Mechanisms of Action of Phytoestrogens and Their Role in Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is a rare disease characterized by the development of adenomatous polyps in the colon and rectum already in adolescence. If left untreated, patients develop colorectal cancer (CRC) with a 100% probability. To date, the gold standard of FAP management is surgery, which is associated with morbidity and mortality. A chemopreventive agent capable of delaying, preventing and reversing the development of CRC has been sought. Several classes of drugs have been used but to date no chemopreventive drug has been found for the management of this disease. In recent years, the importance of estrogen receptors in FAP and CRC, particularly the ß subtype, has emerged. Indeed, the expression of the latter is strongly reduced in adenomatous polyps and CRC and is inversely correlated with the aggressiveness of the disease. Since phytoestrogens have a high affinity for this receptor, they have been suggested for use as chemopreventive agents in FAP and CRC. A combination of phytoestrogens and insoluble fibres has proved particularly effective. In this review, the various mechanisms of action of phytoestrogens were analyzed and the effectiveness of using phytoestrogens as an effective chemopreventive strategy was discussed.

Pancreatic Neuroendocrine Tumors in MEN1 Patients: Difference in Post-Operative Complications and Tumor Progression between Major and Minimal Pancreatic Surgeries.

Pancreatic neuroendocrine neoplasms (PNENs) affect over 80% of patients with multiple endocrine neoplasia type 1 (MEN1). Surgery is usually the therapy of choice, but the real immediate and long-term therapeutic benefit of a partial extensive pancreatic resection remains controversial. We analyzed, in 43 PNEN MEN1 patients who underwent 19 pancreaticoduodenectomies (PD), 19 distal pancreatectomies (DP), and 5 minimal pancreatectomies, the prevalence of surgery-derived early complications and post-operative pancreatic sequelae, and the PNEN relapse-free survival time after surgery, comparing major (PD+DP) and minimal pancreatic surgeries. No post-operative mortality was observed. Metastatic cancers were found in 12 cases, prevalently from duodenal gastrinoma. Long-term cure of endocrine syndromes, by the 38 major pancreatic resections, was obtained in 78.9% of gastrinomas and 92.9% of insulinomas. In only one patient, hepatic metastases, due to gastrinoma, progressed to death. Out of the 38 major surgeries, only one patient was reoperated for the growth of a new PNEN in the remnant pancreas. No functioning PNEN persistence was reported in the five minimal pancreatic surgeries, PNEN relapse occurred in 60% of patients, and 40% of cases needed further pancreatic resection for tumor recurrence. No significant difference in PNEN relapse-free survival time after surgery was found between major and minimal pancreatic surgeries.

Impact of X-Linked Hypophosphatemia on Muscle Symptoms.

X-linked hypophosphatemia (XLH) is the most common hereditary form of rickets and deficiency of renal tubular phosphate transport in humans. XLH is caused by the inactivation of mutations within the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene and follows an X-dominant transmission. It has an estimated frequency of 1 case per 20,000, and over 300 distinct pathogenic variations have been reported that result in an excess of fibroblast growth factor 23 (FGF23) in the serum. Increased levels of FGF23 lead to renal phosphate loss, decreased serum 1,25-dihydroxyvitamin D, and increased metabolism of 1,25-dihydoxyvitamin D, resulting in hypophosphatemia. Major clinical manifestations include rickets, bone deformities, and growth retardation that develop during childhood, and osteomalacia-related fractures or pseudo-fractures, degenerative osteoarthritis, enthesopathy, dental anomalies, and hearing loss during adulthood, which can affect quality of life. In addition, fatigue is also a common symptom in patients with XLH, who experience decreased motion, muscle weakness, and pain, contributing to altered quality of life. The clinical and biomedical characteristics of XLH are extensively defined in bone tissue since skeletal deformations and mineralization defects are the most evident effects of high FGF23 and low serum phosphate levels. However, despite the muscular symptoms that XLH causes, very few reports are available on the effects of FGF23 and phosphate in muscle tissue. Given the close relationship between bones and skeletal muscles, studying the effects of FGF23 and phosphate on muscle could provide additional opportunities to understand the interactions between these two important compartments of the body. By describing the current literature on XLH and skeletal muscle dysfunctions, the purpose of this review is to highlight future areas of research that could contribute to a better understanding of XLH muscular disability and its management.

