The Importance of Perioperative Administration of an Anti-Hyperalgesic Drug in Burn Wounds

The importance of perioperative administration of an anti-hyperalgesic drug in burn wounds

BEL \u3b2\u2010Trefoil Reduces the Migration Ability of RUNX2 Expressing Melanoma Cells in Xenotransplanted Zebrafish

RUNX2, a master osteogenic transcript ion factor, is overexpressed in several cancer cells; in melanoma it promotes cells migration and invasion as well as neoangiogenesis. The annual mortality rates related to metastatic melanoma are high and novel agents are needed to improve melanoma patients\u2019 survival. It has been shown that lectins specifically target malignant cells since they present the Thomsen\u2013Friedenreich antigen. This disaccharide is hidden in normal cells, while it allows selective lectins binding in transformed cells. Recently, an edible lectin named BEL \u3b2-trefoil has been obtained from the wild mushroom Boletus edulis. Our previous study showed BEL \u3b2-trefoil effects on transcription factor RUNX2 downregulation as well as on the migration ability in melanoma cells treated in vitro. Therefore, to better understand the role of this lectin, we investigated the BEL \u3b2-trefoil effects in a zebrafish in vivo model, transplanted with human melanoma cells expressing RUNX2. Our data showed that BEL \u3b2-trefoil is able to spread in the tissues and to reduce the formation of metastases in melanoma xenotransplanted zebrafish. In conclusion, BEL \u3b2-trefoil can be considered an effective biomolecule to counteract melanoma disease

Diffusion of biosimilar hemopoietic growth factors use in oncology practice: an Italian experience

Background: Biosimilars of hemopoietic growth factors present an important saving opportunity in oncology. However, while pharmacologists are aware of their potential benefits, biosimilars are still under-used in Italy. Improved information and guided clinical experience may help to increase the clinical acceptance of these drugs. To this aim, a collaborative educational project was set between an Hospital Oncology Unit and the Local Health Care Authority in Pavia, Italy. Methods: The project lasted 12 months. The strategy included an education-information seminar at startup, a reporting meeting at +6$+6$ months, electronic prescription monitoring and implementation of pharmacovigilance. The target was set to reach 90% of all naïve patients treated with biosimilars. Results: At the end of the study (2013), a dramatic relative increase in the prescription of biosimilar drugs was noted, with virtually 100% of new patients receiving biosimilar drugs during the last 4 months, with a positive impact on average per capita drug expenses. Active pharmacovigilance did not report any serious adverse drug reactions. An anonymous questionnaire showed that oncologists judged the experience quite positively, acquired a positive attitude toward these drugs and considered biosimilars a relevant saving opportunity, while adherence to prescription guidelines was maintained. Analysis of the year following the end of the project, 2014, showed a persistent prescription change. Conclusions: Results from this local experience suggests that specifically designed pragmatic interventions focused on information-education and monitoring may help in promoting the use and acceptance of biosimilar drugs in the real clinical setting

Increased Gene Expression of RUNX2 and SOX9 in Mesenchymal Circulating Progenitors Is Associated with Autophagy during Physical Activity

Lack of physical exercise is considered an important risk factor for chronic diseases. On the contrary, physical exercise reduces the morbidity rates of obesity, diabetes, bone disease, and hypertension. In order to gain novel molecular and cellular clues, we analyzed the effects of physical exercise on differentiation of mesenchymal circulating progenitor cells (M-CPCs) obtained from runners. We also investigated autophagy and telomerase-related gene expression to evaluate the involvement of specific cellular functions in the differentiation process. We performed cellular and molecular analyses in M-CPCs, obtained by a depletion method, of 22 subjects before (PRE RUN) and after (POST RUN) a half marathon performance. In order to prove our findings, we performed also in vitro analyses by testing the effects of runners' sera on a human bone marrow-derived mesenchymal stem (hBM-MSC) cell line. PCR array analyses of PRE RUN versus POST RUN M-CPC total RNAs put in evidence several genes which appeared to be modulated by physical activity. Our results showed that physical exercise promotes differentiation. Osteogenesis-related genes as RUNX2, MSX1, and SPP1 appeared to be upregulated after the run; data showed also increased levels of BMP2 and BMP6 expressions. SOX9, COL2A1, and COMP gene enhanced expression suggested the induction of chondrocytic differentiation as well. The expression of telomerase-associated genes and of two autophagy-related genes, ATG3 and ULK1, was also affected and correlated positively with MSC differentiation. These data highlight an attractive cellular scenario, outlining the role of autophagic response to physical exercise and suggesting new insights into the benefits of physical exercise in counteracting chronic degenerative conditions

