C81-evoked inhibition of the TNFR1-NFκB pathway during inflammatory processes for stabilization of the impaired vascular endothelial barrier for leukocytes.

Chronic inflammation-related diseases are characterized by persistent leukocyte infiltration into the underlying tissue. The vascular endothelium plays a major role in this pathophysiological condition. Only few therapeutic strategies focus on the vascular endothelium as a major target for an anti-inflammatory approach. In this study, we present the natural compound-derived carbazole derivative C81 as chemical modulator interfering with leukocyte-endothelial cell interactions. An in vivo assay employing intravital microscopy to monitor leukocyte trafficking after C81 treatment in postcapillary venules of a murine cremaster muscle was performed. Moreover, in vitro assays using HUVECs and monocytes were implemented. The impact of C81 on cell adhesion molecules and the NFκB signaling cascade was analyzed in vitro in endothelial cells. Effects of C81 on protein translation were determined by incorporation of a puromycin analog-based approach and polysome profiling. We found that C81 significantly reduced TNF-activated leukocyte trafficking in postcapillary venules. Similar results were obtained in vitro when C81 reduced leukocyte-endothelial cell interactions by down-regulating cell adhesion molecules. Focusing on the NFκB signaling cascade, we found that C81 reduced the activation on multiple levels of the cascade through promoted IκBα recovery by attenuation of IκBα ubiquitination and through reduced protein levels of TNFR1 caused by protein translation inhibition. We suggest that C81 might represent a promising lead compound for interfering with inflammation-related processes in endothelial cells by down-regulation of IκBα ubiquitination on the one hand and inhibition of translation on the other hand without exerting cytotoxic effects.

Ginger Constituent 6-Shogaol Inhibits Inflammation- and Angiogenesis-Related Cell Functions in Primary Human Endothelial Cells.

Rhizomes from Zingiber officinale Roscoe are traditionally used for the treatment of a plethora of pathophysiological conditions such as diarrhea, nausea, or rheumatoid arthritis. While 6-gingerol is the pungent principle in fresh ginger, in dried rhizomes, 6-gingerol is dehydrated to 6-shogaol. 6-Shogaol has been demonstrated to exhibit anticancer, antioxidative, and anti-inflammatory actions more effectively than 6-gingerol due to the presence of an electrophilic Michael acceptor moiety. In vitro, 6-shogaol exhibits anti-inflammatory actions in a variety of cell types, including leukocytes. Our study focused on the effects of 6-shogaol on activated endothelial cells. We found that 6-shogaol significantly reduced the adhesion of leukocytes onto lipopolysaccharide (LPS)-activated human umbilical vein endothelial cells (HUVECs), resulting in a significantly reduced transmigration of THP-1 cells through an endothelial cell monolayer. Analyzing the mediators of endothelial cell-leukocyte interactions, we found that 30 µM of 6-shogaol blocked the LPS-triggered mRNA and protein expression of cell adhesion molecules. In concert with this, our study demonstrates that the LPS-induced nuclear factor κB (NFκB) promoter activity was significantly reduced upon treatment with 6-shogaol. Interestingly, the nuclear translocation of p65 was slightly decreased, and protein levels of the LPS receptor Toll-like receptor 4 remained unimpaired. Analyzing the impact of 6-shogaol on angiogenesis-related cell functions in vitro, we found that 6-shogaol attenuated the proliferation as well as the directed and undirected migration of HUVECs. Of note, 6-shogaol also strongly reduced the chemotactic migration of endothelial cells in the direction of a serum gradient. Moreover, 30 µM of 6-shogaol blocked the formation of vascular endothelial growth factor (VEGF)-induced endothelial sprouts from HUVEC spheroids and from murine aortic rings. Importantly, this study shows for the first time that 6-shogaol exhibits a vascular-disruptive impact on angiogenic sprouts from murine aortae. Our study demonstrates that the main bioactive ingredient in dried ginger, 6-shogaol, exhibits beneficial characteristics as an inhibitor of inflammation- and angiogenesis-related processes in vascular endothelial cells.