Autophagy-Related ncRNAs in Pancreatic Cancer.

Pancreatic cancer (PC) is a malignancy accounting for only 3% of total cancers, but with a low 5-year relative survival rate. Approximately 80% of PC patients are diagnosed at a late stage when the disease has already spread from the primary site. Despite advances in PC treatment, there is an urgently needed for the identification of novel therapeutic strategies for PC, particularly for patients who cannot undergo classical surgery. Autophagy is an evolutionarily conserved process used by cells to adapt to metabolic stress via the degrading or recycling of damaged or unnecessary organelles and cellular components. This process is elevated in PC and, thus, it contributes to the onset, progression, and cancer cell resistance to chemotherapy in pancreatic tumors. Autophagy inhibition has been shown to lead to cancer regression and to increase the sensitivity of pancreatic cells to radiation and chemotherapy. Emerging studies have focused on the roles of non-coding RNAs (ncRNAs), such as miRNAs, long non-coding RNAs, and circular RNAs, in PC development and progression. Furthermore, ncRNAs have been reported as crucial regulators of many biological processes, including autophagy, suggesting that ncRNA-based autophagy targeting methods could be promising novel molecular approaches for specifically reducing autophagic flux, thus improving the management of PC patients. In this review, we briefly summarize the existing studies regarding the role and the regulatory mechanisms of autophagy-related ncRNAs in the context of this cancer.

Bone phenotypes in multiple endocrine neoplasia type 1: survey on the MEN1 Florentine database.

Multiple endocrine neoplasia type 1 (MEN1) is a rare, inherited cancer syndrome characterized by the development of multiple endocrine and non-endocrine tumors. MEN1 patients show a reduction of bone mass and a higher prevalence of early onset osteoporosis, compared to healthy population of the same age, gender, and ethnicity. During the monitoring and follow-up of MEN1 patients, the attention of clinicians is primarily focused on the diagnosis and therapy of tumors, while the assessment of bone health and mineral metabolism is, in many cases, marginally considered. In this study, we retrospectively analyzed bone and mineral metabolism features in a series of MEN1 patients from the MEN1 Florentine database. Biochemical markers of bone and mineral metabolism and densitometric parameters of bone mass were retrieved from the database and were analyzed based on age ranges and genders of patients and presence/absence of the three main MEN1-related endocrine tumor types. Our evaluation confirmed that patients with a MEN1 diagnosis have a high prevalence of earlyonset osteopenia and osteoporosis, in association with levels of serum and urinary markers of bone turnover higher than the normal reference values, regardless of their different MEN1 tumors. Fifty percent of patients younger than 26 years manifested osteopenia and 8.3% had osteoporosis, in at least one of the measured bone sites. These data suggest the importance of including biochemical and instrumental monitoring of bone metabolism and bone mass in the routine medical evaluation and follow-up of MEN1 patients and MEN1 carriers as important clinical aspects in the management of the syndrome.

Rapid Nontranscriptional Effects of Calcifediol and Calcitriol.

Classically, a secosteroid hormone, vitamin D, has been implicated in calcium and phosphate homeostasis and has been associated with the pathogenesis of rickets and osteomalacia in patients with severe nutritional vitamin D deficiency. The spectrum of known vitamin D-mediated effects has been expanded in recent years. However, the mechanisms of how exactly this hormone elicits its biological function are still not fully understood. The interaction of this metabolite with the vitamin D receptor (VDR) and, subsequently, with the vitamin D-responsive element in the region of specific target genes leading to the transcription of genes whose protein products are involved in the traditional function of calcitriol (known as genomic actions). Moreover, in addition to these transcription-dependent mechanisms, it has been recognized that the biologically active form of vitamin D3, as well as its immediate precursor metabolite, calcifediol, initiate rapid, non-genomic actions through the membrane receptors that are bound as described for other steroid hormones. So far, among the best candidates responsible for mediating rapid membrane response to vitamin D metabolites are membrane-associated VDR (VDRm) and protein disulfide isomerase family A member 3 (Pdia3). The purpose of this paper is to provide an overview of the rapid, non-genomic effects of calcifediol and calcitriol, whose elucidation could improve the understanding of the vitamin D3 endocrine system. This will contribute to a better recognition of the physiological acute functions of vitamin D3, and it could lead to the identification of novel therapeutic targets able to modulate these actions.

