Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction.

BACKGROUND: The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension. AIMS: These adverse vascular/ metabolic events under clozapine are similar to those caused by polycyclic aromatic hydrocarbons (PAHs), and clozapine shows structural similarity to well-known ligands of the aryl hydrocarbon receptor (AhR). Therefore, we speculated that the side effects caused by clozapine might rely on AhR signaling. METHODS: We examined clozapine-induced AhR activation by luciferase reporter assays in hepatoma HepG2 cells and we proved upregulation of the prototypical AhR target gene Cyp1A1 by realtime-PCR (RT-PCR) analysis and enzyme activity. Next we studied the physiological role of AhR in clozapine's effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-/- mice. RESULTS: In contrast to other antipsychotic drugs (APDs), clozapine triggered AhR activation and Cyp1A1 expression in HepG2 cells and adipocytes. Clozapine induced adipogenesis via AhR signaling. After PGF2α-induced constriction of mouse aortic rings, clozapine strongly reduced the maximal vasorelaxation under acetylcholine in rings from wild-type mice, but only slightly in rings from AhR-/- mice. The reduction was also prevented by pretreatment with the AhR antagonist CH-223191. CONCLUSION: Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.

[Social Security Needs Social Medicine: Self-image of Physicians Practicing Social Medicine in Statutory Health Insurances and Social Security Systems]. / Soziale Sicherheit braucht Sozialmedizin Selbstverständnis von Ärztinnen und Ärzten in der sozialmedizinischen Begutachtung und Beratung.

OBJECTIVE: In January, 2014, the division "Social Medicine in Practice and Rehabilitation" of the German Society for Social Medicine and Prevention established a working group on the self-image of the physicians active in the field of social medicine (medical expertise and counseling). METHODS: The result of this work is the contribution presented here after consensus was achieved by specialists of social medicine from different fields and institutions (social security etc.) and in good cooperation with Prof. Dr. Gostomzyk and Prof. Dr. Robra. RESULTS: Based on the importance of an up to date social medicine for claimants and recipients of benefits on the one hand and the social security system on the other, and also on a description of the subjects, objectives and methods the following aspects are presented: · The perspective of social medicine. · Qualification in social medicine, concerning specialist training and continuing medical education. · The fields of duty of experts in social medicine. · The proceedings in social medicine. The working group identified challenges for the specialists in social medicine by a narrowed perception of social medicine by physicians in hospitals and practice, accompanied by an enlarged importance of expertise in social medicine, by the demand for more "patient orientation" and gain of transparency, and concerning the scientific foundation of social medicine. CONCLUSIONS: The working group postulates: · The perspective of social medicine should be spread more widely.. · Confidence in experts of social medicine and their independency should be strengthened.. · The not case-related consulting of the staff and executives should be expanded.. · Social medicine in practice needs support by politics and society, and especially by research and teaching.. · Good cooperation and transfer of experiences of the different branches of social security are essential for the impact of social medicine..

L-arginine and arginine ethyl ester enhance proliferation of endothelial cells and preadipocytes - how an arginine ethyl ester-releasing biomaterial could support endothelial cell growth in tissue engineering.

Adipose tissue engineering is a promising solution for the reconstruction of soft tissue defects. An insufficient neovascularisation within the scaffolds that leads to necrosis and tissue loss is still a major shortcoming of current tissue engineering attempts. Biomaterials, which release angiogenic factors such as L-arginine, could overcome this challenge by supporting the neovascularisation of the constructs. L-arginine is insoluble in organic solvents and thus cannot be incorporated into commonly used polymers in contrast to its ethyl ester. Here, we compared the effects of arginine and its ethyl ester on endothelial cells and preadipocytes, and generated an arginine ethyl ester-releasing, angiogenic polymer. We cultivated adipose tissue-derived endothelial cells and preadipocytes in arginine-free medium supplemented with L-arginine or L-arginine ethyl ester and assayed the proliferation rate and the degree of adipogenic differentiation, respectively. Additionally, we prepared arginine ethyl ester-releasing poly(D,L-lactide) foils, and investigated their impact on endothelial cell proliferation. We could demonstrate that arginine ethyl ester like arginine significantly increased the proliferation of endothelial cells and preadipocytes without inhibiting an induced adipogenic conversion of the preadipocytes. Further, we could show that the arginine ethyl ester-releasing polymer significantly increased endothelial cell growth. The present data are helpful guidance for generating angiogenic biomaterials that promote endothelial cell growth, and thereby could support neovascularisation within tissue engineering approaches.

