Extracellular Vesicles in Osteosarcoma: Antagonists or Therapeutic Agents?

Osteosarcoma (OS) is a skeletal tumor affecting mainly children and adolescents. The presence of distance metastasis is frequent and it is localized preferentially to the lung, representing the main reason for death among patients. The therapeutic approaches are based on surgery and chemotherapeutics. However, the drug resistance and the side effects associated with the chemotherapy require the identification of new therapeutic approaches. The understanding of the complex biological scenario of the osteosarcoma will open the way for the identification of new targets for its treatment. Recently, a great interest of scientific community is for extracellular vesicles (EVs), that are released in the tumor microenvironment and are important regulators of tumor proliferation and the metastatic process. At the same time, circulating extracellular vesicles can be exploited as diagnostic and prognostic biomarkers, and they can be loaded with drugs as a new therapeutic approach for osteosarcoma patients. Thus, the characterization of OS-related EVs could represent a way to convert these vesicles from antagonists for human health into therapeutic and/or diagnostic agents.     

Insights behind the Relationship between Colorectal Cancer and Obesity: Is Visceral Adipose Tissue the Missing Link?

Colorectal cancer (CRC) is a major health problem worldwide, with an estimated 1.9 million new cases and 915,880 deaths in 2020 alone. The etiology of CRC is complex and involves both genetic and lifestyle factors. Obesity is a major risk factor for CRC, and the mechanisms underlying this link are still unclear. However, the generalized inflammatory state of adipose tissue in obesity is thought to play a role in the association between CRC risk and development. Visceral adipose tissue (VAT) is a major source of proinflammatory cytokines and other factors that contribute to the characteristic systemic low-grade inflammation associated with obesity. VAT is also closely associated with the tumor microenvironment (TME), and recent evidence suggests that adipocytes within the TME undergo phenotypic changes that contribute to tumor progression. In this review, we aim to summarize the current evidence linking obesity and CRC, with a focus on the role of VAT in tumor etiology and progression.     

Hyperhomocysteinemia and Cardiovascular Disease: Is the Adenosinergic System the Missing Link?

The influence of hyperhomocysteinemia (HHCy) on cardiovascular disease (CVD) remains unclear. HHCy is associated with inflammation and atherosclerosis, and it is an independent risk factor for CVD, stroke and myocardial infarction. However, homocysteine (HCy)-lowering therapy does not affect the inflammatory state of CVD patients, and it has little influence on cardiovascular risk. The HCy degradation product hydrogen sulfide (H₂S) is a cardioprotector. Previous research proposed a positive role of H₂S in the cardiovascular system, and we discuss some recent data suggesting that HHCy worsens CVD by increasing the production of H₂S, which decreases the expression of adenosine A_2A receptors on the surface of immune and cardiovascular cells to cause inflammation and ischemia, respectively.     

Vitamin D: Link between Osteoporosis,Obesity, and Diabetes?

Vitamin D (1,25(OH)₂D₃) is a steroid hormone that has a range of physiological functions in skeletal and nonskeletal tissues, and can contribute to prevent and/or treat osteoporosis, obesity, and Type 2 diabetes mellitus (T2DM). In bone metabolism, vitamin D increases the plasma levels of calcium and phosphorus, regulates osteoblast and osteoclast the activity, and combats PTH hypersecretion, promoting bone formation and preventing/treating osteoporosis. This evidence is supported by most clinical studies, especially those that have included calcium and assessed the effects of vitamin D doses (≥800 IU/day) on bone mineral density. However, annual megadoses should be avoided as they impair bone health. Recent findings suggest that low serum vitamin D is the consequence (not the cause) of obesity and the results from randomized double-blind clinical trials are still scarce and inconclusive to establish the relationship between vitamin D, obesity, and T2DM. Nevertheless, there is evidence that vitamin D inhibits fat accumulation, increases insulin synthesis and preserves pancreatic islet cells, decreases insulin resistance and reduces hunger, favoring obesity and T2DM control. To date, there is not enough scientific evidence to support the use of vitamin D as a pathway to prevent and/or treat obesity and T2DM.     

Targeting Inflammation after Myocardial Infarction: A Therapeutic Opportunity for Extracellular Vesicles?