Effect of Oxidative Stress-Induced Apoptosis on Active FGF23 Levels in MLO-Y4 Cells: The Protective Role of 17-ß-Estradiol.

The discovery that osteocytes secrete phosphaturic fibroblast growth factor 23 (FGF23) has defined bone as an endocrine organ. However, the autocrine and paracrine functions of FGF23 are still unknown. The present study focuses on the cellular and molecular mechanisms involved in the complex control of FGF23 production and local bone remodeling functions. FGF23 was assayed using ELISA kit in the presence or absence of 17ß-estradiol in starved MLO-Y4 osteocytes. In these cells, a relationship between oxidative stress-induced apoptosis and up-regulation of active FGF23 levels due to MAP Kinases activation with involvement of the transcriptional factor (NF-kB) has been demonstrated. The active FGF23 increase can be due to up-regulation of its expression and post-transcriptional modifications. 17ß-estradiol prevents the increase of FGF23 by inhibiting JNK and NF-kB activation, osteocyte apoptosis and by the down-regulation of osteoclastogenic factors, such as sclerostin. No alteration in the levels of dentin matrix protein 1, a FGF23 negative regulator, has been determined. The results of this study identify biological targets on which drugs and estrogen may act to control active FGF23 levels in oxidative stress-related bone and non-bone inflammatory diseases.

Endocrine sequelae of hematopoietic stem cell transplantation: Effects on mineral homeostasis and bone metabolism.

Hematopoietic stem cell transplantation (HSCT) is an established therapeutic strategy for the treatment of malignant (leukemia and lymphoma) and non-malignant (thalassemia, anemia, and immunodeficiency) hematopoietic diseases. Thanks to the improvement in patient care and the development of more tolerable conditioning treatments, which has extended the applicability of therapy to the elderly, a growing number of patients have successfully benefited from HSCT therapy and, more importantly, HSCT transplant-related mortality has consistently reduced in recent years. However, concomitantly to long term patient survival, a growing incidence of late HSCT-related sequelae has been reported, being variably associated with negative effects on quality of life of patients and having a non-negligible impact on healthcare systems. The most predominantly observed HSCT-caused complications are chronic alterations of the endocrine system and metabolism, which endanger post-operative quality of life and increase morbidity and mortality of transplanted patients. Here, we specifically review the current knowledge on HSCT-derived side-effects on the perturbation of mineral metabolism; in particular, the homeostasis of calcium, focusing on current reports regarding osteoporosis and recurrent renal dysfunctions that have been observed in a percentage of HSC-transplanted patients. Possible secondary implications of conditioning treatments for HSCT on the physiology of the parathyroid glands and calcium homeostasis, alone or in association with HSCT-caused renal and bone defects, are critically discussed as well.

In Vitro Non-Genomic Effects of Calcifediol on Human Preosteoblastic Cells.

