Depression is one of the global leading causes of disability, but treatments remain limited and classical antidepressants were found to be ineffective in a substantial proportion of patients. Thus, ...novel effective therapies for the treatment of depression are urgently needed. Given the emerging role of inflammation in the etiology and pathophysiology of affective disorders, we herein illustrate how experimental endotoxemia, a translational model of systemic inflammation, could be used as a tool to develop and test new therapeutic options against depression. Our concept is based on the striking overlap of inflammatory, neural, and affective characteristics in patients with inflammation-associated depression and in endotoxin-challenged healthy subjects. Experimental administration of endotoxin in healthy volunteers is safe, well-tolerated, and without known long-term health risks. It offers a highly standardized translational approach to characterize potential targets of therapies against inflammation-associated depression, as well as to identify characteristics of patients that would benefit from these interventions, and, therefore, could contribute to improve personalization of treatment and to increase the overall rate of responders.
Inflammation, both acute and chronic, is associated with testosterone deficiency, raising the possibility of a direct causal link. One potential trigger for inflammation in obese men is the passage ...of intestinal bacteria into the circulation due to a breakdown in mucosal barrier integrity. Recently, we hypothesized that this endotoxin exposure may cause androgen deficiency in obese men. To test this hypothesis, we analyzed the relationship between serum levels of lipopolysaccharide-binding protein (LBP), an indirect measure of endotoxin exposure, against male reproductive hormones, inflammatory markers (C-reactive protein, IL-1β, IL-6, TNF-α), and adiposity in 75 men. Adiposity was positively correlated with endotoxin exposure (LBP) and inflammation (C-reactive protein, IL-6) and negatively correlated with testosterone. Furthermore, endotoxemia (LBP) was negatively correlated with serum testosterone but positively correlated with IL-6. Multivariate analysis revealed a significant, negative correlation between serum IL-6 and free testosterone. In a second interventional study, low-dose endotoxin challenge in lean men produced a transient inflammatory response that was followed by a decline in serum testosterone, without changes in LH or FSH, providing further evidence that endotoxin-driven inflammation may result in impaired Leydig cell function.
Adverse side effects are reported by a large proportion of patients undergoing medical treatment in clinical practice or clinical trials. Nocebo effects, induced by negative treatment expectancies, ...can contribute to negative patient-reported outcomes but have rarely been studied in the context of inflammatory or immune-related conditions. Based on perceived treatment allocation, we herein analyzed nocebo responders in the placebo arms of randomized controlled double-blind experimental endotoxemia studies. We hypothesized that nocebo responders would report more bodily sickness symptoms and greater mood impairment. Out of
= 106 participants who had all received placebo injection,
= 20 (18.9%) wrongly believed they had received endotoxin and were thus considered as nocebo responders. Nocebo responders reported significantly more bodily sickness symptoms, suggesting that the perception of bodily symptoms affected perceived treatment allocation. Against our expectations, we did not find differences between nocebo responders and controls in psychological or physiological parameters. However, exploratory correlational analysis within nocebo responders revealed that more pronounced bodily sickness symptoms in response to placebo were associated with greater state anxiety and negative mood, as well as with the psychological traits catastrophizing and neuroticism. Our findings support that negative affectivity and personality-related factors may contribute to the reporting of sickness symptoms. Nonspecific symptoms experienced by patients undergoing pharmacological treatments or in randomized controlled trials can be misinterpreted and/or misattributed as unwanted side effects affecting perceived treatment allocation and presumably treatment satisfaction or its perceived efficacy. More nocebo research in the context of acute and chronic inflammatory conditions is warranted.
