A Comprehensive Review of Recent Research into the Effects of Antimicrobial Peptides on Biofilms-January 2020 to September 2023.

Microbial biofilm formation creates a persistent and resistant environment in which microorganisms can survive, contributing to antibiotic resistance and chronic inflammatory diseases. Increasingly, biofilms are caused by multi-drug resistant microorganisms, which, coupled with a diminishing supply of effective antibiotics, is driving the search for new antibiotic therapies. In this respect, antimicrobial peptides (AMPs) are short, hydrophobic, and amphipathic peptides that show activity against multidrug-resistant bacteria and biofilm formation. They also possess broad-spectrum activity and diverse mechanisms of action. In this comprehensive review, 150 publications (from January 2020 to September 2023) were collected and categorized using the search terms 'polypeptide antibiotic agent', 'antimicrobial peptide', and 'biofilm'. During this period, a wide range of natural and synthetic AMPs were studied, of which LL-37, polymyxin B, GH12, and Nisin were the most frequently cited. Furthermore, although many microbes were studied, Staphylococcus aureus and Pseudomonas aeruginosa were the most popular. Publications also considered AMP combinations and the potential role of AMP delivery systems in increasing the efficacy of AMPs, including nanoparticle delivery. Relatively few publications focused on AMP resistance. This comprehensive review informs and guides researchers about the latest developments in AMP research, presenting promising evidence of the role of AMPs as effective antimicrobial agents.

The history of circadian rhythm research in Austria.

In view of the recent revival of interest in circadian biology and circadian epidemiology at the Medical University of Vienna, it seems appropriate to highlight the rich and pioneering history of circadian research in Austria. Among the forefathers of circadian research in Vienna are Otto Marburg (1874-1948), who discovered important elements of the pineal gland physiology, Robert Hofstätter (1883-1970), who used pineal gland extract in obstetrics/gynecology, and Paul Engel (1907-1997), who discovered that the pineal gland was controlled by light. More recently, Vera Lapin (1920-2007) showed that surgical removal of the pineal gland increased tumor growth, while Franz Waldhauser (*1946) investigated melatonin in conjunction with night work. Michael Kundi (*1950) and his team conducted among the first studies demonstrating differences in rhythms of night workers and early evidence for health impairments among them. Furthermore, Vienna-born Erhard Haus (1926-2013) pioneered the discovery of the role and importance of melatonin in relation to numerous diseases. This rich pioneering contribution of scientists in Vienna or with roots in Vienna is continued today by a new generation of chronobiologists, epidemiologists and clinicians in Vienna whose new insights contribute to the rapidly developing field of circadian rhythms research. Current topics and contributions relate to the impact of circadian rhythm disruption on health, and the application of chronotherapeutic approaches in clinical and preventive settings.

Antibody Conjugates Bispecific for Pollen Allergens and ICAM-1 with Potential to Prevent Epithelial Allergen Transmigration and Rhinovirus Infection.

Allergy and rhinovirus (RV) infections are major triggers for rhinitis and asthma, causing a socioeconomic burden. As RVs and allergens may act synergistically to promote airway inflammation, simultaneous treatment strategies for both causative agents would be innovative. We have previously identified the transmembrane glycoprotein intercellular adhesion molecule 1 (ICAM-1) as an anchor for antibody conjugates bispecific for ICAM-1 and Phleum pratense (Phl p) 2, a major grass pollen allergen, to block allergen transmigration through the epithelial barrier. Since ICAM-1 is a receptor for the major group RVs, we speculated that our bispecific antibody conjugates may protect against RV infection. Therefore, we created antibody conjugates bispecific for ICAM-1 and the major grass pollen allergen Phl p 5 and analyzed their capacity to affect allergen penetration and RV infection. Bispecific antibody conjugates significantly reduced the trans-epithelial migration of Phl p 5 and thus the basolateral Phl p 5 concentration and allergenic activity as determined by humanized rat basophilic leukemia cells and inhibited RV infection of cultured epithelial cells. A reduction in allergenic activity was obtained only through the prevention of allergen transmigration because the Phl p 5-specific IgG antibody did not block the allergen-IgE interaction. Our results indicate the potential of allergen/ICAM-1-specific antibody conjugates as a topical treatment strategy for allergy and RV infections.