Several recent studies have demonstrated that the direct precursor of vitamin D3, the calcifediol [25(OH)D3], through the binding to the nuclear vitamin D receptor (VDR), is able to regulate the expression of many genes involved in several cellular processes. Considering that itself may function as a VDR ligand, although with a lower affinity, respect than the active form of vitamin D, we have assumed that 25(OH)D3 by binding the VDR could have a vitamin's D3 activity such as activating non-genomic pathways, and in particular we selected mesenchymal stem cells derived from human adipose tissue (hADMSCs) for the in vitro assessment of the intracellular Ca2+ mobilization in response to 25(OH)D3. Our result reveals the ability of 25(OH)D3 to activate rapid, non-genomic pathways, such as an increase of intracellular Ca2+ levels, similar to what observed with the biologically active form of vitamin D3. hADMSCs loaded with Fluo-4 AM exhibited a rapid and sustained increase in intracellular Ca2+ concentration as a result of exposure to 10-5 M of 25(OH)D3. In this work, we show for the first time the in vitro ability of 25(OH)D3 to induce a rapid increase of intracellular Ca2+ levels in hADMSCs. These findings represent an important step to better understand the non-genomic effects of vitamin D3 and its role in endocrine system.

Are Non-Coding RNAs Useful Biomarkers in Parathyroid Tumorigenesis?

Tumors of the parathyroid glands are common endocrine diseases almost always characterized by parathyroid hormone hypersecretion that determines the clinical manifestations of primary hyperparathyroidism, such as fatigue, kidney problems, weakness, brittle bones, and other symptoms. Most parathyroid neoplasia are benign adenomas, although rare malignant forms have been described. They are heterogeneous in terms of clinical presentation and the associated signs and symptoms overlap with those of disease and aging. Furthermore, most patients with hypercalcemia are discovered during routine blood tests for other reasons. Surgical removal is considered the main therapeutic option to cure these endocrine tumors and, therefore, innovative therapeutic approaches are actively required. Recently, a growing number of studies have suggested that alterations to the epigenetic mechanisms could play a pivotal role in parathyroid tumorigenesis. Most of the attention has been focused on non-coding RNAs (ncRNAs) (i.e., miRNAs, lncRNAs, and circRNAs) whose expression profile has been found to be deregulated in parathyroid tumors. The aim of the present paper is to give an insight into the ncRNAs involved in parathyroid tumorigenesis, which could be used in the future either as innovative diagnostic biomarkers or as therapeutic targets for the treatment of this endocrine neoplasia.

Hypoparathyroidism: State of the Art on Cell and Tissue Therapies.

Hypoparathyroidism is an endocrine disorder characterized by low serum calcium levels, high serum phosphorus levels, and by inappropriate or absent secretion of the parathyroid hormone (PTH). The most common therapeutic strategy to treat this condition is hormone replacement therapy with calcium and vitamin D but, unfortunately, in the long term this treatment may not be sufficient to compensate for the loss of endocrine function. Glandular autotransplantation is considered the most effective technique in place of replacement therapy. Although it leads to excellent results in most cases, autotransplantation is not always possible. Allograft is a good way to treat patients who have not been able to undergo autograft, but this technique has limited success due to side effects related to tissue rejection. This therapy is supported by systemic immunosuppression, which leads to the onset of serious side effects in patients, with a risk of endocrine toxicity. Today, research on endocrine disorders is focused on discovering alternative graft therapies that can allow optimal results with the fewest possible side effects. In this review, we will make an update on the current state of the art about the cell and tissue therapy as treatment for hypoparathyroidism, to identify which type of therapeutic strategy could be valid for a future clinical use.

Parathyroid Tumors: Molecular Signatures.

Parathyroid tumors are rare endocrine neoplasms affecting 0.1-0.3% of the general population, including benign parathyroid adenomas (PAs; about 98% of cases), intermediate atypical parathyroid adenomas (aPAs; 1.2-1.3% of cases) and malignant metastatic parathyroid carcinomas (PCs; less than 1% of cases). These tumors are characterized by a variable spectrum of clinical phenotypes and an elevated cellular, histological and molecular heterogeneity that make it difficult to pre-operatively distinguish PAs, aPAs and PCs. Thorough knowledge of genetic, epigenetic, and molecular signatures, which characterize different parathyroid tumor subtypes and drive different tumorigeneses, is a key step to identify potential diagnostic biomarkers able to distinguish among different parathyroid neoplastic types, as well as provide novel therapeutic targets and strategies for these rare neoplasms, which are still a clinical and therapeutic challenge. Here, we review the current knowledge on gene mutations and epigenetic changes that have been associated with the development of different clinical types of parathyroid tumors, both in familial and sporadic forms of these endocrine neoplasms.

