Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes. As a consequence, glutamate levels increase in the extracellular space of Per2[sup.Brdm1] mutant mouse brains. This is accompanied by increased alcohol intake in these animals. In humans, variations of the PER2 gene are associated with regulation of alcohol consumption. Acamprosate, a drug used to prevent craving and relapse in alcoholic patients is thought to act by dampening a hyper-glutamatergic state. This drug reduced augmented glutamate levels and normalized increased alcohol consumption in Per2[sup.Brdm1] mutant mice. Collectively, these data establish glutamate as a link between dysfunction of the circadian clock gene Per2 and enhanced alcohol intake., Author(s): Rainer Spanagel (corresponding author) [1]; Gurudutt Pendyala [2]; Carolina Abarca [1, 3]; Tarek Zghoul [1]; Carles Sanchis-Segura [1]; Maria Chiara Magnone [2]; Jesus Lascorz [1]; Martin Depner [1]; David [...]

Bertolucci, Cristiano, Valeria Anna Sovrano, Maria Chiara Magnone, and Augusto Foa. Role of suprachiasmatic nuclei in circadian and light-entrained behavioral rhythms of lizards. Am J Physiol Regulatory Integrative Comp Physiol 279: R2121-R2131, 2000.--To establish whether the suprachiasmatic nuclei (SCN) of the Ruin lizard (Podarcis sicula) play a role in entrainment of circadian rhythms to light, we examined the effects of exposure to 24-h light-dark (LD) cycles on the locomotor behavior of lizards with SCN lesions. Lizards became arrhythmic in response to complete SCN lesion under constant temperature and constant darkness (DD), and they remained arrhythmic after exposure to LD cycles. Remnants of SCN tissue in other lesioned lizards were sufficient to warrant entrainment to LD cycles. Hence, the SCN of Ruin lizards are essential both to maintain locomotor rhythmicity and to mediate entrainment of these rhythms to light. We also asked whether light causes expression of Fos-like immunoreactivity (Fos-LI) in the SCN. Under LD cycles, the SCN express a daily rhythm in Fos-LI. Because Fos-LI is undetectable in DD, the rhythm seen in LD cycles is caused by light. We further showed that unilateral SCN lesions in DD induce dramatic period changes. Altogether, the present data support the existence of a strong functional similarity between the SCN of lizards and the SCN of mammals. photic entrainment; Fos; circadian rhythms; locomotor activity

Background: The role of myeloperoxidase in chronic kidney disease (CKD) and its association with coronary artery disease (CAD) is controversial. In this study, we compared myeloperoxidase and protein-bound 3-chlorotyrosine (ClY) levels in subjects with varying degrees of CKD and tested their associations with CAD.Methods: From Clinical Phenotyping Resource and Biobank Core, 111 patients were selected from CKD stages 1 to 5. Plasma myeloperoxidase level was measured using enzyme-linked-immunosorbent assay. Plasma protein-bound 3-ClY, a specific product of hypochlorous acid generated by myeloperoxidase was measured by liquid chromatography mass spectrometry.Results: We selected 29, 20, 24, 22, and 16 patients from stages 1 to 5 CKD, respectively. In a sex-adjusted general linear model, mean ± SD of myeloperoxidase levels decreased from 18.1 ± 12.3 pmol in stage 1 to 10.9 ± 4.7 pmol in stage 5 (p = 0.011). In patients with and without CAD, the levels were 19.1 ± 10.1 and 14.8 ± 8.7 pmol (p = 0.036). There was an increase in 3-ClY mean from 0.81 ± 0.36 mmol/mol-tyrosine in stage 1 to 1.42 ± 0.41 mmol/mol-tyrosine in stage 5 (p < 0.001). The mean 3-ClY levels in patients with and without CAD were 1.25 ± 0.44 and 1.04 ± 0.42 mmol/mol-tyrosine (p = 0.023), respectively. C-statistic of ClY when added to myeloperoxidase level to predict CKD stage 5 was 0.86, compared to 0.79 for the myeloperoxidase level alone (p = 0.0097).Conclusion: The myeloperoxidase levels decrease from stages 1 to 5, whereas activity increases. In contrast, both myeloperoxidase and ClY levels rise in the presence of CAD at various stages of CKD. Measuring both plasma myeloperoxidase and 3-CLY levels provide added value to determine the burden of myeloperoxidase-mediated oxidative stress. [ABSTRACT FROM AUTHOR]

