Publications

Inflammatory cytokines have metabolic actions that probably contribute to the general adaptation of the organism during infectious or inflammatory stress. To examine the effects of interleukin 6 (IL-6), the main circulating cytokine, on glucose metabolism in man, we performed dose-response studies of recombinant human IL-6 in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/Kg BW) were injected sc in 15 healthy male volunteers (3 in each dose) after a 12-h fast. All IL-6 doses were tolerated well and produced no significant adverse effects. We measured the circulating levels of glucose, insulin, C-peptide, and glucagon at baseline and half-hourly over 4 h after the IL-6 injection. Mean peak plasma levels of IL-6 were achieved between 120 and 240 min and were 8, 22, 65, 290, and 4050 pg/mL, respectively, for the 5 doses. After administration of the 2 smaller IL-6 doses, we observed no significant changes in plasma glucose levels, which, because of continued fasting, decreased slightly over time. By 60 min after the 3 higher IL-6 doses, however, the decline in fasting blood glucose was arrested, and glucose levels increased in a dose-dependent fashion. The concurrent levels of plasma insulin and C-peptide were not affected by any IL-6 dose. In contrast, IL-6 caused significant increases in plasma glucagon levels, which peaked between 120 and 150 min after the IL-6 injection. In conclusion, sc IL-6 administration induced dose-dependent increases in fasting blood glucose, probably by stimulating glucagon release and other counteregulatory hormones and/or by inducing peripheral resistance to insulin action.

Antigen screening for the SARS-CoV-2 S1 spike protein is among the most promising tools for the mass monitoring of asymptomatic carriers of the virus, especially in limited resource environments. Herewith, we report on the possible use of the angiotensin-converting enzyme 2 (ACE2), the natural receptor and entry point of the virus, as a biorecognition element for the detection of the S1 antigen combined with an established bioelectric biosensor based on membrane-engineered cells. The working principle of our approach is based on the measurable change of the electric potential of membrane-engineered mammalian cells bearing ACE2 after attachment of the respective viral protein. We demonstrate that sensitive and selective detection of the S1 antigen is feasible in just three min, with a limit of detection of 20 fg/mL. In a preliminary clinical application, positive patient-derived samples were identified with a 87.9% score compared to RT-PCR. No cross-reactivity was observed against a wide range of nucleocapsid protein concentrations. The novel biosensor is embedded in a commercially ready-to-use testing platform, complete with the consumable immobilized cell–electrode interface and a portable read-out device operable through smartphone or tablet. In addition, the possible application of the system for the high throughput screening of potential pharmacological inhibitors of the ACE2 receptor-S1 RBD interaction is discussed.

To investigate the effect of endogenous arginine vasopressin (AVP) on ACTH secretion, normal subjects were given infusions of either hypertonic saline (HS) or isotonic saline (NS) combined with human corticotropin-releasing hormone (CRH) or placebo. Basal plasma AVP was 2.3 ± 0.3 (±se) pg/ ml, did not change with NS treatment, and rose to 5.4 ± 0.6 pg/ ml during HS infusion (P < 0.01). Both basal and CRH-stimulated plasma ACTH and cortisol concentrations increased during HS infusion. Peak plasma ACTH and cortisol levels were 11.4 ± 1.5 pg/ml and 8.6 ± 0.8 Mg/dl, respectively, during the HS (plus placebo) infusion. During the NS (plus placebo) infusion, plasma ACTH and cortisol gradually declined to 6.8 ± 0.5 pg/ml and 2.6 ± 0.4 μg/dl. The timing of the rise in ACTH during the HS infusion paralleled the rise in AVP. When an iv dose of 1 μg/kg CRH was administered during the saline infusions, peak plasma ACTH and cortisol levels were 27.7 ± 6.3 pg/ml and 17.5 ± 1.0 μg/dl, respectively, during the HS infusion and 15.6 ± 1.7 pg/ml and 13.4 ± 1.2 μg/dl during the NS infusion. When the areas under the hormone response curves were compared, CRH stimulated ACTH and cortisol secretion to a greater extent than did HS (P < 0.05). The hormonal stimulation due to combined CRH and hypertonic saline was greater than that attributable to either factor alone (P < 0.025), but was not different than the sum of the effects of the individual factors. These results indicate that increases in endogenous AVP produced by HS are associated with increases in both basal and CRH-stimulated ACTH and cortisol release. The effect of HS appears to be additive to but not consistently synergistic with the effect of CRH.