Clodronate as a Therapeutic Strategy against Osteoarthritis

Osteoarthritis (OA), the most prevalent musculoskeletal pathology, is mainly characterized by the progressive degradation of articular cartilage due to an imbalance between anabolic and catabolic processes. Consequently, OA has been associated with defects in the chondrocitic differentiation of progenitor stem cells (PSCs). In addition, SOX9 is the transcription factor responsible for PSCs chondrogenic commitment. To evaluate the effects of the non-amino bisphosphonate clodronate in OA patients we investigated SOX9 gene expression in circulating progenitor cells (CPCs) and in an in vitro OA model. We evaluated pain intensity, mental and physical performance in OA patients, as well as serum biomarkers related to bone metabolism. In addition, in order to improve therapeutic strategies, we assayed nanoparticle-embedded clodronate (NPs-clo) in an in vitro model of chondrogenic differentiation. Our data showed upregulation of SOX9 gene expression upon treatment, suggesting an increase in chondrocytic commitment. Clodronate also reduced osteoarticular pain and improved mental and physical performance in patients. Furthermore, NPs-clo stimulated SOX9 expression more efficaciously than clodronate alone. Clodronate may therefore be considered a good therapeutic tool against OA; its formulation in nanoparticles may represent a promising challenge to counteract cartilage degeneration

Dietary ω-3 fatty acid supplementation improves murine sickle cell bone disease and reprograms adipogenesis

Sickle cell disease (SCD) is a genetic disorder of hemoglobin, leading to chronic hemolytic anemia and multiple organ damage. Among chronic organ complications, sickle cell bone disease (SBD) has a very high prevalence, resulting in long-term disability, chronic pain and fractures. Here, we evaluated the effects of ω-3 (fish oil-based, FD)-enriched diet vs. ω-6 (soybean oil-based, SD)-supplementation on murine SBD. We exposed SCD mice to recurrent hypoxia/reoxygenation (rec H/R), a consolidated model for SBD. In rec H/R SS mice, FD improves osteoblastogenesis/osteogenic activity by downregulating osteoclast activity via miR205 down-modulation and reduces both systemic and local inflammation. We also evaluated adipogenesis in both AA and SS mice fed with either SD or FD and exposed to rec H/R. FD reduced and reprogramed adipogenesis from white to brown adipocyte tissue (BAT) in bone compartments. This was supported by increased expression of uncoupling protein 1(UCP1), a BAT marker, and up-regulation of miR455, which promotes browning of white adipose tissue. Our findings provide new insights on the mechanism of action of ω-3 fatty acid supplementation on the pathogenesis of SBD and strengthen the rationale for ω-3 fatty acid dietary supplementation in SCD as a complementary therapeutic intervention

A novel splicing mutation in FKBP10 causing osteogenesis imperfecta with a possible mineralization defect

Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by bone fragility and osteopenia, with a broad spectrum of clinical severity. The majority of cases are dominantly inherited and due to mutations in type I collagen genes, whereas recessive forms are less frequent and attributable to mutations in different genes involved in collagen I post translational modifications and folding (prolyl-3-hydroxylase complex, SERPINH1, FKBP10). We report the case of a patient with an initially mild and then progressively severe form of osteogenesis imperfecta due to a novel homozygous splicing mutation in FKBP10 (intron 8 c.1399+1G>A), which results in aberrant mRNA processing and consequent lack of FKBP65 chaperone. Although this mutation does not affect collagen type I post translational modifications in dermal fibroblasts, the histomorphometric pattern of our patient's bone sample showed a mineralization defect possibly due to the mutation in FKBP10

The effect of risedronate on osteogenic lineage is mediated by cyclooxygenase-2 gene upregulation.