After myocardial infarction (MI), a strong inflammatory response takes place in the heart to remove the dead tissue resulting from ischemic injury. A growing body of evidence suggests that timely resolution of this inflammatory process may aid in the prevention of adverse cardiac remodeling and heart failure post-MI. The present challenge is to find a way to stimulate this process without interfering with the reparative role of the immune system. Extracellular vesicles (EVs) are natural membrane particles that are released by cells and carry different macromolecules, including proteins and non-coding RNAs. In recent years, EVs derived from various stem and progenitor cells have been demonstrated to possess regenerative properties. They can provide cardioprotection via several mechanisms of action, including immunomodulation. In this review, we summarize the role of the innate immune system in post-MI healing. We then discuss the mechanisms by which EVs modulate cardiac inflammation in preclinical models of myocardial injury through regulation of monocyte influx and macrophage function. Finally, we provide suggestions for further optimization of EV-based therapy to improve its potential for the treatment of MI.     

Glycemic Variability and Oxidative Stress: A Link between Diabetes and Cardiovascular Disease?

Diabetes is associated with a two to three-fold increase in risk of cardiovascular disease. However, intensive glucose-lowering therapy aiming at reducing HbA1c to a near-normal level failed to suppress cardiovascular events in recent randomized controlled trials. HbA1c reflects average glucose level rather than glycemic variability. In in vivo and in vitro studies, glycemic variability has been shown to be associated with greater reactive oxygen species production and vascular damage, compared to chronic hyperglycemia. These findings suggest that management of glycemic variability may reduce cardiovascular disease in patients with diabetes; however, clinical studies have shown conflicting results. This review summarizes the current knowledge on glycemic variability and oxidative stress, and discusses the clinical implications.     

Flexible N-Termini of Amyloid β-Protein Oligomers: A Link between Structure and Activity?

Revised amyloid cascade hypothesis of Alzheimer′s disease (AD) states that amyloid β-protein (Aβ) triggers the disease through formation of soluble low molecular weight (LMW) assemblies, called oligomers, which are challenging to characterize experimentally as well as computationally due to their heterogeneous and polymorphic nature, lack of ordered structure, and short lifetimes. Recent findings challenge the view of Aβ oligomers as exclusively toxic entities by revealing their dual, protective and disruptive nature in the context of immune response and AD, respectively. In this review, the understanding of Aβ oligomer formation and structure is discussed from the AD perspective. The structure-activity relationship (SAR) that implicates flexible, solvent exposed N-termini of Aβ oligomers, observed in computer simulations, in mediating their toxic as well as protective activity is proposed.     

Is There a Link between Oropharyngeal Microbiome and Schizophrenia? A Narrative Review

The study aimed to examine the impact of the oropharyngeal microbiome in the pathophysiology of schizophrenia and to clarify whether there might be a bidirectional link between the oral microbiota and the brain in a context of dysbiosis-related neuroinflammation. We selected nine articles including three systemic reviews with several articles from the same research team. Different themes emerged, which we grouped into 5 distinct parts concerning the oropharyngeal phageome, the oropharyngeal microbiome, the salivary microbiome and periodontal disease potentially associated with schizophrenia, and the impact of drugs on the microbiome and schizophrenia. We pointed out the presence of phageoma in patients suffering from schizophrenia and that periodontal disease reinforces the role of inflammation in the pathophysiology of schizophrenia. Moreover, saliva could be an interesting substrate to characterize the different stages of schizophrenia. However, the few studies we have on the subject are limited in scope, and some of them are the work of a single team. At this stage of knowledge, it is difficult to conclude on the existence of a bidirectional link between the brain and the oral microbiome. Future studies on the subject will clarify these questions that for the moment remain unresolved.     

Extracellular Vesicles in Alzheimer’s Disease: Friends or Foes? Focus on Aβ-Vesicle Interaction

The intercellular transfer of amyloid-β (Aβ) and tau proteins has received increasing attention in Alzheimer’s disease (AD). Among other transfer modes, Aβ and tau dissemination has been suggested to occur through release of Extracellular Vesicles (EVs), which may facilitate delivery of pathogenic proteins over large distances. Recent evidence indicates that EVs carry on their surface, specific molecules which bind to extracellular Aβ, opening the possibility that EVs may also influence Aβ assembly and synaptotoxicity. In this review we focus on studies which investigated the impact of EVs in Aβ-mediated neurodegeneration and showed either detrimental or protective role for EVs in the pathology.     

Indoleamine 2,3 Dioxygenase 1—The Potential Link between the Innate Immunity and the Ischemia-Reperfusion-Induced Acute Kidney Injury?

