Comparison of the antioxidant potential in urine, saliva and skin

Aim: Free radicals, oxidative stress and their possible consequences for health are becoming increasingly important in modern medicine. Reactive species influence the organism, potentially causing oxidative cell damage. They can be produced by exogenous sources, or be a product of a variety of not only physiological metabolic processes, such as immune response, but also pathological processes. The antioxidant protection system protects the organism from oxidative damage caused by reactions producing an excess of free radicals. The analysis of antioxidant potential (AOP) is therefore becoming increasingly important for the diagnosis of individual vitality

The G Protein-Coupled Receptor RAI3 Is an Independent Prognostic Factor for Pancreatic Cancer Survival and Regulates Proliferation via STAT3 Phosphorylation

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest tumors worldwide. Understanding the function of gene expression alterations is a prerequisite for developing new strategies in diagnostic and therapy. GPRC5A (RAI3), coding for a seven transmembrane G protein-coupled receptor is known to be overexpressed in pancreatic cancer and might be an interesting candidate for therapeutic intervention. Expression levels of RAI3 were compared using a tissue microarray of 435 resected patients with pancreatic cancer as well as 209 samples from chronic pancreatitis (CP), intra-ductal papillary mucinous neoplasm (IPMN) and normal pancreatic tissue. To elucidate the function of RAI3 overexpression, siRNA based knock-down was used and transfected cells were analyzed using proliferation and migration assays. Pancreatic cancer patients showed a statistically significant overexpression of RAI3 in comparison to normal and chronic pancreatitis tissue. Especially the loss of apical RAI3 expression represents an independent prognostic parameter for overall survival of patients with pancreatic cancer. Suppression of GPRC5a results in decreased cell growth, proliferation and migration in pancreatic cancer cell lines via a STAT3 modulated pathway, independent from ERK activation

The thyroid hormone transporter Mct10 is a novel regulator of bone mass and bone turnover in male mice: Supplemental Figures

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Low Bone Turnover Due to Hypothyroidism or Anti-Resorptive Treatment Does Not Affect Whole-Body Glucose Homeostasis in Male Mice

Bone is a large and dynamic tissue and its maintenance requires high amounts of energy as old or damaged bone structures need to be replaced during the process of bone remodeling. Glucose homeostasis is an essential prerequisite for a healthy bone and vice versa, the skeleton can act as an endocrine organ on energy metabolism. We recently showed that hypothyroidism in mice leads to an almost complete arrest of bone remodeling. Here, we aimed to investigate whether the profound suppression of bone remodeling affects whole-body glucose homeostasis. To that end, male C57BL/6JRj mice were rendered hypothyroid over 4 weeks using methimazole and sodium perchlorate in the drinking water. We confirmed trabecular bone gain due to decreased bone turnover in hypothyroid mice with decreased cortical but increased vertebral bone strength. Further, we found impaired glucose handling but not insulin resistance with hypothyroidism. In hypothyroid bone, glucose uptake and expression of glucose transporter Glut4 were reduced by 44.3% and 13.9%, respectively, suggesting lower energy demands. Nevertheless, hypothyroidism led to distinct changes in glucose uptake in muscle, liver, and epididymal white adipose tissue (eWAT). Reduced glucose uptake (−30.6%) and Glut1/Glut4 transcript levels (−31.9%/−67.5%) were detected in muscle tissue. In contrast, in liver and eWAT we observed increased glucose uptake by 25.6% and 68.6%, respectively, and upregulated expression of glucose transporters with hypothyroidism. To more specifically target bone metabolism and discriminate between the skeletal and systemic effects of hypothyroidism on energy metabolism, male mice were treated with zoledronate (ZOL), a bisphosphonate, that led to decreased bone turnover, trabecular bone gain, and reduced local glucose uptake into bone (−40.4%). However, ZOL-treated mice did not display alterations of systemic glucose handling nor insulin tolerance. Despite the close mutual crosstalk of bone and glucose metabolism, in this study, we show that suppressing bone remodeling does not influence whole-body glucose homeostasis in male mice