MicroRNAs as Potential Biomarkers in Pituitary Adenomas.

Pituitary adenomas (PAs) are one of the most common lesions of intracranial neoplasms, occurring in approximately 15% of the general population. They are typically benign, although some adenomas show aggressive behavior, exhibiting rapid growth, drug resistance, and invasion of surrounding tissues. Despite ongoing improvements in diagnostic and therapeutic strategies, late first diagnosis is common, and patients with PAs are prone to relapse. Therefore, earlier diagnosis and prevention of recurrence are of importance to improve patient care. MicroRNAs (miRNAs) are short non-coding single stranded RNAs that regulate gene expression at the post-transcriptional level. An increasing number of studies indicate that a deregulation of their expression patterns is related with pituitary tumorigenesis, suggesting that these small molecules could play a critical role in contributing to tumorigenesis and the onset of these tumors by acting either as oncosuppressors or as oncogenes, depending on the biological context. This paper provides an overview of miRNAs involved in PA tumorigenesis, which might serve as novel potential diagnostic and prognostic non-invasive biomarkers, and for the future development of miRNA-based therapeutic strategies for PAs.

Genetic Determinants of Inherited Endocrine Tumors: Do They Have a Direct Role in Bone Metabolism Regulation and Osteoporosis?

Endocrine tumors are neoplasms originating from specialized hormone-secreting cells. They can develop as sporadic tumors, caused by somatic mutations, or in the context of familial Mendelian inherited diseases. Congenital forms, manifesting as syndromic or non-syndromic diseases, are caused by germinal heterozygote autosomal dominant mutations in oncogenes or tumor suppressor genes. The genetic defect leads to a loss of cell growth control in target endocrine tissues and to tumor development. In addition to the classical cancer manifestations, some affected patients can manifest alterations of bone and mineral metabolism, presenting both as pathognomonic and/or non-specific skeletal clinical features, which can be either secondary complications of endocrine functioning primary tumors and/or a direct consequence of the gene mutation. Here, we specifically review the current knowledge on possible direct roles of the genes that cause inherited endocrine tumors in the regulation of bone modeling and remodeling by exploring functional in vitro and in vivo studies highlighting how some of these genes participate in the regulation of molecular pathways involved in bone and mineral metabolism homeostasis, and by describing the potential direct effects of gene mutations on the development of skeletal and mineral metabolism clinical features in patients.

Protective Role of Natural and Semi-Synthetic Tocopherols on TNFα-Induced ROS Production and ICAM-1 and Cl-2 Expression in HT29 Intestinal Epithelial Cells.

Vitamin E, a fat-soluble compound, possesses both antioxidant and non-antioxidant properties. In this study we evaluated, in intestinal HT29 cells, the role of natural tocopherols, α-Toc and δ-Toc, and two semi-synthetic derivatives, namely bis-δ-Toc sulfide (δ-Toc)2S and bis-δ-Toc disulfide (δ-Toc)2S2, on TNFα-induced oxidative stress, and intercellular adhesion molecule-1 (ICAM-1) and claudin-2 (Cl-2) expression. The role of tocopherols was compared to that of N-acetylcysteine (NAC), an antioxidant precursor of glutathione synthesis. The results show that all tocopherol containing derivatives used, prevented TNFα-induced oxidative stress and the increase of ICAM-1 and Cl-2 expression, and that (δ-Toc)2S and (δ-Toc)2S2 are more effective than δ-Toc and α-Toc. The beneficial effects demonstrated were due to tocopherol antioxidant properties, but suppression of TNFα-induced Cl-2 expression seems not only to be related with antioxidant ability. Indeed, while ICAM-1 expression is strongly related to the intracellular redox state, Cl-2 expression is TNFα-up-regulated by both redox and non-redox dependent mechanisms. Since ICAM-1 and Cl-2 increase intestinal bowel diseases, and cause excessive recruitment of immune cells and alteration of the intestinal barrier, natural and, above all, semi-synthetic tocopherols may have a potential role as a therapeutic support against intestinal chronic inflammation, in which TNFα represents an important proinflammatory mediator.