Plumbagin and Plumbago indica Differentially Modulated Cytochrome P450 and Transporter Profiles in BeWo and HepG2 Cells.

<b>Background and Objective:</b> The medicinal herb <i>Plumbago indica</i> (PI) and its major constituent plumbagin have reported pharmacological properties but there is a lack of information about their herb-drug interactions. The effects of methanolic (PI-MeOH) and ethanolic (PI-EtOH) crude extracts of PI and plumbagin on the expression of cytochrome P450s (<i>CYP1A2</i>, <i>CYP2E1</i> and <i>CYP3A4</i>) and transporters (<i>ABCC1</i>, <i>ABCG2</i> and <i>SLC22A11</i>) were investigated in BeWo and HepG2 cells. <b>Materials and Methods:</b> BeWo or HepG2 cells were treated with 0.5-5 µM plumbagin or 25-500 µg mL¹ of PI-MeOH or PI-EtOH for 24 hrs. Total RNA was extracted and mRNA expression of CYPs and transporters were determined using RT-qPCR. <b>Results:</b> PI and plumbagin affected mRNA expression differently in the two tested cell types. In BeWo cells, all concentrations of PI-MeOH induced <i>CYP2E1</i>, 100 and 500 µg Ml¹ PI-MeOH and PI-EtOH up-regulated <i>CYP1A2</i>, <i>CYP3A4 </i>and <i>ABCG2 </i>and 500 µg mL¹ PI-EtOH induced <i>ABCG2</i> expression. Plumbagin suppressed <i>CYP1A2</i> and induced <i>SLC22A11 </i>expression at the highest concentration, 5 µM. In HepG2 cells, 5 µM plumbagin and 500 µg Ml¹ PI-EtOH suppressed <i>CYP3A4 </i>expression and 500 µg mL¹ PI-MeOH and PI-EtOH up-regulated <i>CYP1A2</i> and <i>CYP2E1 </i>expression. <i>ABCC1</i> expression was induced by all treatments while <i>ABCG2</i> and <i>SLC22A11 </i>were induced only by 500 µg mL¹ PI-MeOH and PI-EtOH. <b>Conclusion:</b> The use of PI or plumbagin supplements in large quantities or for long periods should be carefully considered due to the risk of herbal drug interactions via modulated expression of CYPs and transporters.

MoNuSAC2020: A Multi-Organ Nuclei Segmentation and Classification Challenge.

Detecting various types of cells in and around the tumor matrix holds a special significance in characterizing the tumor micro-environment for cancer prognostication and research. Automating the tasks of detecting, segmenting, and classifying nuclei can free up the pathologists' time for higher value tasks and reduce errors due to fatigue and subjectivity. To encourage the computer vision research community to develop and test algorithms for these tasks, we prepared a large and diverse dataset of nucleus boundary annotations and class labels. The dataset has over 46,000 nuclei from 37 hospitals, 71 patients, four organs, and four nucleus types. We also organized a challenge around this dataset as a satellite event at the International Symposium on Biomedical Imaging (ISBI) in April 2020. The challenge saw a wide participation from across the world, and the top methods were able to match inter-human concordance for the challenge metric. In this paper, we summarize the dataset and the key findings of the challenge, including the commonalities and differences between the methods developed by various participants. We have released the MoNuSAC2020 dataset to the public.

Amino Acid Transporter LAT1 (SLC7A5) Mediates MeHg-Induced Oxidative Stress Defense in the Human Placental Cell Line HTR-8/SVneo.

The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter (LAT)1 is involved in placental MeHg uptake, accepting MeHg-L-cysteine conjugates as substrate due to structural similarity to methionine. The aim of the present study was to investigate the antioxidant defense of placental cells to MeHg exposure and the role of LAT1 in this response. When trophoblast-derived HTR-8/SVneo cells were LAT1 depleted by siRNA-mediated knockdown, they accumulated less MeHg. However, they were more susceptible to MeHg-induced toxicity. This was evidenced in decreased cell viability at a usually noncytotoxic concentration of 0.03 µM MeHg (~6 µg/L). Treatment with ≥0.3 µM MeHg increased cytotoxicity, apoptosis rate, and oxidative stress of HTR-8/SVneo cells. These effects were enhanced under LAT1 knockdown. Reduced cell number was seen when MeHg-exposed cells were cultured in medium low in cysteine, a constituent of the tripeptide glutathione (GSH). Because LAT1-deficient HTR-8/SVneo cells have lower GSH levels than control cells (independent of MeHg treatment), we conclude that LAT1 is essential for de novo synthesis of GSH, required to counteract oxidative stress. Genetic predisposition to decreased LAT1 function combined with MeHg exposure could increase the risk of placental damage.