Premature aging, as denoted by a reduced telomere length (TL), has been observed in several chronic inflammatory diseases, such as obesity and type 2 diabetes mellitus (T2DM). However, no study to date has addressed the potential inflammatory influence of the gut-derived Gram-negative bacterial fragments lipopolysaccharide, also referred to as endotoxin, and its influence on TL in low-grade inflammatory states such as type 2 diabetes mellitus (T2DM). The current study therefore investigated the influence of endotoxin and inflammatory factors on telomere length (TL) in adults with (T2DM: n = 387) and without (non-diabetic (ND) controls: n = 417) obesity and T2DM. Anthropometric characteristics were taken, and fasted blood samples were used to measure biomarkers, TL, and endotoxin. The findings from this study highlighted across all participants that circulating endotoxin (r = −0.17, p = 0.01) was inversely associated with TL, noting that endotoxin and triglycerides predicted 18% of the variance perceived in TL (p &lt; 0.001). Further stratification of the participants according to T2DM status and sex highlighted that endotoxin significantly predicted 19% of the variance denoted in TL among male T2DM participants (p = 0.007), where TL was notably influenced. The influence on TL was not observed to be impacted by anti-T2DM medications, statins, or anti-hypertensive therapies. Taken together, these results show that TL attrition was inversely associated with circulating endotoxin levels independent of the presence of T2DM and other cardiometabolic factors, suggesting that low-grade chronic inflammation may trigger premature biological aging. The findings further highlight the clinical relevance of mitigating the levels of circulating endotoxin (e.g., manipulation of gut microbiome) not only for the prevention of chronic diseases but also to promote healthy aging.

Corticotropin-releasing hormone (CRH), originally isolated from the hypothalamus, is widely distributed in many extrahypothalamic central nervous system sites, and in the periphery. Immunoreactive (ir)-CRH has been identified in rat and human inflammatory sites, in rat testicular Leydig cells, and in rat thecal and stromal ovarian cells. In the current study, we investigated whether aging and stress are associated with changes in ovarian ir-CRH in the rat. Healthy young (3–4 mo) and old (24 mo) female Fischer 344/N rats (6 per group) were studied in the morning, before and after being stressed by 120 min of immobilization, and were sacrificed by decapitation. Young females were all in proestrous, and old females were in constant anestrous. Pre-immobilization corticosterone (CORT) levels were similar in both age groups; immobilization produced a dramatic increase in CORT in both groups; however, the increase was smaller in the old rats, although this did not reach statistical significance (P < 0.06). Immunoreactive CRH was detected in the ovaries of all rats, and its distribution and intensity were quantified masked to the age and treatment group, in the theca, granulosa, stroma, and corpus luteum. At baseline, ir-CRH was 50% lower in old than in young rats in the theca and stroma by both distribution and intensity. Stress was associated with a decrease of ir-CRH levels in the theca in both age groups, albeit to a significantly lesser extent in old rats (old 35% versus young 70%). These data suggest a functional and, perhaps, developmental role for ovarian CRH.