Causal illness attributions in somatoform disorders: associations with comorbidity and illness behavior.

OBJECTIVE: To compare causal illness beliefs between patients with unexplained physical symptoms and different comorbid disorders and to assess the association of causal illness beliefs with illness behavior. METHODS: We examined a sample of 233 patients attending treatment in primary care. Inclusion criteria were "unexplained physical symptoms." All patients were investigated using structured interviews and self-rating scales [Screening for Somatoform Symptoms (SOMS), Beck Depression Inventory (BDI), Beck Anxiety Inventory, and a 12-item instrument to assess causal attributions]. By means of factor analysis, the following illness attributions were considered: vulnerability to infection and environmental factors, psychological factors, organic causes including genetic and aging factors, and distress (including exhaustion and time pressure). RESULTS: Most patients reported multiple illness attributions. The more somatoform symptoms patients had, the more explanations in general they considered. Especially for vulnerability and organic illness beliefs, patients with somatoform symptoms had increased scores. Comorbidity with depression and with anxiety disorders was associated with more psychological attributions. Even when the influence of somatization, depression, and anxiety is controlled for, illness beliefs still showed associations with illness behavior. Organic causal beliefs and vulnerability attributions were associated with a need for medical diagnostic examinations, increased expression of symptoms, increased illness consequences, and bodily scanning. CONCLUSIONS: Multiple causal attributions can coexist demonstrating different associations with comorbid depression and illness behavior.

Patients with medically unexplained symptoms and their significant others: illness attributions and behaviors as predictors of patient functioning over time.

OBJECTIVE: Previous research suggests that medically unexplained symptoms (MUS) are maintained in an interpersonal context. The current study examined MUS concurrently and prospectively by measuring specific interpersonal predictors of symptom severity and health care use. METHODS: A total of 127 patients with MUS and their significant others were recruited through primary care offices and assessed with self-report questionnaires and structured interviews about illness attributions, illness behavior and responses, relationship quality, symptom severity, and health care use at baseline and 6-month follow-up. RESULTS: Illness attributions and interpersonal illness behaviors of patients with MUS were cross-sectionally associated with illness attributions and responses of the patients' significant others. Relationship quality was related to specific illness behaviors and responses. Symptom severity at baseline was predicted by patients' somatic illness attributions. Symptom severity at 6-month follow-up was predicted by somatic illness attributions of patients and withdrawal of patients' significant others at baseline, but these predictors became insignificant when correcting for baseline symptomatology. Health care use at baseline was predicted by a greater amount of coping behavior and higher anxiety scores of patients, and health care use at 6-month follow-up was predicted by more attention-seeking behaviors and health care use of patients at baseline. CONCLUSION: The results document the interpersonal influences on the maintenance of MUS. The perspective of significant others should be considered for enhancement of psychological approaches to the treatment of patients with MUS.

Evaluation of general practitioners' training: how to manage patients with unexplained physical symptoms.

Patients with unexplained physical symptoms ("somatoform disorders") tend to overuse the healthcare system. Therefore, the authors aimed to assess whether a training session for general practitioners (GPs) on managing patients with unexplained physical symptoms would be acceptable to GPs and lead to improvements in patient care. In a randomized clinical trial (GPs randomized), GPs got a 1-day training session and additional materials. Included were 26 GP offices in primary care and 295 patients with unexplained physical symptoms (minimum of two symptoms required). Outcome measures were healthcare utilization (number of doctor visits) 6 months before and 6 months after the index visit to the GP, somatization severity, depression, and hypochondriacal fears at the index visit to the GP's office and 6 months later. Training GPs to manage these patients led to significant reductions in healthcare utilization; patients of untrained GPs showed comparable attendance rates in the 6 months before and after the index visit. Differences in depression, somatization, and hypochondriacal fears, however, could not be attributed to the GP training. GPs rated the training as being highly relevant for their everyday practices, underlining the need for and acceptance of the training. Training GPs in managing patients with unexplained physical symptoms seems to be helpful for the reduction of excessive healthcare utilization. These 1-day workshops have high acceptability, so this approach could be a good model for empirically-validated continuing-education programs.