Human placental cell line HTR-8/SVneo accumulates cadmium by divalent metal transporters DMT1 and ZIP14.

Cadmium (Cd) is a global pollutant that accumulates in the placenta and can cause placental dysfunction. Although iron transporters have been suggested to participate in placental Cd uptake, it is still unknown which transporters are actually involved in this process. We specifically aimed to study the role of three iron transporters in the uptake of Cd into the placental cell line HTR-8/SVneo. For this purpose, Divalent Metal Transporter (DMT)1 and ZRT/IRT like protein (ZIP)8 and ZIP14 were downregulated and changes in cellular Cd levels analysed in relation to controls. As clearly shown by the reduction of the Cd content by ∼60% in DMT1- and ZIP14-downregulated cells, the two proteins are essential for Cd accumulation in HTR-8/SVneo cells. Using a validated antibody, we show DMT1 to be localised in situ in trophoblast and stromal cells. We further wanted to investigate how placental cells cope with Cd loading and which metallothionein (MT) isoforms they express. Cd-exposed cells accumulate Cd in a dose-dependent manner and upregulate MT2A accordingly (up to 15-fold induction upon 5 µM CdCl2 treatment for 72 h). 5 µM Cd exposure for 72 h decreased cell number to 60%, an effect that was aggravated by MT2A depletion (cell number reduced to 30%) indicating additive effects. In conclusion, our data suggest that DMT1 and ZIP14 are required for Cd uptake into human placental cells that upregulate MT2A to store and detoxify the metal. Cd storage in the placenta reduces Cd transport to the fetus, which, however, could impair placental functions and fetal development.

In vitro function and in situ localization of Multidrug Resistance-associated Protein (MRP)1 (ABCC1) suggest a protective role against methyl mercury-induced oxidative stress in the human placenta.

Methyl mercury (MeHg) is an organic highly toxic compound that is transported efficiently via the human placenta. Our previous data suggest that MeHg is taken up into placental cells by amino acid transporters while mercury export from placental cells mainly involves ATP binding cassette (ABC) transporters. We hypothesized that the ABC transporter multidrug resistance-associated protein (MRP)1 (ABCC1) plays an essential role in mercury export from the human placenta. Transwell transport studies with MRP1-overexpressing Madin-Darby Canine Kidney (MDCK)II cells confirmed the function of MRP1 in polarized mercury efflux. Consistent with this, siRNA-mediated MRP1 gene knockdown in the human placental cell line HTR-8/SVneo resulted in intracellular mercury accumulation, which was associated with reduced cell viability, accompanied by increased cytotoxicity, apoptosis, and oxidative stress as determined via the glutathione (GSH) status. In addition, the many sources claiming different localization of MRP1 in the placenta required a re-evaluation of its localization in placental tissue sections by immunofluorescence microscopy using an MRP1-specific antibody that was validated in-house. Taken together, our results show that (1) MRP1 preferentially mediates apical-to-basolateral mercury transport in epithelial cells, (2) MRP1 regulates the GSH status of placental cells, (3) MRP1 function has a decisive influence on the viability of placental cells exposed to low MeHg concentrations, and (4) the in situ localization of MRP1 corresponds to mercury transport from maternal circulation to the placenta and fetus. We conclude that MRP1 protects placental cells from MeHg-induced oxidative stress by exporting the toxic metal and by maintaining the placental cells' GSH status in equilibrium.

The effects of skin lesion segmentation on the performance of dermatoscopic image classification.