Abstract The pervasive and frequently devastating nature of aggressive behavior calls for a collective effort to understand its psychosocial and neurobiological underpinnings. Regarding the latter, diverse brain areas, neural networks, neurotransmitters, hormones, and candidate genes have been associated with antisocial and aggressive behavior in humans and animals. This review focuses on the role of monoamine oxidases (MAOs) and the genes coding for them, in the modulation of aggression. During the past 20 years, a substantial number of studies using both pharmacological and genetic approaches have linked the MAO system with aggressive and impulsive behaviors in healthy and clinical populations, including the recent discovery of MAALIN , a long noncoding RNA (lncRNA) regulating the MAO-A gene in the human brain. Here, we first provide an overview of the MAOs and their physiological functions, we then summarize recent key findings linking MAO-related enzymatic and gene activity and aggressive behavior, and, finally, we offer novel insights into the mechanisms underlying this association. Using the existing experimental evidence as a foundation, we discuss the translational implications of these findings in clinical practice and highlight what we believe are outstanding conceptual and methodological questions in the field. Ultimately, we propose that unraveling the specific role of MAO in aggression requires an integrated approach, where this question is pursued by combining psychological, radiological, and genetic/genomic assessments. The translational benefits of such an approach include the discovery of novel biomarkers of aggression and targeting the MAO system to modulate pathological aggression in clinical populations.

Nuclear receptors (NRs) are one of the most diverse and well-reported family of proteins. They are involved in numerous cellular processes as they play pivotal roles in cell signaling and the cell cycle. The participation of NRs in various applications in medicine and biology has greatly attracted the interest of the pharmaceutical industry for the discovery of novel and/or improved drugs for the treatment of several diseases, including cancer, diabetes or infertility. In the present study, in an effort to elucidate the molecular function of this superfamily and to identify novel pharmacological targets, a comprehensive sequence and structural analysis was performed using all available information from a repertoire of depositories. Functional conserved motifs were identified and analyzed with regards to their potential roles and implications in a number of biological processes. The essential differences among them were also addressed and discussed. In addition, these motifs were characterized in the main groups of the NRs, such as that of the steroid hormone receptors.

Heart rate variability i.e. the continuous oscillation of the R-R interval around its mean value can be evaluated using Poincare plots. Narrow Poincare scattergrams indicate enhanced sympathetic activity. The aim of this study was to confirm increased sympathetic tone in children with obstructive sleep apnea (OSA) by applying graphic analysis of the Poincare plot. Methods: Subjects with and without OSA were recruited. The width of the plot obtained during overnight polysomnography and the norepinephrine concentration in morning urine specimen were the outcome measures. Results: Fourty four children with OSA (24 with SpO2 nadir ≥90% or mild hypoxemia; 20 with SpO2 nadir

Abstract High concentrations of 'peripheral' benzodiazepine binding sites have been described in the pituitary gland and in several other endocrine glands, such as the adrenal glands and the testes. The role played by these receptors on the regulation of the endocrine system is largely unknown. In this study, we report the effects of two ligands of the 'peripheral' benzodiazepine receptor, Ro5-4864 and PK 11195, on prolactin (PRL) release in the adult male rat. Ro5-4864 stimulated PRL release with half maximal and maximal stimulatory doses of about 0.6 and 1.2 mg/kg, respectively. Pretreatment with the 'peripheral' benzodiazepine receptor antagonist PK 11195 did not have any effect on Ro5-4864-induced PRL release. Accordingly, PK 11195, given alone, stimulated PRL release in a dose-dependent fashion. To examine whether the stimulatory effect of Ro5-4864 and PK 11195 on PRL release was due to a direct effect of these compounds at the pituitary gland, we used primary cultures of anterior pituicytes. Neither Ro5-4864 nor PK 11195 had an effect on basal PRL release nor were these agents capable of modulating thyrotropin-releasing hormone-stimulated or dopamine-inhibited PRL release. These findings suggest that administration of agents that interact with the 'peripheral' benzodiazepine binding receptor cause PRL release without directly stimulating the pituitary gland. We speculate that Ro5-4864 and PK 11195 increase plasma PRL levels by modulating brain release of neurotransmitters and/or neuropeptides involved in the regulation of PRL release.