In this study, molecular dynamics (MD) simulations were applied to model the lipidic nanoscale droplets that form when self-emulsifying drug-delivery systems (SEDDS) disperse into microemulsions in ...the gastrointestinal (GI) tract. The influence of the excipient composition on the droplet nanostructure and on the localization of drug molecules was monitored by the drug immersion depth and the molecular association bias between hydrophilic and hydrophobic moieties. A SEDDS standard system consisting of capric (C10) fatty acid chain length triglycerides and drug molecule cyclosporin A (CyA) was compared to systematic excipient variations. Investigating the drug-loading capacity of droplets yielded a negligible influence of drug molecules on the droplet nanostructure; increasing the drug load merely resulted in increased drug exposure to the aqueous environment. The variation of triglyceride fatty acid chain lengths yielded clearly distinguishable droplet association patterns (random, lamellar-like, and vesicle-like), which could prove beneficial for predicting and engineering drug solubilization in SEDDS. The addition of surfactant poly(ethylene glycol) (PEG-6) revealed the formation of an encapsulating surfactant shell with a negligible impact on the droplet interior triglyceride nanostructure, which could potentially be utilized to protect drug molecules from digestion. Mono- and diglyceride molecules displayed an increased tendency to accumulate at the droplet surface as well, in accordance with their capacity to act as surfactants, while also significantly interfering with the interior droplet nanostructure. The addition of monoglyceride molecules in particular caused the CyA molecule to be solubilized in a hydrophilic droplet core region consisting of polar triglyceride moieties. This mode of drug localization was in stark contrast to that of other systems, where CyA was predominantly found in the interfacial region of the aqueous environment.
Translational research aiming to elucidate mediators and moderators of placebo and nocebo effects is highly relevant. This experimental study tested effects of a brief progressive muscle relaxation ...(PMR) exercise, designed to alter psychobiological stress parameters, on the magnitude of placebo and nocebo effects in a standardized psychosocial treatment context. In 120 healthy volunteers (60 men, 60 women), pain expectation, pain intensity, and pain unpleasantness in response to individually-calibrated rectal distensions were measured with visual analog scales during a baseline. Participants were then randomized to exercise PMR (relaxation group:
= 60) or a simple task (control group:
= 60), prior to receiving positive (placebo), negative (nocebo) or neutral suggestions regarding an intravenous administration that was in reality saline in all groups. Identical distensions were repeated (test). State anxiety, salivary cortisol, heart rate, and blood pressure were assessed repeatedly. Data were analyzed using analysis of covariance, planned Bonferroni-corrected group comparisons, as well as exploratory correlational and mediation analyses. Treatment suggestions induced group-specific changes in pain expectation, with significantly
expectation in placebo and
expectation in nocebo groups. PMR had no discernable effect on pain expectation, state anxiety or cortisol, but led to significantly lower heart rate and systolic blood pressure. Relaxation significantly interacted with positive treatment suggestions, which only induced placebo analgesia in relaxed participants. No effects of negative suggestions were found in planned group comparisons, irrespective of relaxation. Exploratory correlation and mediation analyses revealed that pain expectation was a mediator to explain the association between treatment suggestions and pain-related outcomes. Clearly, visceral pain modulation is complex and involves many cognitive, emotional, and possibly neurobiological factors that remain to be fully understood. Our findings suggest that a brief relaxation exercise may facilitate the induction of placebo analgesia by positive when compared to neutral treatment suggestions. They underscore the contribution of relaxation and stress as psychobiological states within the psychosocial treatment context-factors which clearly deserve more attention in translational studies aiming to maximize positive expectancy effects in clinical settings.
Highlights • LPS administration is well-established to assess behavioral aspects of inflammation. • We analyzed predictors of LPS-induced state anxiety in a large pooled sample. • LPS-induced state ...anxiety increase was predicted by greater cytokine responses. • Pre-existing anxiety symptoms predicted a lower increase in state anxiety. • Our findings support a role of inflammation in the pathophysiology of anxiety.