BACKGROUND AND OBJECTIVE: Malignant melanoma (MM) is one of the deadliest types of skin cancer. Analysing dermatoscopic images plays an important role in the early detection of MM and other pigmented skin lesions. Among different computer-based methods, deep learning-based approaches and in particular convolutional neural networks have shown excellent classification and segmentation performances for dermatoscopic skin lesion images. These models can be trained end-to-end without requiring any hand-crafted features. However, the effect of using lesion segmentation information on classification performance has remained an open question. METHODS: In this study, we explicitly investigated the impact of using skin lesion segmentation masks on the performance of dermatoscopic image classification. To do this, first, we developed a baseline classifier as the reference model without using any segmentation masks. Then, we used either manually or automatically created segmentation masks in both training and test phases in different scenarios and investigated the classification performances. The different scenarios included approaches that exploited the segmentation masks either for cropping of skin lesion images or removing the surrounding background or using the segmentation masks as an additional input channel for model training. RESULTS: Evaluated on the ISIC 2017 challenge dataset which contained two binary classification tasks (i.e. MM vs. all and seborrheic keratosis (SK) vs. all) and based on the derived area under the receiver operating characteristic curve scores, we observed four main outcomes. Our results show that 1) using segmentation masks did not significantly improve the MM classification performance in any scenario, 2) in one of the scenarios (using segmentation masks for dilated cropping), SK classification performance was significantly improved, 3) removing all background information by the segmentation masks significantly degraded the overall classification performance, and 4) in case of using the appropriate scenario (using segmentation for dilated cropping), there is no significant difference of using manually or automatically created segmentation masks. CONCLUSIONS: We systematically explored the effects of using image segmentation on the performance of dermatoscopic skin lesion classification.

Transfer learning using a multi-scale and multi-network ensemble for skin lesion classification.

BACKGROUND AND OBJECTIVE: Skin cancer is among the most common cancer types in the white population and consequently computer aided methods for skin lesion classification based on dermoscopic images are of great interest. A promising approach for this uses transfer learning to adapt pre-trained convolutional neural networks (CNNs) for skin lesion diagnosis. Since pre-training commonly occurs with natural images of a fixed image resolution and these training images are usually significantly smaller than dermoscopic images, downsampling or cropping of skin lesion images is required. This however may result in a loss of useful medical information, while the ideal resizing or cropping factor of dermoscopic images for the fine-tuning process remains unknown. METHODS: We investigate the effect of image size for skin lesion classification based on pre-trained CNNs and transfer learning. Dermoscopic images from the International Skin Imaging Collaboration (ISIC) skin lesion classification challenge datasets are either resized to or cropped at six different sizes ranging from 224 × 224 to 450 × 450. The resulting classification performance of three well established CNNs, namely EfficientNetB0, EfficientNetB1 and SeReNeXt-50 is explored. We also propose and evaluate a multi-scale multi-CNN (MSM-CNN) fusion approach based on a three-level ensemble strategy that utilises the three network architectures trained on cropped dermoscopic images of various scales. RESULTS: Our results show that image cropping is a better strategy compared to image resizing delivering superior classification performance at all explored image scales. Moreover, fusing the results of all three fine-tuned networks using cropped images at all six scales in the proposed MSM-CNN approach boosts the classification performance compared to a single network or a single image scale. On the ISIC 2018 skin lesion classification challenge test set, our MSM-CNN algorithm yields a balanced multi-class accuracy of 86.2% making it the currently second ranked algorithm on the live leaderboard. CONCLUSIONS: We confirm that the image size has an effect on skin lesion classification performance when employing transfer learning of CNNs. We also show that image cropping results in better performance compared to image resizing. Finally, a straightforward ensembling approach that fuses the results from images cropped at six scales and three fine-tuned CNNs is shown to lead to the best classification performance.

Fish-derived low molecular weight components modify bronchial epithelial barrier properties and release of pro-inflammatory cytokines.

