Stabilization of angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system (RAAS), is a promising candidate as a treatment for cancer that reflects its antiproliferative and anti-angiogenic properties. However, the peptide’s therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer

Perioperative Quality Initiative (POQI) consensus statement on fundamental concepts in perioperative fluid management: fluid responsiveness and venous capacitance

Background: Optimal fluid therapy in the perioperative and critical care settings depends on understanding the underlying cardiovascular physiology and individualizing assessment of the dynamic patient state. Methods: The Perioperative Quality Initiative (POQI-5) consensus conference brought together an international team of multidisciplinary experts to survey and evaluate the literature on the physiology of volume responsiveness and perioperative fluid management. The group used a modified Delphi method to develop consensus statements applicable to the physiologically based management of intravenous fluid therapy in the perioperative setting. Discussion: We discussed the clinical and physiological evidence underlying fluid responsiveness and venous capacitance as relevant factors in fluid management and developed consensus statements with clinical implications for a broad group of clinicians involved in intravenous fluid therapy. Two key concepts emerged as follows: (1) The ultimate goal of fluid therapy and hemodynamic management is to support the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) optimal fluid and hemodynamic management is dependent on an understanding of the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties

An Integrative Approach to Understanding Counterproductive Work Behavior: The Roles of Stressors, Negative Emotions, and Moral Disengagement

Several scholars have highlighted the importance of examining moral disengagement (MD) in understanding aggression and deviant conduct across different contexts. The present study investigates the role of MD as a specific social-cognitive construct that, in the organizational context, may intervene in the process leading from stressors to counterproductive work behavior (CWB). Assuming the theoretical framework of the stressor-emotion model of CWB, we hypothesized that MD mediates, at least partially, the relation between negative emotions in reaction to perceived stressors and CWB by promoting or justifying aggressive responses to frustrating situations or events. In a sample of 1,147 Italian workers, we tested a structural equations model. The results support our hypothesis: the more workers experienced negative emotions in response to stressors, the more they morally disengaged and, in turn, enacted CW

Perioperative fluid and volume management: physiological basis, tools and strategies

Fluid and volume therapy is an important cornerstone of treating critically ill patients in the intensive care unit and in the operating room. New findings concerning the vascular barrier, its physiological functions, and its role regarding vascular leakage have lead to a new view of fluid and volume administration. Avoiding hypervolemia, as well as hypovolemia, plays a pivotal role when treating patients both perioperatively and in the intensive care unit. The various studies comparing restrictive vs. liberal fluid and volume management are not directly comparable, do not differ (in most instances) between colloid and crystalloid administration, and mostly do not refer to the vascular barrier's physiologic basis. In addition, very few studies have analyzed the use of advanced hemodynamic monitoring for volume management

Reproductive Hormone-Dependent and -Independent Contributions to Developmental Changes in Kisspeptin in GnRH-Deficient Hypogonadal Mice

Kisspeptin is a potent activator of GnRH-induced gonadotropin secretion and is a proposed central regulator of pubertal onset. In mice, there is a neuroanatomical separation of two discrete kisspeptin neuronal populations, which are sexually dimorphic and are believed to make distinct contributions to reproductive physiology. Within these kisspeptin neuron populations, Kiss1 expression is directly regulated by sex hormones, thereby confounding the roles of sex differences and early activational events that drive the establishment of kisspeptin neurons. In order to better understand sex steroid hormone-dependent and -independent effects on the maturation of kisspeptin neurons, hypogonadal (hpg) mice deficient in GnRH and its downstream effectors were used to determine changes in the developmental kisspeptin expression. In hpg mice, sex differences in Kiss1 mRNA levels and kisspeptin immunoreactivity, typically present at 30 days of age, were absent in the anteroventral periventricular nucleus (AVPV). Although immunoreactive kisspeptin increased from 10 to 30 days of age to levels intermediate between wild type (WT) females and males, corresponding increases in Kiss1 mRNA were not detected. In contrast, the hpg arcuate nucleus (ARC) demonstrated a 10-fold increase in Kiss1 mRNA between 10 and 30 days in both females and males, suggesting that the ARC is a significant center for sex steroid-independent pubertal kisspeptin expression. Interestingly, the normal positive feedback response of AVPV kisspeptin neurons to estrogen observed in WT mice was lost in hpg females, suggesting that exposure to reproductive hormones during development may contribute to the establishment of the ovulatory gonadotropin surge mechanism. Overall, these studies suggest that the onset of pubertal kisspeptin expression is not dependent on reproductive hormones, but that gonadal sex steroids critically shape the hypothalamic kisspeptin neuronal subpopulations to make distinct contributions to the activation and control of the reproductive hormone cascade at the time of puberty

Microcirculatory alterations: potential mechanisms and implications for therapy

Multiple experimental and human trials have shown that microcirculatory alterations are frequent in sepsis. In this review, we discuss the characteristics of these alterations, the various mechanisms potentially involved, and the implications for therapy. Sepsis-induced microvascular alterations are characterized by a decrease in capillary density with an increased number of stopped-flow and intermittent-flow capillaries, in close vicinity to well-perfused capillaries. Accordingly, the surface available for exchange is decreased but also is highly heterogeneous. Multiple mechanisms may contribute to these alterations, including endothelial dysfunction, impaired inter-cell communication, altered glycocalyx, adhesion and rolling of white blood cells and platelets, and altered red blood cell deformability. Given the heterogeneous nature of these alterations and the mechanisms potentially involved, classical hemodynamic interventions, such as fluids, red blood cell transfusions, vasopressors, and inotropic agents, have only a limited impact, and the microcirculatory changes often persist after resuscitation. Nevertheless, fluids seem to improve the microcirculation in the early phase of sepsis and dobutamine also can improve the microcirculation, although the magnitude of this effect varies considerably among patients. Finally, maintaining a sufficient perfusion pressure seems to positively influence the microcirculation; however, which mean arterial pressure levels should be targeted remains controversial. Some trials using vasodilating agents, especially nitroglycerin, showed promising initial results but they were challenged in other trials, so it is difficult to recommend the use of these agents in current practice. Other agents can markedly improve the microcirculation, including activated protein C and antithrombin, vitamin C, or steroids. In conclusion, microcirculatory alterations may play an important role in the development of sepsis-related organ dysfunction. At this stage, therapies to target microcirculation specifically are still being investigated

Inhibition of the Progesterone Nuclear Receptor during the Bone Linear Growth Phase Increases Peak Bone Mass in Female Mice

Augmentation of the peak bone mass (PBM) may be one of the most effective interventions to reduce the risk of developing osteoporosis later in life; however treatments to augment PBM are currently limited. Our study evaluated whether a greater PBM could be achieved either in the progesterone nuclear receptor knockout mice (PRKO) or by using a nuclear progesterone receptor (nPR) antagonist, RU486 in mice. Compared to their wild type (WT) littermates the female PRKO mice developed significantly higher cancellous and cortical mass in the distal femurs, and this was associated with increased bone formation. The high bone mass phenotype was partially reproduced by administering RU486 in female WT mice from 1–3 months of age. Our results suggest that the inhibition of the nPR during the rapid bone growth period (1–3 months) increases osteogenesis, which results in acquisition of higher bone mass. Our findings suggest a crucial role for progesterone signaling in bone acquisition and inhibition of the nPR as a novel approach to augment bone mass, which may have the potential to reduce the burden of osteoporosis