Ischemia-reperfusion injury (IRI) is of the most common causes of acute kidney injury (AKI); nevertheless, the mechanisms responsible for both early kidney injury and the reparative phase are not fully recognised. The inflammatory response following ischemia is characterised by the crosstalk between cells belonging to the innate immune system—dendritic cells (DCs), macrophages, neutrophils, natural killer (NK) cells, and renal tubular epithelial cells (RTECs). A tough inflammatory response can damage the renal tissue; it may also have a protective effect leading to the repair after IRI. Indoleamine 2,3 dioxygenase 1 (IDO1), the principal enzyme of the kynurenine pathway (KP), has a broad spectrum of immunological activity from stimulation to immunosuppressive activity in inflamed areas. IDO1 expression occurs in cells of the innate immunity and RTECs during IRI, resulting in local tryptophan (TRP) depletion and generation of kynurenines, and both of these mechanisms contribute to the immunosuppressive effect. Nonetheless, it is unknown if the above mechanism can play a harmful or preventive role in IRI-induced AKI. Despite the scarcity of literature in this field, the current review attempts to present a possible role of IDO1 activation in the regulation of the innate immune system in IRI-induced AKI.     

What Is the Role of HLA-I on Cancer Derived Extracellular Vesicles? Defining the Challenges in Characterisation and Potential Uses of This Ligandome

The Human Leukocyte Antigen class I (HLA-I) system is an essential part of the immune system that is fundamental to the successful activation of cytotoxic lymphocytes, and an effective subsequent immune attack against both pathogen-infected and cancer cells. The importance of cytotoxic T cell activity and ability to detect foreign cancer-related antigenic peptides has recently been highlighted by the successful application of monoclonal antibody-based checkpoint inhibitors as novel immune therapies. Thus, there is an increased interest in fully characterising the repertoire of peptides that are being presented to cytotoxic CD8+ T cells by cancer cells. However, HLA-I is also known to be present on the surface of extracellular vesicles, which are released by most if not all cancer cells. Whilst the peptide ligandome presented by cell surface HLA class I molecules on cancer cells has been studied extensively, the ligandome of extracellular vesicles remains relatively poorly defined. Here, we will describe the current understanding of the HLA-I peptide ligandome and its role on cancer-derived extracellular vesicles, and evaluate the aspects of the system that have the potential to advance immune-based therapeutic approaches for the effective treatment of cancer.     

The Association between Gut Microbiota and Osteoarthritis: Does the Disease Begin in the Gut?

Some say that all diseases begin in the gut. Interestingly, this concept is actually quite old, since it is attributed to the Ancient Greek physician Hippocrates, who proposed the hypothesis nearly 2500 years ago. The continuous breakthroughs in modern medicine have transformed our classic understanding of the gastrointestinal tract (GIT) and human health. Although the gut microbiota (GMB) has proven to be a core component of human health under standard metabolic conditions, there is now also a strong link connecting the composition and function of the GMB to the development of numerous diseases, especially the ones of musculoskeletal nature. The symbiotic microbes that reside in the gastrointestinal tract are very sensitive to biochemical stimuli and may respond in many different ways depending on the nature of these biological signals. Certain variables such as nutrition and physical modulation can either enhance or disrupt the equilibrium between the various species of gut microbes. In fact, fat-rich diets can cause dysbiosis, which decreases the number of protective bacteria and compromises the integrity of the epithelial barrier in the GIT. Overgrowth of pathogenic microbes then release higher quantities of toxic metabolites into the circulatory system, especially the pro-inflammatory cytokines detected in osteoarthritis (OA), thereby promoting inflammation and the initiation of many disease processes throughout the body. Although many studies link OA with GMB perturbations, further research is still needed.     

Relationship between Oxytocin and Osteoarthritis: Hope or Despair?

Oxytocin (OT) is involved in breastfeeding and childbirth and appears to play a role in regulating the bone matrix. OT is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and is released in response to numerous stimuli. It also appears to be produced by osteoblasts in the bone marrow, acting as a paracrine–autocrine regulator of bone formation. Osteoarthritis (OA) is a disease of the whole joint. Different tissues involved in OA express OT receptors (OTRs), such as chondrocytes and osteoblasts. This hormone, which levels are reduced in patients with OA, appears to have a stimulatory effect on chondrogenesis. OT involvement in bone biology could occur at both the osteoblast and chondrocyte levels. The relationships between metabolic syndrome, body weight, and OA are well documented, and the possible effects of OT on different parameters of metabolic syndrome, such as diabetes and body weight, are important. In addition, the effects of OT on adipokines and inflammation are also discussed, especially since recent data have shown that low-grade inflammation is also associated with OA. Furthermore, OT also appears to mediate endogenous analgesia in animal and human studies. These observations provide support for the possible interest of OT in OA and its potential therapeutic treatment.     