The prevalence of fish allergy among fish-processing workers is higher than in the general population, possibly due to sensitization via inhalation and higher exposure. However, the response of the bronchial epithelium to fish allergens has never been explored. Parvalbumins (PVs) from bony fish are major sensitizers in fish allergy, while cartilaginous fish and their PVs are considered less allergenic. Increasing evidence demonstrates that components other than proteins from the allergen source, such as low molecular weight components smaller than 3 kDa (LMC) from pollen, may act as adjuvants during allergic sensitization. We investigated the response of bronchial epithelial cells to PVs and to LMC from Atlantic cod, a bony fish, and gummy shark, a cartilaginous fish. Polarized monolayers of the bronchial epithelial cell line 16HBE14o- were stimulated apically with fish PVs and/-or the corresponding fish LMC. Barrier integrity, transport of PVs across the monolayers and release of mediators were monitored. Intact PVs from both the bony and the cartilaginous fish were rapidly internalized by the cells and transported to the basolateral side of the monolayers. The PVs did not disrupt the epithelial barrier integrity nor did they modify the release of proinflammatory cytokines. In contrast, LMC from both fish species modified the physical and immunological properties of the epithelial barrier and the responses differed between bony and cartilaginous fish. While the barrier integrity was lowered by cod LMC 24 h after cell stimulation, it was increased by up to 2.3-fold by shark LMC. Furthermore, LMC from both fish species increased basolateral and apical release of IL-6 and IL-8, while CCL2 release was increased by cod but not by shark LMC. In summary, our study demonstrated the rapid transport of PVs across the epithelium which may result in their availability to antigen presenting cells required for allergic sensitization. Moreover, different cell responses to LMC derived from bony versus cartilaginous fish were observed, which may play a role in different allergenic potentials of these two fish classes.

Fusing fine-tuned deep features for skin lesion classification.

Malignant melanoma is one of the most aggressive forms of skin cancer. Early detection is important as it significantly improves survival rates. Consequently, accurate discrimination of malignant skin lesions from benign lesions such as seborrheic keratoses or benign nevi is crucial, while accurate computerised classification of skin lesion images is of great interest to support diagnosis. In this paper, we propose a fully automatic computerised method to classify skin lesions from dermoscopic images. Our approach is based on a novel ensemble scheme for convolutional neural networks (CNNs) that combines intra-architecture and inter-architecture network fusion. The proposed method consists of multiple sets of CNNs of different architecture that represent different feature abstraction levels. Each set of CNNs consists of a number of pre-trained networks that have identical architecture but are fine-tuned on dermoscopic skin lesion images with different settings. The deep features of each network were used to train different support vector machine classifiers. Finally, the average prediction probability classification vectors from different sets are fused to provide the final prediction. Evaluated on the 600 test images of the ISIC 2017 skin lesion classification challenge, the proposed algorithm yields an area under receiver operating characteristic curve of 87.3% for melanoma classification and an area under receiver operating characteristic curve of 95.5% for seborrheic keratosis classification, outperforming the top-ranked methods of the challenge while being simpler compared to them. The obtained results convincingly demonstrate our proposed approach to represent a reliable and robust method for feature extraction, model fusion and classification of dermoscopic skin lesion images.

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta.

The steroid hormones progestagens, estrogens, androgens, and glucocorticoids as well as their precursor cholesterol are required for successful establishment and maintenance of pregnancy and proper development of the fetus. The human placenta forms at the interface of maternal and fetal circulation. It participates in biosynthesis and metabolism of steroids as well as their regulated exchange between maternal and fetal compartment. This review outlines the mechanisms of human placental handling of steroid compounds. Cholesterol is transported from mother to offspring involving lipoprotein receptors such as low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SRB1) as well as ATP-binding cassette (ABC)-transporters, ABCA1 and ABCG1. Additionally, cholesterol is also a precursor for placental progesterone and estrogen synthesis. Hormone synthesis is predominantly performed by members of the cytochrome P-450 (CYP) enzyme family including CYP11A1 or CYP19A1 and hydroxysteroid dehydrogenases (HSDs) such as 3ß-HSD and 17ß-HSD. Placental estrogen synthesis requires delivery of sulfate-conjugated precursor molecules from fetal and maternal serum. Placental uptake of these precursors is mediated by members of the solute carrier (SLC) family including sodium-dependent organic anion transporter (SOAT), organic anion transporter 4 (OAT4), and organic anion transporting polypeptide 2B1 (OATP2B1). Maternal-fetal glucocorticoid transport has to be tightly regulated in order to ensure healthy fetal growth and development. For that purpose, the placenta expresses the enzymes 11ß-HSD 1 and 2 as well as the transporter ABCB1. This article also summarizes the impact of diverse compounds and diseases on the expression level and activity of the involved transporters, receptors, and metabolizing enzymes and concludes that the regulatory mechanisms changing the physiological to a pathophysiological state are barely explored. The structure and the cellular composition of the human placental barrier are introduced. While steroid production, metabolism and transport in the placental syncytiotrophoblast have been explored for decades, few information is available for the role of placental-fetal endothelial cells in these processes. With regard to placental structure and function, significant differences exist between species. To further decipher physiologic pathways and their pathologic alterations in placental steroid handling, proper model systems are mandatory.