Introduction: The purpose of this study was to evaluate the effects of risedronate (Ris) in the modulation of bone formation in rats with glucocorticoid (GC)-induced osteoporosis by histomorphometric, immunohistochemical and gene expression analyses. Methods: We analyzed structure, turnover and microarchitecture, cyclooxygenase 2 (COX-2) levels and osteocyte apoptosis in 40 female rats divided as follows: 1) vehicle of methylprednisolone (vGC) + vehicle of risedronate (vRis); 2) Ris 5 \u3bcg/Kg + vGC; 3) methylprednisolone (GC) 7 mg/Kg + vRis; 4) GC 7 mg/Kg +Ris 5 \u3bcg/Kg. In addition, we evaluated cell proliferation and expression of COX-2 and bone alkaline phosphatase (b-ALP) genes in bone marrow cells and MLO-y4 osteocytes treated with Ris alone or in co-treatment with the selective COX-2 inhibitor NS-398 or with dexametasone. Results: Ris reduced apoptosis induced by GC of osteocytes (41% vs 86%, P < 0.0001) and increased COX-2 expression with respect to controls (Immuno-Hystochemical Score (IHS): 8.75 vs 1.00, P < 0.0001). These positive effects of Ris in bone formation were confirmed by in vitro data as the viability and expression of b-ALP gene in bone marrow cells resulted increased in a dose dependent manner. Conclusions: These findings suggest a positive effect of Ris in bone formation and support the hypothesis that the up-regulation of COX-2 could be an additional mechanism of anabolic effect of Ris

Role of Ox-PAPCs in the Differentiation of Mesenchymal Stem Cells (MSCs) and Runx2 and PPARγ2 Expression in MSCs-Like of Osteoporotic Patients

BACKGROUND: Mesenchymal stem cells (MSCs) can differentiate into osteoblasts and adipocytes and conditions causing bone loss may induce a switch from the osteoblast to adipocyte lineage. In addition, the expression of Runx2 and the PPARγ2 transcription factor genes is essential for cellular commitment to an osteogenic and adipogenic differentiation, respectively. Modified lipoproteins derived from the oxidation of arachidonate-containing phospholipids (ox-PAPCs: POVPC, PGPC and PEIPC) are considered important factors in atherogenesis. METHODOLOGY: We investigated the effect of ox-PAPCs on osteogenesis and adipogenesis in human mesenchymal stem cells (hMSCs). In particular, we analyzed the transcription factor Runx2 and the PPARγ2 gene expression during osteogenic and adipogenic differentiation in absence and in presence of ox-PAPCs. We also analyzed gene expression level in a panel of osteoblastic and adipogenic differentiation markers. In addition, as circulating blood cells can be used as a "sentinel" that responds to changes in the macro- or micro-environment, we analyzed the Runx2 and the PPARγ2 gene expression in MSCs-like and ox-PAPC levels in serum of osteoporotic patients (OPs). Finally, we examined the effects of sera obtained from OPs in hMSCs comparing the results with age-matched normal donors (NDs). PRINCIPAL FINDINGS: Quantitative RT-PCR demonstrated that ox-PAPCs enhanced PPARγ2 and adipogenic gene expression and reduced Runx2 and osteoblast differentiation marker gene expression in differentiating hMSCs. In OPs, ox-PAPC levels and PPARγ2 expression were higher than in NDs, whereas Runx2 was lower than in ND circulant MSCs-like. CONCLUSIONS: Ox-PAPCs affect the osteogenic differentiation by promoting adipogenic differentiation and this effect may appear involved in bone loss in OPs