Candida antarctica lipase B (CalB) acts as a lipase when adsorbed to an acylglyceride interface and as an esterase when exposed to an aqueous environment. The effect of the molecular self-assembly ...nanostructure of triglyceride–water interfaces on structural conformations of adsorbed CalB and the implications to its catalytic function were studied by molecular dynamics simulations. Systems of CalB adsorbed to interfaces and solvated in water were compared. The two environments induced relative motions of helices α5 and α10 that resulted in open and closed conformations. The open conformation was stabilized by interactions between the polar and nonpolar amino acids of α5 and α10 and the nanostructure of triglyceride aggregates, which self-assembled into crystalline-like patterns of alternating polar and nonpolar lamellae. Thus, the structure of CalB has been adapted by evolution to the geometric constraints imposed by the interface nanostructure for optimized catalytic activity. Helices α5 and α10 have two functions. As mobile elements, they ensure access of bulky substrates to the active site in the open conformation. As a part of the active site pocket, they ensure binding of substrate molecules in a productive orientation near the active site. In water, access to the binding site is limited, and the smaller substrate binding site is beneficial for the binding of small, water-soluble substrates. The CalB crystal structure commonly used for protein engineering studies represents an intermediate state between open and closed, and may thus not be adequate to assess the function of CalB, neither as lipase nor as esterase.
Highlights • We tested effects of experimental endotoxemia on resting state brain activity. • Resting-state brain activity is altered during systemic inflammation. • Connectivity between the thalamus ...and the default mode network was increased. • Connectivity emanating from amygdala, insula, and cingulate cortex was reduced. • This may reflect central processes involved in restoring homeostasis.
In recent work, we discovered that the presence of highly substoichiometric amounts (10−8 molar ratio) of lipopolysaccharide (LPS) from Gram-negative bacteria caused fibrinogen clotting to lead to ...the formation of an amyloid form of fibrin. We here show that the broadly equivalent lipoteichoic acids (LTAs) from two species of Gram-positive bacteria have similarly (if not more) potent effects. Using thioflavin T fluorescence to detect amyloid as before, the addition of low concentrations of free ferric ion is found to have similar effects. Luminescent conjugated oligothiophene dyes (LCOs), marketed under the trade name Amytracker™, also stain classical amyloid structures. We here show that they too give very large fluorescence enhancements when clotting is initiated in the presence of the four amyloidogens (LPS, ferric ions and two LTA types). The staining patterns differ significantly as a function of both the amyloidogens and the dyes used to assess them, indicating clearly that the nature of the clots formed is different. This is also the case when clotting is measured viscometrically using thromboelastography. Overall, the data provide further evidence for an important role of bacterial cell wall products in the various coagulopathies that are observable in chronic, inflammatory diseases. The assays may have potential in both diagnostics and therapeutics.
Placebo responses are primarily mediated via two neuropsychological mechanisms: patients' expectation towards the benefit of a treatment and associative learning processes. Immune functions, like ...other physiological responses, can be modulated through behavioral conditioning. However, it is unknown whether learned immune responses are affected by the number of re-expositions to the conditioned stimulus (CS) during evocation. Moreover, it is unclear whether immune functions can also be modulated through mere verbally induced expectation. In the experiments reported here, we investigated in healthy male volunteers with an established model of learned immunosuppression whether a single re-exposition to the CS is able to induce a behaviorally conditioned immunosuppression. This conditioned immunosuppression is reflected through a significantly decreased interleukin (IL)-2 production by anti-CD3 stimulated peripheral blood mononuclear cells. Our data revealed that in contrast to four CS re-expositions (control group n = 15; experimental group n = 17), a single CS re-exposition was not sufficient to significantly suppress IL-2 production (control group n = 9, experimental group n = 10). Furthermore, we could demonstrate that mere expectation of taking an immunosuppressant did not cause an immunosuppressive response (n = 8-9 per expectation condition). Together, these findings extend our knowledge about the kinetics and mechanisms of placebo-induced immunosuppression and provide therewith information for designing conditioning protocols, which might be employed as a supportive therapy in clinical settings.
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