Estrogen-enhanced apical and basolateral secretion of apolipoprotein B-100 by polarized trophoblast-derived BeWo cells.

Cholesterol is an important nutrient for fetal development and transplacental transport occurs at all stages of human pregnancy. Furthermore, cholesterol is required for membrane building as well as steroid hormone synthesis. Therefore, all placental cell types require cholesterol for proper function. In human term placenta, the syncytiotrophoblast (STB) faces the maternal circulation. Uptake of maternal-derived cholesterol at the apical membrane of the STB is well understood, but the route by which cholesterol exits at the basal side for subsequent transfer across the fetal endothelial cells (FEC) or to other placental cell types remains not well characterized. Our aim was to provide evidence for basal secretion of apolipoprotein B-100 (apoB) containing lipoproteins. Furthermore, we investigated the placental localization of apolipoprotein receptors (LRP2, LDLR and LRP1) to identify cell targets of lipoprotein particles secreted in a polarized fashion by the STB. In trophoblast-derived BeWo cells grown on permeable filter supports, we demonstrate by immunoprecipitation apical as well as basolateral apoB secretion, which was significantly upregulated by estrogen-treatment for 24 or 48 h. Furthermore, we showed by immunofluorescence microscopy apoB and microsomal triglyceride transfer protein subunits localization in the STB and placental stromal cells in situ. All investigated receptors were detected by RT-qPCR and western blot in BeWo cells, but only expression of LRP2 was estrogen-inducible. In situ, the multi-ligand receptor LRP2 was expressed exclusively in the cytotrophoblast (CTB), the STB precursor cell type. LDLR and LRP1 localized to trophoblasts as well as stromal cells in situ. In summary, basal apoB secretion by BeWo cells supports the concept of basal lipoprotein particle secretion by placental STB. These lipoprotein particles may serve as cholesterol source for STB precursor cells, the CTBs, as well as all stromal cells of the chorionic villi including FECs, which were herein demonstrated to express apoB receptors, LRP2 and LDLR, respectively.

Mercury toxicokinetics of the healthy human term placenta involve amino acid transporters and ABC transporters.

BACKGROUND: The capacity of the human placenta to handle exogenous stressors is poorly understood. The heavy metal mercury is well-known to pass the placenta and to affect brain development. An active transport across the placenta has been assumed. The underlying mechanisms however are virtually unknown. OBJECTIVES: Uptake and efflux transporters (17 candidate proteins) assumed to play a key role in placental mercury transfer were examined for expression, localization and function in human primary trophoblast cells and the trophoblast-derived choriocarcinoma cell line BeWo. METHODS: To prove involvement of the transporters, we used small interfering RNA (siRNA) and exposed cells to methylmercury (MeHg). Total mercury contents of cells were analyzed by Cold vapor-atomic fluorescence spectrometry (CV-AFS). Localization of the proteins in human term placenta sections was determined via immunofluorescence microscopy. RESULTS: We found the amino acid transporter subunits L-type amino acid transporter (LAT)1 and rBAT (related to b(0,+) type amino acid transporter) as well as the efflux transporter multidrug resistance associated protein (MRP)1 to be involved in mercury kinetics of trophoblast cells (t-test P<0.05). CONCLUSION: The amino acid transporters located at the apical side of the syncytiotrophoblast (STB) manage uptake of MeHg. Mercury conjugated to glutathione (GSH) is effluxed via MRP1 localized to the basal side of the STB. The findings can well explain why mercury is transported primarily towards the fetal side.

