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Collagen is increasingly used as material for medical devices because of its excellent biocompatibility. To achieve long-term durability, the collagen materials are dried and subsequently sterilized. Most common sterilization methods are unsuitable as they cause denaturation. Currently, only ethylenoxide or γ irradiation preserves the microscopic and macroscopic collagen structure. However, both methods require high safety standards and include the risk of uncontrolled crosslinking or cleavage of protein chains. Here, supercritical carbon dioxide is used for the sterilization of different collagen devices. Thereby, the influence of pressure, temperature, sterilization aid and dosage, and different operation modes is determined. The method is a promising alternative to existing sterilization techniques. [ABSTRACT FROM AUTHOR]

Extracts from Pygeum africanum are used in the treatment of prostatitis, benign prostatic hyperplasia and prostate cancer (Pca), major health problems of men in Western countries. The ligand-activated human androgen receptor (AR) supports the growth of the prostate gland. Inhibition of human AR by androgen ablation therapy and by applying synthetic anti-androgens is therefore the primary goal in treatment of patients. Here, we show that atraric acid (AA) isolated from bark material of Pygeum africanum has anti-androgenic activity, inhibiting the transactivation mediated by the ligand-activated human AR. This androgen antagonistic activity is receptor specific and does not inhibit the closely related glucocorticoid or progesterone receptors. Mechanistically, AA inhibits nuclear transport of AR. Importantly, AA is able to efficiently repress the growth of both the androgen-dependent LNCaP and also the androgen-independent C4–2 Pca cells but not that of PC3 or CV1 cells lacking AR. In line with this, AA inhibits the expression of the endogenous prostate specific antigen gene in both LNCaP und C4–2 cells. Analyses of cell invasion revealed that AA inhibits the invasiveness of LNCaP cells through extracellular matrix. Thus, this study provides a molecular insight for AA as a natural anti-androgenic compound and may serve as a basis for AA derivatives as a new chemical lead structure for novel therapeutic compounds as AR antagonists, that can be used for prophylaxis or treatment of prostatic diseases. [ABSTRACT FROM AUTHOR]

Androgens play a central role in prostate development and prostate cancer proliferation. Induction of telomerase is an early event in prostate carcinogenesis and is considered as a marker for both primary tumors and metastases. Interestingly, several reports suggest that telomerase activity is regulated by androgens in vivo. Here, we show that the wild-type (WT) human androgen receptor (AR) inhibits the expression of the human telomerase reverse transcriptase (hTERT) and telomerase activity via inhibition of hTERT promoter activity in the presence of androgen receptor agonists. However, pure androgen antagonists failed to repress hTERT transcription. The androgenmediated repression of hTERT is abrogated in a human prostate cancer cell line exhibiting hormone-dependent growth, which expresses a mutant AR (T877A) frequently occurring in prostate cancer. We reveal that this single amino acid exchange is sufficient for the lack of transrepression. Interestingly, chromatin immunoprecipitation data suggest that, in contrast to the WT AR, the mutant AR is recruited less efficiently to the hTERT promoter in vivo, indicating that loss of transrepression results from reduced chromatin recruitment. Thus, our findings suggest that the WT AR inhibits expression of hTERT, which is indicative of a protective mechanism, whereas the T877A mutation of AR not only broadens the ligand spectrum of the receptor but abrogates this inhibitory mechanism in prostate cancer cells. This novel role of AR mutations in prostate cancer development suggests the benefit to a search for new AR antagonists that inhibit transactivation but allow transrepression. [ABSTRACT FROM AUTHOR]

Collagen is increasingly used as material for medical devices because of its excellent biocompatibility. To achieve long-term durability, the collagen materials are dried and subsequently sterilized. Most common sterilization methods are unsuitable as they cause denaturation. Currently, only ethylenoxide or γ irradiation preserves the microscopic and macroscopic collagen structure. However, both methods require high safety standards and include the risk of uncontrolled crosslinking or cleavage of protein chains. Here, supercritical carbon dioxide is used for the sterilization of different collagen devices. Thereby, the influence of pressure, temperature, sterilization aid and dosage, and different operation modes is determined. The method is a promising alternative to existing sterilization techniques. [ABSTRACT FROM AUTHOR]

The incorporation of bioactive ions into biomaterials has gained significant attention as a strategy to enhance bone tissue regeneration on the molecular level. However, little knowledge exists about the effects of the addition of these ions on the immune response and especially on the most important cellular regulators, the macrophages. Thus, this study aimed to investigate the in vitro cytocompatibility and in vivo regulation of bone remodeling and material-related immune responses of a biphasic bone substitute (BBS) coated with metal ions (Sr 2+ /Mg 2+ ) and PLGA, using the pure BBS as control group. Initially, two cytocompatible modified material variants were identified according to the in vitro results obtained following the DIN EN ISO 10993-5 protocol. The surface structure and ion release of both materials were characterized using SEM-EDX and ICP-OES. The materials were then implanted into Wistar rats for 10, 30, and 90 days using a cranial defect model. Histopathological and histomorphometrical analyses were applied to evaluate material degradation, bone regeneration, osteoconductivity, and immune response. The findings revealed that in all study groups comparable new bone formation were found. However, during the early implantation period, the BBS_Sr 2+ group exhibited significantly faster regeneration compared to the other two groups. Additionally, all materials induced comparable tissue and immune responses involving high numbers of both pro-inflammatory macrophages and multinucleated giant cells (MNGCs). In conclusion, this study delved into the repercussions of therapeutic ion doping on bone regeneration patterns and inflammatory responses, offering insights for the advancement of a new generation of biphasic calcium phosphate materials with potential clinical applicability., Competing Interests: Author SA was employed by company BerlinAnalytix GmbH. Author AK was employed by Biotrics Bioimplants AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ren, Jung, Batinic, Burckhardt, Görke, Alkildani, Köwitsch, Najman, Stojanovic, Liu, Prade and Barbeck.)

Virtually all solid tumors are dependent on a vascular network to provide them with the right amount of nutrients and oxygen. In that sense, low oxygen tension or hypoxia leads to an adaptive response that is transcriptionally regulated by the hypoxia-inducible factors (HIF), which are tightly controlled by the HIF prolyl hydroxylases (PHD). In this study, we show that inhibition of the oxygen sensor PHD2 in tumor cells stimulates vessel formation but paradoxically results in a profound reduction of tumor growth. This effect relies on the antiproliferative nature of the TGFβ signaling pathway, in a largely HIF-independent manner. Moreover, our findings reveal that PHD2 has an essential function in controlling the dual nature of TGFβ during tumorigenesis and may offer an alternative opportunity for anticancer therapy.