The difference in behaviour between calcitic and dolomitic lime mortars set under dry conditions: The relationship between textural and physical–mechanical properties

Differences in the texture, mineralogy, hygric and mechanical properties of mortars prepared with dry hydrated limes of calcitic and dolomitic composition are investigated in this work. Special attention is given to the influence of the lime microstructure and the mortars curing condition. The effect of using two different aggregates (natural and crushed of calcitic and siliceous composition) is also examined. Results showed that the use of dolomitic lime is not recommendable if mortars are applied in dry areas since, under these conditions, a great shrinkage occurs and no strength improvement is induced. Moreover, dolomitic mortars presented a pore network that negatively affects the water transfer properties. On the contrary, calcitic mortars present higher carbonation degree and better physical–mechanical properties. Finally, the use of a calcareous aggregate is preferred because it produces better cohesion in the mortar.     

The Enigmatic Role of TP53 in Germ Cell Tumours: Are We Missing Something?

The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience of Center of reference for both GCTs and cancer predisposing syndromes.     

Selected Biomarkers of Depression: What Are the Effects of Cytokines and Inflammation?

Depression is one of the leading mental illnesses worldwide and lowers the quality of life of many. According to WHO, about 5% of the worldwide population suffers from depression. Newer studies report a staggering global prevalence of 27.6%, and it is rising. Professionally, depression belonging to affective disorders is a psychiatric illness, and the category of major depressive disorder (MDD) comprises various diagnoses related to persistent and disruptive mood disorders. Due to this fact, it is imperative to find a way to assess depression quantitatively using a specific biomarker or a panel of biomarkers that would be able to reflect the patients’ state and the effects of therapy. Cytokines, hormones, oxidative stress markers, and neuropeptides are studied in association with depression. The latest research into inflammatory cytokines shows that their relationship with the etiology of depression is causative. There are stronger cytokine reactions to pathogens and stressors in depression. If combined with other predisposing factors, responses lead to prolonged inflammatory processes, prolonged dysregulation of various axes, stress, pain, mood changes, anxiety, and depression. This review focuses on the most recent data on cytokines as markers of depression concerning their roles in its pathogenesis, their possible use in diagnosis and management, their different levels in bodily fluids, and their similarities in animal studies. However, cytokines are not isolated from the pathophysiologic mechanisms of depression or other psychiatric disorders. Their effects are only a part of the whole pathway.     

Evaluation and Management of Neurogenic Bladder: What Is New in China?

Neurogenic bladder (NB) or neurogenic lower urinary tract dysfunction (NLUTD), a dysfunction of the urinary bladder and urethra due to disease of the central nervous system or peripheral nerves, is a major global medical and social problem. Numerous nervous system abnormalities, such as: stroke, Alzheimer’s and Parkinson’s diseases, traumatic spinal cord injury, spinal cord tumors, congenital spina bifida, and diabetes, can cause NB/NLUTD. There are two major types of bladder control problems associated with NB/NLUTD: the bladder becomes either overactive or underactive depending on the nature, level, and extent of nerve damage. This review specifically focuses on the diagnosis and management of NB/NLUTD in China as well as on recent efforts to treat this disease.     

Exercise and Zoledronic Acid on Lipid Profile and Bone Remodeling in Ovariectomized Rats: a Paradoxical Negative Association?

Exercise (EXE) and amino-bisphosphonates (BP) are both considered as useful strategies in the prevention of post-menopausal bone loss. Exercise reduces lipid levels, and BP may induce increase in high-density lipoprotein cholesterol (HDL-C). We hypothesized that combined effects of BP and exercise would produce a better improvement of lipid profile. We studied the specific and combined effects of zoledronic acid (Z) and EXE on lipid profile and bone remodeling in mature ovariectomized (OVX) rats. Six-month old female rats were randomly assigned to either a sham-ovx group (n = 12) or one of four OVX groups (n = 12): vehicle-treated sedentary (OVX); OVX + EXE (OVX-E, running on a treadmill for 12 weeks); OVX + Z (20 μg/kg, i.v.), (OVX-Z); OVX + Z+EXE (OVX-ZE). Total cholesterol (TC), HDL-C and bone remodeling markers were measured at baseline and at the end of the study. We demonstrated that both Z and EXE prevented the increase in bone resorption resulting from OVX, and individually improved the atherosclerotic risk index. Therapy with Z resulted in significant increase (39.00 ± 0.03 vs. 53.6 ± 0.01 mg/dl; +37.4%, P < 0.05) in serum concentration of HDL-C and a non significant decrease in TC (135.30 ± 0.03 vs. 144.80 ± 0.05 mg/dl; −5.8%) in the OVX-Z group compared to the OVX group. Post-menopausal women have elevated risk of CVD and bone resorption, hence, these data ultimately demonstrate (except for the elevated ratio in the combined group) that exercise and zoledronic acid are useful in minimizing the impact of these two processes in women and the combination of the two may be clinically relevant.