Zymosan-induced inflammation stimulates neo-adipogenesis.

OBJECTIVE: To investigate the potential of inflammation to induce new adipose tissue formation in the in vivo environment. METHODS AND RESULTS: Using an established model of in vivo adipogenesis, a silicone chamber containing a Matrigel and fibroblast growth factor 2 (1 microg/ml) matrix was implanted into each groin of an adult male C57Bl6 mouse and vascularized with the inferior epigastric vessels. Sterile inflammation was induced in one of the two chambers by suspending Zymosan-A (ZA) (200-0.02 microg/ml) in the matrix at implantation. Adipose tissue formation was assessed at 6, 8, 12 and 24 weeks. ZA induced significant adipogenesis in an inverse dose-dependent manner (P<0.001). At 6 weeks adipose tissue formation was greatest with the lowest concentrations of ZA and least with the highest. Adipogenesis occurred both locally in the chamber containing ZA and in the ZA-free chamber in the contralateral groin of the same animal. ZA induced a systemic inflammatory response characterized by elevated serum tumour necrosis factor-alpha levels at early time points. Aminoguanidine (40 microg/ml) inhibited the adipogenic response to ZA-induced inflammation. Adipose tissue formed in response to ZA remained stable for 24 weeks, even when exposed to the normal tissue environment. CONCLUSIONS: These results demonstrate that inflammation can drive neo-adipogenesis in vivo. This suggests the existence of a positive feedback mechanism in obesity, whereby the state of chronic, low-grade inflammation, characteristic of the condition, may promote further adipogenesis. The mobilization and recruitment of a circulating population of adipose precursor cells is likely to be implicated in this mechanism.

Polyesteramide-derived nonwovens as innovative degradable matrices support preadipocyte adhesion, proliferation, and differentiation.

Extended soft tissue defects resulting from injuries or tumor resections are still an unresolved problem in plastic and reconstructive surgery because adequate reconstruction is difficult. Immature adipogenic precursor cells, called preadipocytes, which are located between mature adipocytes in adipose tissue, represent a powerful tool for soft tissue engineering because of their ability to proliferate and differentiate into adipose tissue after transplantation. In previous studies, we compared preadipocyte-loaded hyaluronan or collagen biomaterials and their applicability for adipose tissue engineering. Our findings demonstrated successful de novo formation of adipose tissue in vivo but pore size and stiffness were limiting factors not allowing for sufficient cell distribution in the construct. This study presents a nonwoven made of novel bioabsorbable co-poly(ester amide) based on e-caprolactam, adipic acid, and 1,4-butanediol in an innovative 3-dimensional architecture. The material was formed into nonwovens by textile manufacturing using an aerodynamic web formation process and a needle felting technique. Carriers were seeded with human preadipocytes and examined for cellular proliferation and differentiation. In addition, methods of preparing scaffolds for optimal cell interaction were evaluated. Our findings show that polyesteramide-derived nonwovens allow good adherence, proliferation, and differentiation of preadipocytes. These results are promising guidance toward an optimally designed scaffold for in vivo use.

Preadipocyte-loaded collagen scaffolds with enlarged pore size for improved soft tissue engineering.

Extended soft tissue defects after extensive deep burns or tumor resections are still an unresolved problem in plastic and reconstructive surgery. There is a clinical need for an adequate solution to this problem but currently, no adequate implant material is available for the correction of these defects. Since the autologous transplantation of mature adipose tissue gives poor results, this study explores the advantages of using human preadipocytes in collagen sponges for tissue reconstruction purposes. Human preadipocytes of young adults were isolated, cultured, seeded onto collagen sponges with uniform pore size, and implanted into immunodeficient mice. After 24 hours of incubation in vitro and after explantation at 3, 8, and 12 weeks, sponges were examined for macroscopic appearance, weight, thickness, histology, immuno-histochemistry, and ultrastructure. We find good penetration of cells into the scaffold, layers of adipose tissue, and new vessels on all grafts while controls appear unchanged. These results are promising for improving the reconstruction of soft tissue defects.