Irisin and Bone in Sickness and in Health: A Narrative Review of the Literature

Irisin is a hormone-like myokine produced by the skeletal muscle in response to exercise. Upon its release into the circulation, it is involved in the browning process and thermogenesis, but recent evidence indicates that this myokine could also regulate the functions of osteoblasts, osteoclasts, and osteocytes. Most human studies have reported that serum irisin levels decrease with age and in conditions involving bone diseases, including both primary and secondary osteoporosis. However, it should be emphasized that recent findings have called into question the importance of circulating irisin, as well as the validity and reproducibility of current methods of irisin measurement. In this review, we summarize data pertaining to the role of irisin in the bone homeostasis of healthy children and adults, as well as in the context of primary and secondary osteoporosis. Additional research is required to address methodological issues, and functional studies are required to clarify whether muscle and bone damage per se affect circulating levels of irisin or whether the modulation of this myokine is caused by the inherent mechanisms of underlying diseases, such as genetic or inflammatory causes. These investigations would shed further light on the effects of irisin on bone homeostasis and bone disease

Detection of COPB2 as a KRAS synthetic lethal partner through integration of functional genomics screens

Mutated KRAS plays an important role in many cancers. Although targeting KRAS directly is difficult, indirect inactivation via synthetic lethal partners (SLPs) is promising. Yet to date, there are no SLPs from high-throughput RNAi screening, which are supported by multiple screens. Here, we address this problem by aggregating and ranking data over three independent high-throughput screens. We integrate rankings by minimizing the displacement and by considering established methods such as RIGER and RSA. Our meta analysis reveals COPB2 as a potential SLP of KRAS with good support from all three screens. COPB2 is a coatomer subunit and its knock down has already been linked to disabled autophagy and reduced tumor growth. We confirm COPB2 as SLP in knock down experiments on pancreas and colorectal cancer cell lines. Overall, consistent integration of high throughput data can generate candidate synthetic lethal partners, which individual screens do not uncover. Concretely, we reveal and confirm that COPB2 is a synthetic lethal partner of KRAS and hence a promising cancer target. Ligands inhibiting COPB2 may, therefore, be promising new cancer drugs

Reduced Bone Mass and Increased Osteocyte Tartrate-Resistant Acid Phosphatase (TRAP) Activity, But Not Low Mineralized Matrix Around Osteocyte Lacunae, Are Restored After Recovery From Exogenous Hyperthyroidism in Male Mice

Hyperthyroidism causes secondary osteoporosis through favoring bone resorption over bone formation, leading to bone loss with elevated bone fragility. Osteocytes that reside within lacunae inside the mineralized bone matrix orchestrate the process of bone remodeling and can themselves actively resorb bone upon certain stimuli. Nevertheless, the interaction between thyroid hormones and osteocytes and the impact of hyperthyroidism on osteocyte cell function are still unknown. In a preliminary study, we analyzed bones from male C57BL/6 mice with drug-induced hyperthyroidism, which led to mild osteocytic osteolysis with 1.14-fold larger osteocyte lacunae and by 108.33% higher tartrate-resistant acid phosphatase (TRAP) activity in osteocytes of hyperthyroid mice compared to euthyroid mice. To test whether hyperthyroidism-induced bone changes are reversible, we rendered male mice hyperthyroid by adding levothyroxine into their drinking water for 4 weeks, followed by a weaning period of 4 weeks with access to normal drinking water. Hyperthyroid mice displayed cortical and trabecular bone loss due to high bone turnover, which recovered with weaning. Although canalicular number and osteocyte lacunar area were similar in euthyroid, hyperthyroid and weaned mice, the number of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive osteocytes was 100% lower in the weaning group compared to euthyroid mice and the osteocytic TRAP activity was eightfold higher in hyperthyroid animals. The latter, along with a 3.75% lower average mineralization around the osteocyte lacunae in trabecular bone, suggests osteocytic osteolysis activity that, however, did not result in significantly enlarged osteocyte lacunae. In conclusion, we show a recovery of bone microarchitecture and turnover after reversal of hyperthyroidism to a euthyroid state. In contrast, osteocytic osteolysis was initiated in hyperthyroidism, but its effects were not reversed after 4 weeks of weaning. Due to the vast number of osteocytes in bone, we speculate that even minor individual cell functions might contribute to altered bone quality and mineral homeostasis in the setting of hyperthyroidism-induced bone disease. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)