Primary human hepatocytes are widely used as an in vitro system for the assessment of drug metabolism and toxicity. Nevertheless a cell system with higher stability of physiological functions is required for the investigation of drugs’ mode of action, pathway analyses and biomarkers evaluations. We recently discovered that the human hepatocellular carcinoma cell line, HepG2/C3A, cultured as spheroids in a 3D system can recover their main functions after trypsinisation within about 18 days. The objective of this study was to investigate whether the spheroids’ metabolic functions remained stable after this recovery period. Therefore we evaluated physiological capabilities of the spheroids (cell survival, growth rate, glycogenesis, ATP, cholesterol and urea synthesis and drug metabolism) and the expression of key genes related to the main liver pathways in spheroids cultured for an additional 24 days after full recovery (day 18). Here we show that after the recovery period, the 3D spheroid culture can provide a metabolically competent homeostatic cell model which is in equilibrium with its culture environment for more than 3 weeks. Such a stable system could be used for the assessment of the drugs’ mode of action, for biomarkers evaluation and for any systems biology studies which require medium- to long-term stability of metabolic functions [ABSTRACT FROM AUTHOR]

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The article presents a reprint of the article "Short commentary on 'a consensus protocol for the standardization of cerebrospinal fluid collection and biobanking', " by C. E. Teunissen and colleagues, which appeared in the previous issue of the journal. It discusses a study about a standardization protocol for biobanking and cerebrospinal fluid (CSF) collection. It provides tables that depict guidelines for CSF withdrawal and information requirements of patients with multiple sclerosis (MS).

Background: The present study has investigated the protein tyrosine phosphatase H1 (PTPH1) expression pattern in mouse brain and its impact on CNS functions. Methods: We have previously described a PTPH1-KO mouse, generated by replacing the PTP catalytic and the PDZ domain with a LacZ neomycin cassette. PTPH1 expression pattern was evaluated by LacZ staining in the brain and PTPH1-KO and WT mice (n = 10 per gender per genotype) were also behaviorally tested for CNS functions. Results: In CNS, PTPH1 is expressed during development and in adulthood and mainly localized in hippocampus, thalamus, cortex and cerebellum neurons. The behavioral tests performed on the PTPH1-KO mice showed an impact on working memory in male mice and an impaired learning performance at rotarod in females. Conclusion: These results demonstrate for the first time a neuronal expression of PTPH1 and its functionality at the level of cognition. [ABSTRACT FROM AUTHOR]

Single biweekly injections of exogenous melatonin were given to ruin lizards (Podarcis sicula) whose circadian locomotor rhythms were recorded under constant temperature (29°C) and darkness. To generate a phase-response curve the direction and amount of phase shift were plotted versus the time at which the injection was given. The results showed, for the second time in the animal kingdom, the existence of a phase-response curve for melatonin. The area under the delay part of the phase-response curve is much greater than the area under the advance part, and there is no dead zone. The phase-response curve for melatonin was generated in summer, but the repetition of experiments in autumn-winter did not generate any phase-response curve for melatonin in these seasons. In autumn-winter no one phase of the ruin lizards' circadian cycle was shifted in response to melatonin injections. This confirms several previous results in ruin lizards, showing that melatonin is centrally involved in determining circadian organization in summer and only marginally involved in autumn-winter. [ABSTRACT FROM AUTHOR]