Analysis of a Preliminary microRNA Expression Signature in a Human Telangiectatic Osteogenic Sarcoma Cancer Cell Line.

Telangiectatic osteosarcoma (TOS) is an aggressive variant of osteosarcoma (OS) with distinctive radiographic, gross, microscopic features, and prognostic implications. Despite several studies on OS, we are still far from understanding the molecular mechanisms of TOS. In recent years, many studies have demonstrated not only that microRNAs (miRNAs) are involved in OS tumorigenesis, development, and metastasis, but also that the presence in high-grade types of OS of cancer stem cells (CSCs) plays an important role in tumor progression. Despite these findings, nothing has been described previously about the expression of miRNAs and the presence of CSCs in human TOS. Therefore, we have isolated/characterized a putative CSC cell line from human TOS (TOS-CSCs) and evaluated the expression levels of several miRNAs in TOS-CSCs using real-time quantitative assays. We show, for the first time, the existence of CSCs in human TOS, highlighting the in vitro establishment of this unique stabilized cell line and an identification of a preliminary expression of the miRNA profile, characteristic of TOS-CSCs. These findings represent an important step in the study of the biology of one of the most aggressive variants of OS and the role of miRNAs in TOS-CSC behavior.

Blueberry Juice Antioxidants Protect Osteogenic Activity against Oxidative Stress and Improve Long-Term Activation of the Mineralization Process in Human Osteoblast-Like SaOS-2 Cells: Involvement of SIRT1.

Diets rich in fruits and vegetables with many antioxidants can be very important in the prevention and treatment of osteoporosis. Studies show that oxidative stress, often due to lack of antioxidants, is involved in alteration of bone remodeling and reduction in bone density. This study demonstrates in human osteoblast-like SaOS-2 cells that blueberry juice (BJ), containing 7.5 or 15 µg∙mL-1 total soluble polyphenols (TSP), is able to prevent the inhibition of osteogenic differentiation and the mineralization process due to oxidative stress induced by glutathione depletion. This situation mimics a metabolic condition of oxidative stress that may occur during estrogen deficiency. The effect of BJ phytochemicals occurs through redox- and non-redox-regulated mechanisms. BJ protects from oxidative damage factors related to bone remodeling and bone formation, such as alkaline phosphatase and Runt-related transcription factor 2. It upregulates these factors by activation of sirtuin type 1 deacetylase expression, a possible molecular target for anti-osteoporotic drugs. Quantitative analysis of TSP in BJ shows high levels of anthocyanins with high antioxidant capacity and bioavailability. These novel data may be important to elucidate the molecular and cellular beneficial effects of blueberry polyphenols on bone regeneration, and they suggest their use as a dietary supplement for osteoporosis prevention and therapies.

Resveratrol decreases TNFα-induced ICAM-1 expression and release by Sirt-1-independent mechanism in intestinal myofibroblasts.

Up-regulation of intercellular adhesion molecule-1 (ICAM-1) and its soluble form are involved in the chronic inflammation. For the first time, we demonstrated that resveratrol (RE), a natural polyphenol with antioxidant and anti-inflammatory properties, reduces the increase of expression and release of ICAM-1, due to TNFα-induced oxidative stress, in a myofibroblast cell line derived from human colonic (18Co cells). RE is scavenger of radical oxygen species (ROS) and modulates signaling pathways in which Sirt-1 and NF-κB are involved. Effectively, in TNFα-stimulated 18Co cells RE decreases ROS production and increases Sirt-1 expression and activity, but it reduces TNFα-induced ICAM-1 up-regulation by a Sirt-1-independent mechanism, as demonstrated by EX527 and Sirt-1 siRNA treatments. RE inhibits TNFα-induced activation of NF-κB by reducing both ROS and the degradation of IκB-α, an endogenous inhibitor of NF-κB, with consequent decrease of NF-κB nuclear translocation. This study also shows that NF-κB is not the only factor involved in the TNFα-induced ICAM-1 up-regulation and confirms our previous evidence according to which TNFα increases ICAM-1 levels by redox- and non-redox-regulated mechanisms. RE can represent good and useful support in therapies for intestinal inflammatory diseases in which TNFα plays a crucial role in the increase of adhesion molecule expression.