Immunology of Osteoporosis: A Mini-Review.

Osteoporosis is a major cause of fractures and associated morbidity in the aged population. The pathogenesis of osteoporosis is multifactorial; whereas traditional pathophysiological concepts emphasize endocrine mechanisms, it has been recognized that also components of the immune system have a significant impact on bone. Since 2000, when the term 'osteoimmunology' was coined, novel insights into the role of inflammatory cytokines by influencing the fine-tuned balance between bone resorption and bone formation have helped to explain the occurrence of osteoporosis in conjunction with chronic inflammatory reactions. Moreover, the phenomenon of a low-grade, chronic, systemic inflammatory state associated with aging has been defined as 'inflamm-aging' by Claudio Franceschi and has been linked to age-related diseases such as osteoporosis. Given the tight anatomical and physiological coexistence of B cells and the bone-forming units in the bone marrow, a role of B cells in osteoimmunological interactions has long been suspected. Recent findings of B cells as active regulators of the RANK/RANKL/OPG axis, of altered RANKL/OPG production by B cells in HIV-associated bone loss or of a modulated expression of genes linked to B-cell biology in response to estrogen deficiency support this assumption. Furthermore, oxidative stress and the generation of advanced glycation end products have emerged as links between inflammation and bone destruction.

HFcRn-mediated transplacental immunoglobulin G transport: protection of and threat to the human fetus and newborn.

In human newborns, endogenous levels of plasma immunoglobulin G (IgG) begin to rise slowly after birth following exposure to the environment. For immunoprotection during fetal and early neonatal life, maternal IgG is provided by transplacental transport. While cellular immunoprotective IgG effects are mainly triggered by FcγRI, -RII and -RIII, transplacental IgG transfer is mediated by the MHC class I-like neonatal Fc-receptor, hFcRn. This compact review explains the mechanism of hFcRn-mediated IgG transcytosis across the placental barrier - syncytiotrophoblast and fetal endothelial cells. Restrictions of this IgG transport are summarized. These include IgG subclass discrimination and limited IgG transport before the third trimester that can cause insufficient protection from infections of preterm (≤ 35 th week) delivered babies. As hFcRn does not discriminate beneficial from hazardous IgGs, maternal auto- and alloimmune as well as therapeutic antibodies can reach the fetus. The consequences including severe diseases of the newborn are summarized in this article.

The analysis of organic anion transporting polypeptide (OATP) mRNA and protein patterns in primary and metastatic liver cancer.

Organic anion transporting polypeptides (OATP, SLCO genes) mediate the uptake of endobiotics and drugs. Thus, their expression levels and pattern could be of relevance for cancer therapy. This prompted us to investigate the expression of poorly characterized OATPs, namely OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in hepatic cancer of different origin. First, mRNA levels of all eleven OATPs were determined in paired (cancerous and adjacent non-cancerous) specimens from 43 patients with primary liver cancer (hepatocellular carcinoma, HCC; cholangiocellular carcinoma, CCC) and liver metastases from colon tumors (MLT). Real-time RT-PCR analysis revealed that all OATPs, except OATP1C1 and OATP6A1, are extensively expressed in nearly all samples. In contrast to downregulated OATP1B1, OATP1B3, OATP1A2 and OATP2B1 in cancerous vs. non-cancerous samples, an increase in OATP2A1, OATP3A1, OATP4A1 and OATP5A1 mRNA levels was seen in tumors (up to 40-fold for OATP5A1 in the MLT group). Therefore, OATP2A1, OATP3A1, OATP4A1 and OATP5A1 were further investigated by immunofluorescence microscopy on paraffin-embedded cancerous and non-cancerous sections (seven per group). OATP-derived immunoreactivity was observed in plasma membranes and cytosol of hepatic tumor cells, and additionally, in various cytokeratin 19 positive bile ducts. An increased percentage of immunoreactive cells and a higher staining intensity in cancerous vs. non-cancerous paraffin sections paralleled higher mRNA levels of OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in cancerous tissues of HCC, CCC and MLT patients. The extensive expression of OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in hepatic tumors of different origin suggests that these transporters might be further exploited for the discovery of novel anticancer agents.