Blueberry juice protects osteocytes and bone precursor cells against oxidative stress partly through SIRT1.

Oxidative stress and abnormal osteocyte apoptosis are often related to dysregulation of bone turnover and chronic bone loss, and so fruit and vegetables with high antioxidant potential may play an important role in the prevention and/or management of osteoporosis. Osteocytes are the main regulators of bone remodelling. For the first time, we demonstrate here that blueberry juice (BJ), obtained from Vaccinium myrtillus, rich in polyphenols, shows antioxidant and antiosteoclastogenic properties in MLO-Y4 osteocytes. We report that BJ prevents oxidative stress-induced apoptosis and reverses the increase in receptor activator of nuclear factor κB ligand and sclerostin expression, crucial factors for osteoclast activation and bone resorption. BJ is also able to prevent oxidative stress-induced cell cytotoxicity in bone marrow mesenchymal stromal cells (MSCs), which are considered to be an important tool for cell therapy in bone disorders. No significant difference in preventing these events was observed between BJ and blueberry dry extract containing equal amounts of total soluble polyphenols. We have also shown that blueberry acts as both an antioxidant and an activator of sirtuin type 1, a class III histone deacetylase involved in cell death regulation and considered a molecular target for blocking bone resorption without affecting osteoclast survival. Overall, these novel data obtained in osteocytes and MSCs may help us clarify the mechanisms by which blueberry counteracts oxidative stress-induced damage in bone remodelling and osteogenesis at the cellular and molecular level. Our findings are consistent with the reported beneficial effects of blueberry on bone tissue reported in animal studies, which suggest that blueberry may be a useful supplement for the prevention and/or management of osteoporosis and osteogenic process.

Oxidative stress in bone remodeling: role of antioxidants.

ROS are highly reactive molecules which consist of a number of diverse chemical species, including radical and non-radical oxygen species. Oxidative stress occurs as a result of an overproduction of ROS not balanced by an adequate level of antioxidants. The natural antioxidants are: thiol compounds among which GSH is the most representative, and non-thiol compounds such as polyphenols, vitamins and also various enzymes. Many diseases have been linked to oxidative stress including bone diseases among which one of the most important is the osteoporosis. The redox state changes are also related to the bone remodeling process which allows the continuous bone regeneration through the coordinated action of bone cells: osteoclasts, osteoblasts and osteocytes. Changes in ROS and/or antioxidant systems seem to be involved in the pathogenesis of bone loss. ROS induce the apoptosis of osteoblasts and osteocytes, and this favours osteoclastogenesis and inhibits the mineralization and osteogenesis. Excessive osteocyte apoptosis correlates with oxidative stress causing an imbalance in favor of osteoclastogenesis which leads to increased turnover of bone remodeling and bone loss. Antioxidants either directly or by counteracting the action of oxidants contribute to activate the differentiation of osteoblasts, mineralization process and the reduction of osteoclast activity. In fact, a marked decrease in plasma antioxidants was found in aged or osteoporotic women. Some evidence shows a link among nutrients, antioxidant intake and bone health. Recent data demonstrate the antioxidant properties of various nutrients and their influence on bone metabolism. Polyphenols and anthocyanins are the most abundant antioxidants in the diet, and nutritional approaches to antioxidant strategies, in animals or selected groups of patients with osteoporosis or inflammatory bone diseases, suggest the antioxidant use in anti-resorptive therapies for the treatment and prevention of bone loss.